WO2018147685A1 - Composition contenant de l'acide ursodésoxycholique pour la prévention ou le traitement d'une déficience visuelle - Google Patents

Composition contenant de l'acide ursodésoxycholique pour la prévention ou le traitement d'une déficience visuelle Download PDF

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WO2018147685A1
WO2018147685A1 PCT/KR2018/001770 KR2018001770W WO2018147685A1 WO 2018147685 A1 WO2018147685 A1 WO 2018147685A1 KR 2018001770 W KR2018001770 W KR 2018001770W WO 2018147685 A1 WO2018147685 A1 WO 2018147685A1
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udca
composition
treatment
disease
macular degeneration
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PCT/KR2018/001770
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English (en)
Korean (ko)
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송영호
고휘진
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주식회사 유스바이오팜
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Priority claimed from KR1020180015944A external-priority patent/KR102252450B1/ko
Priority to AU2018218696A priority Critical patent/AU2018218696B2/en
Priority to RU2019111077A priority patent/RU2723988C1/ru
Priority to EP18751361.9A priority patent/EP3581185A4/fr
Priority to GB1904993.1A priority patent/GB2571644A/en
Priority to CA3039500A priority patent/CA3039500C/fr
Priority to CN201880005395.0A priority patent/CN110177556A/zh
Priority to BR112019009202-1A priority patent/BR112019009202A2/pt
Application filed by 주식회사 유스바이오팜 filed Critical 주식회사 유스바이오팜
Priority to MX2019008963A priority patent/MX2019008963A/es
Priority to SG11201906169QA priority patent/SG11201906169QA/en
Priority to JP2019520858A priority patent/JP6901739B2/ja
Publication of WO2018147685A1 publication Critical patent/WO2018147685A1/fr
Priority to US16/400,969 priority patent/US20190255074A1/en
Priority to AU2020204384A priority patent/AU2020204384B2/en
Priority to US17/224,731 priority patent/US20210252022A1/en
Priority to AU2021204660A priority patent/AU2021204660A1/en

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/718—Starch or degraded starch, e.g. amylose, amylopectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present invention relates to a composition for the prevention or treatment of visual impairments containing ursodeoxycholic acid (hereinafter, used in combination with UDCA). More specifically, the present invention is aqueous solubilized ursodeoxycholic acid, oral administration, intraocular injection, intravenous injection, or eye drop administration, and macular degeneration, glaucoma and diabetic retina.
  • the present invention relates to a pharmaceutical composition excellent in preventing or treating a disease causing visual impairment such as a disease.
  • Macular degeneration, glaucoma and diabetic retinopathy are known as the three major blindness diseases that threaten eye health.
  • the leading cause of blindness is aging diseases caused by aging, and a study conducted in the UK in 2006, according to a study conducted in the UK in 2006, accounted for 74% of all three blindness diseases.
  • Glaucoma is so common that 2% of adults over 40 years old are patients, and the optic nerve is damaged due to abnormally high intraocular pressure. Glaucoma is divided into primary glaucoma, which is associated with cardiovascular disease or diabetes, and secondary glaucoma due to cataracts, uveitis, or eye surgery complications. There are few symptoms and the vision is narrower and darker than normal. Glaucoma is also easy to neglect because there are no symptoms at first, and if the optic nerve is damaged, there is no way to recover from drugs or surgery, so prevention and early detection are the solutions to slow the progression of the disease.
  • Diabetic retinopathy is a complication caused by circulatory disorders in the peripheral blood vessels of the retina. It occurs in almost all patients 15 to 20 years after the onset of diabetes. Diabetic retinopathy is divided into non-proliferative and proliferative. Non-proliferative, which is 80% of diabetic retinopathy, is a disease in which the leaking blood from the retinal capillaries flows into the retina, making it difficult to distinguish colors and distinguish objects at night. Proliferative properties can lead to the formation of new blood vessels due to lack of oxygen in the blood vessels, and the effects of diabetes on the blood vessels that easily explode, causing intraocular hemorrhage, leading to severe vision damage.
