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WO2020091430A1 - Composition de prévention ou de traitement de la dégénérescence maculaire - Google Patents

Composition de prévention ou de traitement de la dégénérescence maculaire Download PDF

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WO2020091430A1
WO2020091430A1 PCT/KR2019/014500 KR2019014500W WO2020091430A1 WO 2020091430 A1 WO2020091430 A1 WO 2020091430A1 KR 2019014500 W KR2019014500 W KR 2019014500W WO 2020091430 A1 WO2020091430 A1 WO 2020091430A1
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Prior art keywords
macular degeneration
neovascular
pharmaceutical composition
age
present
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Ceased
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English (en)
Korean (ko)
Inventor
박동호
이인규
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Industry Academic Cooperation Foundation of KNU
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Industry Academic Cooperation Foundation of KNU
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Priority to US17/282,547 priority Critical patent/US12239644B2/en
Priority to JP2021518126A priority patent/JP7280353B2/ja
Priority to EP19878702.0A priority patent/EP3875092B1/fr
Priority claimed from KR1020190136771A external-priority patent/KR102294439B1/ko
Publication of WO2020091430A1 publication Critical patent/WO2020091430A1/fr
Anticipated expiration legal-status Critical
Priority to JP2023022976A priority patent/JP2023062085A/ja
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health

Definitions

  • the present invention was made by the task number HI16C1501 under the support of the Ministry of Health and Welfare, and the research institute specializing in the task is the Korea Health Industry Development Institute, the research project name is "Leading-type specialized research and development project”, and the research project title is "Diabetes cardiovascular complications treatment And Efficacy Evaluation System Development ", the main institution is Kyungpook National University Hospital, and the research period is 2016.04.01 ⁇ 2021.03.31.
  • the present invention was made by task number 2017R1D1A1B03027966 under the support of the Ministry of Education, the research institute specializing in the project is the Korea Research Foundation, the research project name is “Personal Basic Research Support Project for Science and Engineering”, and the research project title is "Semaphorin 3A and Angiopoietin- Evaluation of the efficacy of regulating choroidal retinal neovascularization and vascular permeability by microRNA control targeting like 4 ", the main institution is Kyungpook National University Industry-Academic Cooperation Foundation, and the research period is 2017.06.01 ⁇ 2020.05.31
  • the present invention was made by task number 2019R1A2C1084371 under the support of the Ministry of Education, the research institute specializing in the above task is the Korea Research Foundation, the research project name is “Scientific Researcher Support Project”, and the research project title is "Mitochondrial energy metabolism of immune cells Research on new treatment mechanism of age-related macular degeneration through reprogramming and inflammation activation control ", Organizing organization is Kyungpook National University Industry-Academy Cooperation Group, Research period is 2019.09.01 ⁇ 2024.02.29.
  • the present invention relates to a composition for preventing or treating macular degeneration. More particularly, the present invention relates to a composition for the prevention or treatment of macular degeneration comprising fursultiamine or salts thereof.
  • macular degeneration is an ocular disease that causes vision impairment due to degeneration in the macular area, and it is known that the pathogenesis is related to age, family history, race, and smoking.
  • the field of vision is blurred and the sight of the nearby vision is distorted, and later blindness occurs.
  • Age-related macular degeneration causes severe irreversible vision loss and is known to be the leading cause of blindness in people over 50.
  • the prevalence rate was reported to be 1.2% of the 52-64-year-old population in the United States, and the rate was reported to be higher at 20-37% for people over 75 years of age, and the prevalence was expected to increase gradually as the average age increased. do.
  • age-related macular degeneration There are two types of age-related macular degeneration. The first is non-angiogenic age-related macular degeneration, which is the most common and accounts for 85% of all age-related macular degeneration. This type of dryness is characterized by grease and atrophic changes in the retinal pigment epithelium. The second is neovascular age-related macular degeneration, characterized by choroidal neovascularization. Choroidal neovascularization is a newly formed blood vessel that tends to leak blood and body fluids. This leads to the formation of lesions in which fibrous tissue proliferates in the retinal tissue and the photoreceptors are lost, and continues to cause severe and irreversible vision loss.
  • vascular endothelial growth factor Treatment of neovascular age-related macular degeneration includes photodynamic therapy and injection of drugs into the eye to block vascular endothelial growth factors.
  • photodynamic therapy Treatment of neovascular age-related macular degeneration includes photodynamic therapy and injection of drugs into the eye to block vascular endothelial growth factors.
  • VEGF vascular endothelial growth factor
  • Ranibizumab Libizumab, Lucentis®
  • Ranibizumab has been reported to be an effective and safe treatment in patients with neovascular age-related macular degeneration through various clinical studies and is widely used worldwide.
  • the lesion frequently recurs, the number of injections increases, which places a considerable burden on the patient. In some patients, the lesion does not improve despite the injection.
  • vascular endothelial growth factor acts as a powerful vasodilator, it serves to maintain the blood circulation and relaxation of the coronary arteries of the heart. Because age-related macular degeneration patients are older and at higher risk for cardiovascular disease, vascular endothelial growth factor injections also pose a risk of serious side effects.
  • the present invention intends to propose a new therapeutic composition that reduces the risk of side effects and brings an effective treatment effect against macular degeneration.
  • the present inventors have made extensive efforts to develop a therapeutic agent for macular degeneration with reduced risk of side effects. As a result, the present inventors completed the present invention by confirming that fursultiamine decreases the expression of increased HIF-1 ⁇ in retinal pigment epithelial cells and inhibits choroidal vascular endothelial cell growth.
  • an object of the present invention is to provide a pharmaceutical composition for preventing or treating macular degeneration.
  • Another object of the present invention is to provide a food composition for preventing or improving macular degeneration.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating neovascular ocular disease.
  • Another object of the present invention is to provide a food composition for preventing or improving neovascular eye disease.
  • Another object of the present invention is to provide a method for treating macular degeneration.
  • Another object of the present invention is to provide a method for treating neovascular eye disease.
  • One aspect of the present invention relates to a pharmaceutical composition for preventing or treating macular degeneration, including fursultiamine or salts thereof.
  • the present inventors have made extensive efforts to develop a therapeutic agent for macular degeneration with reduced risk of side effects. As a result, the present inventors confirmed that fursulthiamine reduces the expression of increased HIF-1 ⁇ in retinal pigment epithelial cells and inhibits choroidal vascular endothelial cell growth.
  • Greener sulfonic thiamine is a vitamin of the vitamin B 1 activity for the treatment of thiamine deficiency, and thiamine disulfide derivative. Compared to vitamin B 1 , it is better absorbed into cells and produces a large amount of co-carboxylase, which improves neurological dysfunction, myocardial metabolic disorders, etc. that are physiologically related to deficiency of vitamin B 1 or metabolic disorders. It is known.
  • the causes of macular degeneration are age increase, family history, race, and smoking, but are mainly caused by age increase.
  • macular degeneration a yellow deposit called drusen (accumulation of extracellular proteins and lipids) gradually accumulates in the macula (part of the retina) between the retinal pigment epithelium and the choroid.
  • Age-related macular degeneration as a function of age increases is based on the degree (size and number) of drusen, which is early, intermediate, and late. It is divided into stages.
  • the macular degeneration is age-related macular degeneration (AMD).
  • AMD age-related macular degeneration
  • the macular degeneration is late age-related macular degeneration (late AMD).
  • Late AMD retinal damage occurs, resulting in symptomatic vision loss in addition to drusen.
  • Late AMD is divided into dry AMD and wet AMD depending on the type of damage. Dry AMD is characterized by geographic atrophy and is non-angiogenic AMD.
  • wet AMD is neovascular AMD (A neovascular AMD) in which choroidal neovascularization occurs.
  • the macular degeneration is neovascular age-related macular degeneration (Neovascular age-related macular degeneration, Neovascular AMD) or non-angiogenic age-related macular degeneration (Non-neovascular age-related macular degeneration, Non -neovascular AMD).