  • Macular degeneration is the most common cause of blindness (57.2%) (Journal of the British Ophthalmological Society, 2006), and it is a dangerous disease that causes dysfunction due to degenerative changes as the age of the macula in the center of the retina grows. . It is a frequent disease among the elderly, with an increase in the incidence in populations over 65 years of age worldwide, with a prevalence of about 30% in people over 75 years of age. In Korea, there are 140,000 patients in 2013 (40% increase in 2009-2013, according to the National Health Insurance Review & Assessment Service) due to the recent changes in the environment such as aging and computer use. It is rapidly increasing to 16.5% (2008-2012, 2012 National Health and Nutrition Survey).
  • Macular or senile macular degeneration is clinically divided into two types: dry, atrophic, and non-exudative type, and wet, neovascular, and exudative type. Severe loss of vision usually occurs in wet macular degeneration, but 20% of blindness due to the disease is also caused by dry macular degeneration. Dry or non-exudative macular degeneration refers to a lesion such as drusen or atrophy of the retinal pigment epithelium in the retina. Visual cells in the macula gradually atrophy, and the visual acuity gradually decreases over time, and may develop into a wet form. Wet or exudative macular degeneration may cause choroidal neovascularization under the retina, causing severe visual damage due to bleeding and exudation from the blood vessels, and blindness after a certain period of time.
  • causes of macular degeneration include smoking, hypertension, cholesterol, obesity, arteriosclerosis, family history, etc. in addition to aging, and may also be caused by the side effects of the treatment of other diseases, including chloroquine (malaria). However, the exact cause is still unknown, and apoptosis of the macula-related cells is considered to be the main cause.
  • macular degeneration as a treatment for dry macular degeneration does not have a fundamental treatment, and is simply satisfied with symptomatic therapy such as taking antioxidants. Disease progression can no longer be prevented or treated.
  • symptomatic therapy such as taking antioxidants.
  • Disease progression can no longer be prevented or treated.
  • wet macular degeneration there is no cure for inhibiting apoptosis of macular-related cells, and intraocular injection method, antibody type and location of an antibody therapeutic agent that inhibits vascular endothelial growth factor (VEGF) activity.
  • VEGF vascular endothelial growth factor
  • Bijudine was first developed as a treatment for wet macular degeneration. However, in the clinical trials of treatment, the bijudine-treated group showed statistically significant effect compared to the placebo group at 1 year after the treatment (86%, placebo 67%), but it was no longer significant at 2 years after the treatment. There is a drawback that the effect is low enough to be absent (79% of bijudine, 72% of placebo).
  • Makuzen is a substance that inhibits vascular endothelial growth factor in the eye and is injected into the eye every six weeks. In clinical trials, compared to 22% of the control group, 33% of the treated patients had the effect of maintaining or improving their vision and actually lowering the visual loss rate of macular degeneration patients due to aging. However, Makuzen has the disadvantage that its vision maintenance and enhancement effects are lower than Lucentis ® or Eylea ® . In addition, less than 1% of treated patients develop serious side effects such as retinal detachment and endophthalmitis, and 40% of patients complain of side effects such as floatation in the eye or discomfort in the eye.
  • Lucentis ® has the function of inhibiting the action of vascular endothelial growth factor (VEGF) and is injected intraocularly every four weeks. Lucentis shows 40% visual acuity and 90% visual acuity, but intravitreal injection generally gives the patient fear and discomfort.
  • VEGF vascular endothelial growth factor
  • Isle Ria other antibody therapeutics is a drug also received FDA approval in November 2011 with the ability to inhibit wet (age-related) activity of vascular endothelial growth factor in macular degeneration like Lucerne teeth. Intraocular injections are given every month for the first three months, followed by intraocular injections every eight weeks. Eylea ® has the same therapeutic effect as Lucentis, but has the advantage of reducing the number of intraocular injections. However, since Eylea ® is also an intravitreal injection method, it has the disadvantage of causing fear and discomfort to patients upon injection, such as Lucentis ® .
  • the implantable telephoto lens approved in July 2010, is an aid to enlarge the image in the retina in order to improve damaged central vision in patients with severely advanced macular degeneration and does not prevent or improve the progression of macular degeneration itself.
  • Ursodeoxycholic acid a type of bile acid
  • Efforts have been made to treat wet (exudative or senile) macular degeneration using UDCA) or UDCA in vivo metabolite tauroursodeoxycholic acid (tUDCA).
  • UDCA or tUDCA can protect and treat retinal cells in retinal degeneration animals.
  • the question was whether the drug product and drug delivery method used could be applied to the human body.
  • the question was how to easily deliver the therapeutically active amount of the patient's eyeballs without side effects while increasing the patient's convenience.
  • Non-Patent Document 1 Subcutaneous injection methods of bile acids have also been tried. Dr. Bowlite of Emory University in the United States conducted an experiment to prevent the retinal degeneration of the mouse by the use of tUDCA, and as a result, it was shown that tUDCA can significantly suppress the retinal degeneration (Non-Patent Document 1). However, the drug delivery method was subcutaneous injection of tUDCA in sodium carbonate buffer and subcutaneous injection at the nape of the neck near the eye of the mouse. The reason for using tUDCA, a water-soluble metabolite of UDCA instead of UDCA, is that it has a slightly higher solubility in water than UDCA (UDCA solubility; 20 mg / l; tUDCA solubility 200 mg / l).
  • crystalline tUDCA is also almost insoluble in water, and only dissolved in a solvent called DMSO and mixed with PBS (pH 7.2) solution 1: 4 to about 200 mg / l.
  • PBS pH 7.2
  • crystalline tUDCA is a strong hydrophilic taurine metabolite of UDCA, so it is difficult to pass through the cell membrane in the human body, and the formulation is difficult due to strong acidity (pH: 1 or less). That is, even if it is dissolved in sodium carbonate buffer, tUDCA is precipitated after a certain time, it is difficult to maintain stability for more than one day, when the formulation of the drug is insufficient stability of the drug.
  • TUDCA has high manufacturing cost compared to UDCA and is expensive, and there are many problems in producing tUDCA as an intraocular injection formulation due to new substances such as toxicity, side effects, or new mechanisms of unknown mechanism of action.
  • Non-Patent Document 2 The method of injection into the abdominal cavity also has a disadvantage that can not be applied to the human body. This is because celiac injection is a drug delivery method that is rarely used in the human body.
  • UDCA is a planar amphoteric molecule having both hydrophobic and hydrophilic surfaces containing no hydroxyl groups at the same time because of its molecular nature, and dihydroxy-bile acids having two other hydroxyl groups, which are a type of bile acid. It is because it exists in the protonated form () and practically insoluble in water (solubility: 53 ⁇ M). Another reason is that UDCA is classified as entero-hepatic circulation, so it is slightly dissolved in the vicinity of the duodenum during oral administration, absorbed more than 95% of the liver mainly through the small intestine, and then flows into the small intestine.
  • retinal blood vessels have a structure called a blood-retinal barrier (BRB) with selective permeability to protect retinal nerve cells from foreign substances.
  • BRB blood-retinal barrier
  • the BRB structure is an optional barrier to protect nerve cells and to prevent toxic substances flowing with the blood from easily entering the retina and destroying nerve tissue.
  • the BRB structure is divided into two parts.
  • Inner BRB (tight junctions) with vascular endothelial cells in the retina protects nerves of the retina from external toxins.
  • Retinal pigment epithelium (RPE) of outer BRB protects the retina by selectively blocking the transport of substances from the leaky choroid vessels to the retina.
  • the crystalline UDCA is classified as a skin irritant, and its pKa is acidic in water at around 5.0, which can be harmful to the eye or eye area.
  • crystalline ursodeoxycholic acid has a very sharp needle-like structure, and when it comes into contact with the eye, it enters the pores and wounds between the cornea or the surrounding tissue, and the pH of the eye is 7.4, so it does not melt well and tears well.