  • the macular degeneration is neovascular age-related macular degeneration.
  • the pharmaceutical composition of the present invention has an effective amount of fursulthiamine or a salt thereof from 100 mg / 60 kg / day to 240 mg / 60 kg / day.
  • the fursulthiamine used as an active ingredient in the present invention may be used in itself or in the form of a salt, preferably in the form of a pharmaceutically acceptable salt.
  • the salt is preferably an acid addition salt formed by free acid.
  • the free acid may be an organic acid and / or an inorganic acid.
  • the organic acids include citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutanoic acid and aspartic acid. It may be, but is not limited thereto.
  • the inorganic acid may be hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid, but is not limited thereto.
  • the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier, in addition to fursulthiamine or a salt thereof.
  • the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, Polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, but is not limited thereto.
  • the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components.
  • a lubricant e.g., a talc, a kaolin, a kaolin, a kaolin, a kaolin, a kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, a talct, a talct, a talct, a stevia, glycerin, a stevia, glycerin, glycerin, g
  • composition of the present invention can be administered orally or parenterally.
  • intravenous injection for parenteral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, ocular administration, or topical ocular administration may be used.
  • Topical administration of the eye is administered directly intraocularly, around the eyeball, around the eyeball, subretinal, central retinal, outside the fovea, subconjunctival, intravitreal ( intravitreous, intracameral or suprachoroidal.
  • the pharmaceutical composition of the present invention may also be administered through an insertion device.
  • Suitable dosages of the pharmaceutical compositions of the present invention vary by factors such as formulation method, mode of administration, patient's age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion, and sensitivity to radiation response. , Usually, a skilled physician can easily determine and prescribe a dose effective for the desired treatment.
  • the pharmaceutical composition of the present invention is prepared in a unit dose form by formulating using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily carried out by those skilled in the art to which the present invention pertains. Or it can be manufactured by incorporating into a multi-dose container.
  • the formulation may be in the form of a solution, suspension, or emulsion in an oil or aqueous medium, or may be in the form of an ointment, ex-agent, powder, granule, tablet or capsule, and may further include a dispersant or stabilizer.
  • Another aspect of the present invention relates to a food composition for preventing or improving macular degeneration comprising fursulthiamine or a salt thereof.
  • composition of the present invention is a food composition
  • it may be prepared in the form of powder, granule, tablet, capsule or beverage.
  • the food may be candy, drink, gum, tea, vitamin complex, or health supplement food.
  • the food composition of the present invention may include fursultiamine or a salt thereof as an active ingredient, as well as ingredients commonly added in food production, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents.
  • the aforementioned carbohydrates include monosaccharides, such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, oligosaccharides, etc .; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • flavoring agents natural flavoring agents (Tau Martin, Stevia extract (eg, rebaudioside A, glycyrrhizine, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.
  • the food composition of the present invention is prepared as a drink agent, in addition to fursultiamine or a salt thereof, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, peaworm extract, jujube extract, licorice extract, etc. may be additionally included. have.
  • Another aspect of the present invention relates to a pharmaceutical composition for preventing or treating neovascular ocular disease comprising fursulthiamine or a salt thereof.
  • Another aspect of the present invention relates to a food composition for preventing or improving neovascular eye disease comprising fursulthiamine or a salt thereof.
  • the pharmaceutical composition and food composition for preventing or treating neovascular ocular disease of the present invention include fursultiamine or a salt thereof, which is the same active ingredient as the pharmaceutical composition for preventing or treating macular degeneration of the present invention, between the two In order to avoid excessive complexity of the specification according to repeated description, the description is omitted.
  • neovascular vascular disease in the present specification is a pathological angiogenesis-related disease occurring in the eye, for example, corneal neovascularization, retinal neovascularization, choroidal neovascularization. , Including intraocular neovascularization, neovascular glaucoma, proliferative diabetic retinopathy, neovascular macular degeneration, and retinopathy of prematurity do.