  • Direct use of eye drops is not appropriate unless special preparations or methods are available because they do not wash away and can remain in the area and cause irritation.
  • Intravenous injections can also be considered, but as with eye drops, UDCA is almost insoluble in water and precipitates near 7.0, the pH of the blood, and cannot be uniformly dissolved in water in the form of a single molecule. Direct use of intravenous infusions is not appropriate unless there is a potential for the design of dangerous and specific intravenous formulations and methods.
  • crystalline UDCA can be easily transported to the eye in a therapeutically active amount without side effects, drug delivery methods applicable to the human body, that is, while increasing the convenience of patients and therapeutic effects, there is no industrially available bile acid drug formulation. If oral administration alone delivers a therapeutically effective concentration of UDCA / tUDCA across the retinal vascular barrier and into the eye without side effects, it may have the same therapeutic effect as existing antibody therapeutics such as Lucentis ® or Eylea ® . Bile acid preparations can eliminate the disadvantages of intraocular injection and can be the best treatment in terms of improving patient convenience and improving vision.
  • oral administration alone provides a therapeutically active amount of UDCA / tUDCA to the blood and transports it to the intraocular retina across the blood-retina barrier to protect the retina.
  • UDCA / tUDCA intraocularly as above or intraorally across the retinal vascular barrier.
  • the object of the present invention is that the chemical properties are classified as skin deposits, strong acidic, needle-like crystal structure and insoluble in water, which can cause tingling on direct contact with the eye and cause adverse reactions to the retina during intraocular injection. It is to solve the problem of crystalline UDCA which is harmful. That is, an object of the present invention is to solubilize the UDCA in water in the form of a clean aqueous solution so that it can be used as an intraocular injection or eye drop, so that visual disorders such as macular degeneration, glaucoma and diabetic retinal diseases It is to provide a composition for the prevention or treatment of.
  • Another object of the present invention is to solve the problem of crystalline UDCA, which is aggregated in micelle form even though it is dissolved in a small amount due to the inherent chemical properties of both hydrophilic and hydrophobic. That is, another object of the present invention is to prevent intermolecular aggregation at any pH range in the human body or near the pH of tears of 7.4 so that precipitation does not occur in the eye tissues during intraocular injection and does not cause adverse reactions in the retina. It is solubilized in the form of a clean aqueous solution in water to provide a composition for the prevention or treatment of visual disorders such as macular degeneration, glaucoma and diabetic retinal diseases.
  • Another object of the present invention is to be classified as enterohepatic circulation (oral hepatic circulation) due to its chemical properties during oral administration and high transport of hepatic UDCA to the blood and eye because of high hepatic first-pass clearance It solves the problem of the crystalline UDCA which did not exist. That is, another object of the present invention is to solubilize UDCA in water in the form of a clean solution in macular degeneration, glaucoma and diabetes so as to deliver therapeutically active amounts across the plasma and retinal vascular barriers to the eye, even by oral administration alone. It is provided as a composition for the prevention or treatment of visual disorders such as sexual retinal diseases.
  • an object of the present invention is to remove macular degeneration, glaucoma, and solubilized UDCA which greatly increases intraocular absorption with therapeutically active amount only by oral administration to eliminate pain and fear caused by intraocular injection to patients. And it is to provide a composition for the prevention or treatment of diabetic retinopathy and visual disorders such as.
  • UDCA is solubilized in water in the form of a clean aqueous solution to provide a composition for the prevention and treatment of visual impairment diseases.
  • Another object of the present invention is to prevent the intermolecular aggregation of UDCA crystals having unique chemical properties of hydrophilic and hydrophobic at the same time, the aqueous phase (hydrophilic) and oil phase in the preparation of eye drops and intraocular injections It is to provide a composition for the prevention or treatment of visually impaired diseases that is easy to mix and formulate with (lipophilic), and excellent in drug stability without the precipitation phenomenon over time.
  • a further object of the present invention is a therapeutic conventional age-related macular degeneration diseases, such as protein antibody Lucerne tooth (Lucentis ®) or Isle Liao (Eylea ®) and administered in combination upon injection eye, or non judain medication and combination of It is to provide a composition for the prevention or treatment of macular degeneration disease that can give a synergistic effect to the prevention or treatment of macular degeneration disease.
  • a therapeutic conventional age-related macular degeneration diseases such as protein antibody Lucerne tooth (Lucentis ®) or Isle Liao (Eylea ®) and administered in combination upon injection eye, or non judain medication and combination of It is to provide a composition for the prevention or treatment of macular degeneration disease that can give a synergistic effect to the prevention or treatment of macular degeneration disease.
  • ursodeoxycholic acid ursodeoxycholic acid, UDCA
  • water soluble starch preparations water as an active ingredient and comprising a solubilized ursodeoxycholic acid in a clear aqueous solution to all pH values.
  • the composition is intravitreal injection (Intravitreal injection)
  • the UDCA can be delivered to the retina by intraocular injection and does not cause skin redness or inflammation in the eye after injection.
  • the single intraocular injection of UDCA of the composition may be 50-100 ⁇ l at a concentration of 0.1-1.5 mg / ml.
  • the composition is intended for oral administration (Oral administration), to deliver the UDCA to the blood, and then to deliver a therapeutically active amount to the eye across the blood-retinal barrier.
  • Oral administration Oral administration
  • the daily oral dose of UDCA of the composition may be 5 ⁇ 30 mg / kg.
  • the composition may be orally administered 20 or more days and once a day.
  • the UDCA of the composition may start to be distributed in the eye between 5 to 10 minutes after oral administration, and stay for a predetermined time, that is, about 1 hour and then be washed out.
  • the composition is administered intravenously, and is directly administered to the blood so as not to block blood vessels and to cause skin irritation.
  • the composition may be administered as eye drops.
  • the UDCA of the composition administered with the eye drop may be transported from the outside of the eye to the eye without causing skin redness and adverse reactions around the eyes or the eyes.
  • the dose amount of UDCA of the composition may be 30 to 50 ⁇ l at a concentration of 0.1 to 2.0 mg / ml.
  • the proper number of eye drops per day of the UDCA of the composition is once to 10 times, but is characterized in that the number is not limited.
  • the visual impairment disease may be selected from the group consisting of macular degeneration, glaucoma and diabetic retinal disease.
  • the visual impaired disease may be macular degeneration.
  • the visually impaired disease may be wet-type age-related macular degeneration.
  • the composition may function at least one of inhibition of choroidal neovascularization, promotion of retinal function, and expression control of vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • the UDCA may be solubilized as a UDCA selected from soluble UDCA, water soluble UDCA derivatives, UDCA salts, and UDCA conjugated with amines.
  • the UDCA is solubilized with at least one UDCA selected from ursodeoxycholic acid (UDCA), taurusodeoxycholic acid (tUDCA) and glycoursodeoxycholic acid (gUDCA). It may be.
  • UDCA ursodeoxycholic acid
  • tUDCA taurusodeoxycholic acid
  • gUDCA glycoursodeoxycholic acid
  • the UDCA may be present in a therapeutically active amount.
  • the UDCA may include 0.01 to 5 parts by weight based on the total weight of the composition.
  • the UDCA may include 0.04 to 0.16 parts by weight based on the total weight of the composition.
  • the water-soluble starch preparation is maltodextrin
  • the maltodextrin may comprise 1 to 70 parts by weight based on the total weight of the composition.
  • the pH value of the composition is 3 to 9
  • the water-soluble starch invert is maltodextrin
  • the minimum weight ratio of maltodextrin to UDCA can be 1:16 to 1:30 have.
  • the pH value of the composition is 6.5 to 8
  • the water-soluble starch invert is maltodextrin
  • the minimum weight ratio of maltodextrin to UDCA can be 1:13 to 1:30 have.