  • Another aspect of the invention relates to a method for treating macular degeneration, comprising administering a pharmaceutical composition comprising fursulthiamine or a salt thereof to a subject in need thereof.
  • Another aspect of the present invention relates to a method of treating angiogenesis ocular disease, comprising administering a pharmaceutical composition comprising fursulthiamine or a salt thereof to a subject in need thereof.
  • administration means providing a substance to a subject in any suitable way.
  • the route of administration of the pharmaceutical composition of the present invention can be administered orally or parenterally through all general routes as long as it can reach the target tissue.
  • the pharmaceutical composition of the present invention may be administered using any device capable of delivering the active ingredient to target cells or organs.
  • subject herein is not particularly limited, for example, human, monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, mouse, rabbit, or Guinea pigs, preferably mammals, more preferably humans.
  • the present invention relates to a pharmaceutical composition for preventing or treating macular degeneration, comprising fursultiamine or salts thereof.
  • composition comprising the fursulthiamine or a salt thereof of the present invention can also be used as a therapeutic agent for various neovascular eye diseases.
  • 1 is a graph showing the effect of fursultiamine suppressing HIF-1 ⁇ expression induced by hypoxic conditions in ARPE-19 cells.
  • Figure 2a shows the results of the choroid sprouting assay (choroid sprouting assay).
  • the sprueing area was reduced by fursulthiamine. (Microscope magnification: 40 times)
  • FIG. 2B is a graph showing quantitative analysis of the sprouting distance of FIG. 2A.
  • FIG. 3 is a graph showing that in ARPE-19 cells, fursulthiamine inhibits increased VEGF secretion under hypoxic conditions.
  • 4A-4B are results comparing vascular leakage through fluorescein angiography in a laser-induced choroidal neovascular model (laser-induced CNV). It can be seen that the degree of vascular leakage was decreased by fursulthiamine. 0: no laser spots, 1: no fluorescence brightness and size change between early and late, 2A: only fluorescence brightness between early and late changes, 2B: fluorescence brightness between early and late There is a change in both size and size.
  • Figure 6a is a graph of oxygen consumption change in the ARPE-19 cells, to confirm the energy metabolic changes of mitochondria.
  • 6B is a spare capacity graph showing that in ARPE-19 cells, the metabolism of mitochondria, which was reduced by LPS, is recovered by fursulthiamine.
  • the present invention relates to a pharmaceutical composition for preventing or treating macular degeneration, including fursultiamine or salts thereof.
  • Neovascular Age-related macular degeneration is characterized by choroidal neovascularization. It is known that the hypoxia environment of the retina or choroid expresses hypoxia inducible factor 1 alpha (HIF-1 ⁇ ), thereby promoting vascular endothelial cell factor to induce the development of new blood vessels in the choroid. The development of new blood vessels in the choroid eventually leads to visual impairment.
  • hypoxia inducible factor 1 alpha HIF-1 ⁇
  • HIF-1 ⁇ inhibition by the thiamine derivative fursultiamine and pursultiamine in the choroid to determine the effect of preventing the development of new blood vessels.
  • retinal cell ARPE-19 Adult Retinal Pigment Epithelial cell line-19
  • ARPE-19 cells were dispensed in a 60 mm dish and allowed to adhere for about a day. The next day, 0 ⁇ M, 20 uM, 50 uM, and 100 uM of fursulthiamin hydrochloride (Toronto research chemical) and vehicle (Dimethyl sulfoxide (DMSO), Sigma-Aldrich) were treated by concentration in each cell. After 1 hour, they were placed in a hypoxic chamber (INVIVO 2 400, Baker) and exposed to 1% oxygen. And after 4-6 hours, the cells were taken out and treated with a protein lysis buffer to dissolve the cells, and then the proteins were separated.
  • fursulthiamin hydrochloride Toronto research chemical
  • vehicle Dimethyl sulfoxide (DMSO), Sigma-Aldrich
  • the sample was mixed with a sample of the same protein amount and 4X loading buffer and heated to denature the protein to a primary structure.