  • the water soluble starch invert may be at least one of maltodextrin, dextrin, liquid glucose, corn syrup solids, soluble starch, dextran, guar gum, pectin and soluble non-starch polysaccharides.
  • the composition may be a syrup, cream, paste or dried formulation.
  • the composition may be administered in combination with a macular degeneration disease treatment.
  • the macular degeneration disease treatment agent may be an anti-vascular endothelial growth factor antibody.
  • the agent for treating macular degeneration may be for intraocular injection.
  • composition for the prevention or treatment of visual impairment disease is in the form of a UDCA formulation solubilized in water in the form of a clean aqueous solution, skin irritation and eye contact, which is a fundamental problem of the conventional crystalline UDCA, There is an advantage that can solve the problem that is causing.
  • the UDCA is solubilized in water in the form of a single molecule at a high concentration and maintains a stable state for a certain period of time, the conventional crystalline UDCA is limited to intermolecular aggregation. There is an advantage in that it can provide an intraocular injection that was impossible.
  • the composition for the prevention or treatment of visual impairment diseases is unable to transport UDCA at high concentrations in the blood due to limitations classified as enteric circulatory material, which is a characteristic of conventional crystalline UDCA preparations (tablets, capsules).
  • enteric circulatory material which is a characteristic of conventional crystalline UDCA preparations (tablets, capsules).
  • oral administration has the advantage of delivering a therapeutically active amount of UDCA to the eye when transported into the blood and across the retinal vascular barrier. Therefore, according to the present invention, it is possible to deliver a sufficient amount of UDCA effective for treatment only by oral administration to the eye, thereby eliminating the pain and fear caused by intraocular injection to patients and improving patient convenience.
  • composition for the prevention or treatment of visual impairment disease is well absorbed without causing adverse reactions to the retina during intraocular injection, inhibiting choroidal neovascularization, promoting retinal function recovery, and vascular endothelial growth factor.
  • VEGF vascular endothelial growth factor
  • composition for the prevention or treatment of visual impairment diseases has the advantage that can be used as eye drops for the eye to solve the stinging for the eye that is a disadvantage of the conventional crystalline UDCA. Therefore, the patient can eliminate the pain and fear associated with intraocular injection and increase patient convenience.
  • composition for the prevention or treatment of a visual impairment disease When using the composition for the prevention or treatment of a visual impairment disease according to an embodiment of the present invention there is little discomfort such as foreign body tingling and tingling of the eyes of the UDCA, stability of the UDCA formulation that does not precipitate even in the pH change Eye drops and intraocular injections for the prevention or treatment of high visual impairment diseases can be provided.
  • a composition for preventing or treating macular degeneration disease that can effectively deliver UDCA or tUDCA or gUDCA, which is an in vivo metabolite of UDCA, to the eye without adverse reaction of the retina.
  • the composition for preventing or treating macular degeneration disease according to the present invention is equivalent to or equal to Lucentis ® or Eylea ® , which is a protein antibody therapeutic agent that is a conventional intraocular injection. This is an advantage that can achieve the effect of preventing or treating macular degeneration.
  • the composition for preventing or treating macular degeneration disease according to the present invention may be administered with a conventional macular degeneration agent, it may have a synergistic effect on the treatment effect of macular degeneration disease.
  • the composition for the prevention or treatment of macular degeneration disease according to the present invention can achieve the effect of preventing or treating macular degeneration disease by oral administration or eye drops in addition to intraocular injection, oral administration and eye drops In this way there is an advantage that can maximize the convenience of the patient to the treatment of macular degeneration.
  • the composition for the prevention or treatment of macular degeneration disease according to the present invention is a low molecular chemical compound has the advantage that it is easy to manufacture compared to the high-cost antibody new drug and can provide a therapeutic agent at a low price due to low production cost .
  • the present invention can prevent or treat diseases causing visual impairments such as macular degeneration, glaucoma and diabetic retinal disease at a lower cost than antibody therapeutic agents such as Lucentis ® or Eylea ® . .
  • Figure 1 shows whether or not to generate a clean aqueous solution according to the pH value of the UDCA solution prepared in Example 3 of the present invention.
  • Figure 2 shows whether the generation of a clean aqueous solution according to the pH value of the UDCA solution prepared by Example 4 of the present invention.
  • Figure 3 shows whether or not to generate a clean aqueous solution according to the pH value of the UDCA solution prepared in Example 5 of the present invention.
  • Figure 4 shows whether or not to generate a clean aqueous solution according to the pH value of the UDCA solution prepared by Example 6 of the present invention.
  • Example 5 shows whether a clean aqueous solution is produced according to the pH value of the UDCA solution prepared by Example 7 of the present invention.
  • Figure 6 is a schematic diagram showing the overall experimental method of the efficacy test in a laser-induced choroidal neovascularization animal model (CNV mouse) to confirm the effect of choroidal neovascularization by intraocular injection of the composition according to the present invention.
  • CNV mouse laser-induced choroidal neovascularization animal model
  • Fig. 7a ⁇ 7f are also within the eye YSB201-1 (Example 8) ⁇ YSB201-3 (Example 10) or a conventional VEGF antibody treatment of Isle Liao ((Eylea ®, control) in accordance with embodiments of the present invention
  • fluorescence photographs and graphs of quantification of fluorescence are compared to show a reduction in laser induced choroidal damage (angiogenesis).
  • Figures 8a-8f are also within the eye YSB201-1 (Example 8) - YSB201-3 (Example 10), or conventional therapeutic antibody VEGG the Isle Liao ((Eylea ®, control) in accordance with embodiments of the present invention
  • the CT scan shows the extent of laser induced choroidal damage (angiogenesis) and a graph of the size of CNV lesions.
  • Figure 9a ⁇ Figure 9g is YSB201-1 (Example 8) ⁇ YSB201-3 (Example 10), each three times or Isle Liao (Eylea ® in accordance with embodiments of the present invention in the mouse retina is damaged by the laser, 15 days after the intraocular injection of the control group), it is a graph comparing the retinal potential diagrams by the single white light in the cancer-adapted state.
  • VEGF vascular endothelial growth factor
  • Figure 11 is a schematic diagram showing the overall experimental method of the efficacy test in a laser-induced choroidal neovascularization animal model for confirming the inhibitory effect of choroidal neovascularization by oral administration of the composition according to the invention, the mouse retina 10 days before the laser damage, YSB201-4 (125 mg / kg / day, Example 11), YSB201-4 (250 mg / kg), and olive oil as a control and solubilized ursodeoxycholic acid / day, Example 12) was orally administered once daily, and then administered orally until 10 days after the laser injury.
  • 12A-12D show the reduction of laser induced choroidal damage (angiogenesis) by oral administration of YSB201-4 (Example 11) and YSB201-5 (Example 12) according to embodiments of the present invention. It is a graph showing the fluorescence picture and the degree of fluorescence in comparison.
  • FIGS 13A to 13D show the degree of reduction of laser induced choroidal damage (angiogenesis) by oral administration of YSB201-4 (Example 11) and YSB201-5 (Example 12) according to embodiments of the present invention.
  • Retinal tomography pictures showing the retinal damage (CNV lesions) is a graph quantifying the size.
  • 14A to 14E illustrate olive oil, YSB201-4 (Example 11), and YSB201-5 (Example 12), respectively, 10 days before the laser eye damage was performed according to embodiments of the present invention. It is a graph comparing oral administration once a day, and after oral administration for 10 days after laser damage and retinal potential by single white light in a cancer-adapted state on day 15 of retinal injury by laser.
  • Figure 15 shows the oral administration of YSB201-4 (Example 11) or YSB201-5 (Example 12) according to embodiments of the present invention in the choroid and retina of a mouse damaged by laser vascular endothelial growth factor (VEGF) Data showing the effect on the degree of expression of is shown.
  • VEGF vascular endothelial growth factor
  • FIG. 16 and FIG. 17 are pharmacokinetic (PK) data showing changes over time of bile acids carried into plasma after oral administration of YSB201.