  • the same amount of protein sample was loaded onto the SDS-PAGE gel and transferred to a PVDF membrane.
  • the HIF-1a antibody (Novus, NB100-479) was diluted in a 5% BSA (bovine serum albumin) solution and incubated overnight at 4 ° C.
  • the membrane was incubated with a secondary antibody bound to HRP (Horseradish peroxidase), and reacted with an enhanced chemiluminescence (ECL) solution to induce chemiluminescence.
  • HRP Hemseradish peroxidase
  • ECL enhanced chemiluminescence
  • Chemofluorescence image analysis equipment GE Healthcare, LAS-4000 was used to detect the degree of luminescence according to the amount of protein to obtain an image.
  • ⁇ -tubulin was used to show that the same amount of protein was loaded.
  • Example 2 Inhibitory effect of fursulthiamine on angiogenesis-decreased choroidal vascular endothelial cell growth
  • the eyeballs of C57 black / 6J (C57BL / 6J) from Jackson Laboratory, 3 or 4 weeks of age, were removed to separate the choroid / sclera and cut to a size of 1 mm ⁇ 1 mm. Meanwhile, 300 ul of liquid meth gel (Becton Dickinson, BD matrigel) was dissolved in ice into a 24-well plate, and cut choroids / sclera were planted one by one. Subsequently, the mixture was placed in a 37 ° C incubator for 10 minutes to harden the meth gel, and then 500 ul of EGM medium (Lonza, Endothelial Growth Medium) was added.
  • EGM medium Longza, Endothelial Growth Medium
  • vascular endothelial cells were induced in a 37 ° C incubator.
  • the medium was changed once every two days, at which time the fursulthiamine hydrochloride was treated at a concentration of 20 uM or 50 uM.
  • the growth of vascular endothelial cells growing in the choroid was confirmed by observing 3 to 5 days after the planting of the choroid / sclera.
  • the distance from the tissue to the sprawled range was measured and averaged at a total of four locations using the ImageJ program.
  • Statistical processing was indicated to be significant when the p value was 0.05 or less (p ⁇ 0.05) using the Prism program.
  • ARPE-19 cells were dispensed in a 60 mm dish and allowed to adhere for about a day. The next day, after replacing with serum-free medium, 0 ⁇ M, 50 uM, and 100 uM (Toronto research chemical) and vehicle (DMSO, Sigma-Aldrich) of fursulthiamine hydrochloride were treated for each cell by concentration. And placed in a hypoxic chamber (INVIVO 2 400, Baker) and exposed to 1% oxygen.
  • serum-free medium 0 ⁇ M, 50 uM, and 100 uM (Toronto research chemical) and vehicle (DMSO, Sigma-Aldrich) of fursulthiamine hydrochloride were treated for each cell by concentration. And placed in a hypoxic chamber (INVIVO 2 400, Baker) and exposed to 1% oxygen.
  • VEGF secreted in the medium was measured with a human VEGF enzyme immunoassay kit (Enzyme linked immunoassay (ELISA), R & D systems).
  • ELISA Enzyme linked immunoassay
  • concentration calculation were performed according to the manual provided in the kit. Statistical processing was indicated to be significant when the p value was 0.05 or less (p ⁇ 0.05) using the Prism program.
  • Example 4 Comparison of the degree of vascular leakage through fluorescein angiography
  • C57BL / 6J mice To view drug efficacy in a laser-induced choroidal retinopathy model, an animal model of macular degeneration, 7-8 week old C57 black / 6J (C57BL / 6J) mice were used. Fursultiamine (Fursultiamine) administration group and control (Control) 10 were used, respectively, 50 mg / kg of fursultiamine was orally administered for 8 days from the day before laser irradiation to the week after laser irradiation. As a control, sterile distilled water used as a solvent was administered in the same manner.
  • Mice were anesthetized with avertin (Sigma-Aldrich), and pupils were expanded by administering an antiseptic (Midrinpi, Taejun Pharmaceutical) to both eyes.
  • Argon laser Argon laser (Oculight GL, IRIDEX) was irradiated to both eyes to produce 4 laser spots per eye.
  • fluorescein AK-FLUOR 10%, Akorn
  • angiography images of the base of the retina and fluorescein were taken using a MICRON IV Basic System (Phoenix Research Labs).
  • Example 5 Laser-induced choroidal neovascularization model (laser-induced CNV), confirming the size of CNV lesions by fursulthiamine
  • mice were anesthetized, and after fluorescein angiography, the eyes were removed for tissue staining and fixed in 4% paraformaldehyde (4% PFA, EMS) for 30 minutes. After removing the cornea and lens, the retina and choroid were separated. The separated choroid was put into a blocking buffer (blocking buffer, 0.2% bovine serum albumin, 5% normal goat serum, 0.5% Triton X-100) and reacted for 1 hour.
  • a blocking buffer blocking buffer, 0.2% bovine serum albumin, 5% normal goat serum, 0.5% Triton X-100
  • Isolectin IB4-Alexa Fluor 488, Invitrogen was diluted in a blocking buffer, and then put into a tissue to react. After that, the choroid was flattened, and a mount solution (Mountant, Thermo scientific) was placed thereon to cover and stabilize the cover glass.
  • neovascular age-related macular degeneration is known to be a major pathological mechanism, it was confirmed whether mitochondrial metabolism is restored by pursulthiamine treatment and the effect of suppressing inflammation. Since metabolic changes in mitochondria may cause inflammation or exacerbation, it is predicted that when fursulthiamine restores the metabolism of mitochondria, it can be applied to the prevention or treatment of neovascular eye diseases accompanying inflammation.
  • ARPE-19 cells were dispensed into 96-well XF plates, and the medium was changed once every 2 days.
  • LPS Lipopolysaccharides, Sigma-Aldrich
  • fursulthiamine was treated with 50 uM.
  • XF medium Seahorse XF DMEM medium, Agilent
  • the intracellular oxygen consumption rate was measured with a Seahorse XF analyzer (Seahorse XFe96 analyzer, Agilent). The measurement method was conducted according to the manual provided by the Seahorse XF96 analyzer (Agilent).
  • the present invention relates to a composition for preventing or treating macular degeneration. More particularly, the present invention relates to a composition for the prevention or treatment of macular degeneration comprising fursultiamine or salts thereof.

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Abstract

La présente invention concerne une composition pharmaceutique qui permet de prévenir ou de traiter la dégénérescence maculaire et qui contient de la fursultiamine ou des sels de celle-ci. La fursulthiamine fait diminuer l'expression de l'HIF-1α qui est augmentée dans les cellules de l'épithélium pigmentaire rétinien, et inhibe la croissance des cellules endothéliales vasculaires choroïdiennes. Une composition pharmaceutique de la présente invention contenant de la fursultiamine ou des sels de celle-ci peut également être utilisée comme agent destiné au traitement de diverses maladies oculaires liées à une néovascularisation.
PCT/KR2019/014500 2018-11-02 2019-10-30 Composition de prévention ou de traitement de la dégénérescence maculaire Ceased WO2020091430A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US17/282,547 US12239644B2 (en) 2018-11-02 2019-10-30 Composition for prevention or treatment of macular degeneration
JP2021518126A JP7280353B2 (ja) 2018-11-02 2019-10-30 黄斑変性予防又は治療用組成物
EP19878702.0A EP3875092B1 (fr) 2018-11-02 2019-10-30 Composition de prévention ou de traitement de la dégénérescence maculaire
JP2023022976A JP2023062085A (ja) 2018-11-02 2023-02-17 黄斑変性予防又は治療用組成物

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KR102866612B1 (ko) * 2024-01-26 2025-10-01 충북대학교 산학협력단 셀라폴린 a-1을 포함하는 황반변성, 신생혈관성 안질환, 또는 안구 내 섬유증의 예방 또는 치료용 조성물

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