  • UDCA series bile acids refers to the sum of the concentrations of UDCA and its metabolites tUDCA, gUDCA having a cytoprotective effect, and the bile acids (other bile acids) functioning as a surfactant Means sum of concentrations of other bile acids except for the three types of bile acids.
  • PK pharmacokinetic
  • FIG. 22 is pharmacokinetic (PK) data showing the amount of change over time of UDCA and UDCA metabolites, UDCA, tUDCA, gUDCA, plus the concentrations of other bile acids, added to plasma after oral administration of YSB201.
  • PK pharmacokinetic
  • FIG. 23 is pharmacokinetic (PK) data showing the amount of change over time of the sum of the concentrations of UDCA and UDCA metabolites, UDCA, tUDCA and gUDCA, plus the concentrations of other bile acids after intraoral administration of YSB201. .
  • PK pharmacokinetic
  • FIG. 24 is pharmacokinetic (PK) data showing the change over time of UDCA and UDCA metabolites, ie, the sum of the concentrations of UDCA, tUDCA and gUDCA, plus the concentrations of other bile acids combined after oral administration of YSB201.
  • PK pharmacokinetic
  • treatment refers to any action by which administration of the composition of the present invention does not exacerbate, improve or beneficially alter the symptoms of a blind disorder.
  • the term “comprising as an active ingredient” or “comprising a therapeutically active amount” means a composition for the prevention or treatment of a visual impairment disease, a composition for intraocular injections, oral dosages, eye drops and intravenous injections.
  • the effect can be exhibited, for example, it means containing it to the extent that it can exhibit a preventive effect, a therapeutic effect and the like.
  • prevention refers to any action that results in at least a reduction in the parameters associated with the condition being treated after oral administration after the onset of the disease, followed by oral administration after the onset.
  • the term "clear aqueous solution” or "clean aqueous solution” means a solution state substantially free of visual precipitates.
  • visual disorder disease includes macular degeneration, glaucoma and diabetic retinal disease.
  • ursodeoxycholic acid ursodeoxycholic acid, UDCA
  • water soluble starch preparations water as an active ingredient, the composition for the prophylaxis or treatment of visual impairment diseases, including solubilized ursodeoxycholic acid in a clear aqueous solution to all pH values.
  • Ursodeoxycholic acid is a hydrophilic bile acid, is orally administrable and has a low concentration of only about 3% of the total bile acid in the human body, but is usually present in human bile and as a treatment for primary cholestatic cirrhosis by the US FDA. It is the only drug approved.
  • UDCA pharmacological effects
  • the pharmacological effects of UDCA include antioxidant, anti-inflammatory and anti-cell death. These effects are very important mechanisms for the treatment of starting disorders, and are more pronounced when UDCA acts as a single molecule. Therefore, the problem is how to effectively absorb and deliver the substance having the effect to the human eyeball.
  • Crystalline UDCA is classified as a skin deposit, and it is an amphiphilic molecule that has both hydrophilicity and lipophilic properties, so it forms dimers, tetramers, or micelles even though it is hardly dissolved in water and is dissolved in small amounts. Since it is difficult to act as a UDCA single molecule, the composition of the present invention makes it possible to solubilize UDCA crystals in water at high concentration so that it can function as a single molecule.
  • the aqueous solubilized UDCA stabilized the UDCA in water with maltodextrin, resulting in a more than 3,000-fold increase in the water-soluble solubility of pure UDCA molecules.
  • the solubilized ursodeoxycholic acid is a nonionic molecule having amphiphilic properties due to its molecular characteristics. Since it is dissolved in an aqueous solution in the form of a single molecule, the biodegradation between the cells and the cells is rapidly carried out by passive mechanisms as well as by the rapid dispersion rate due to the difference in concentration. The absorption rate of UDCA is dramatically increased because of the absorption.
  • solubilized UDCA which contains UDCA dissolved in water at a high concentration of up to 60 g / L, is the most ideal multifunctional drug for visual disorders such as macular degeneration with intraocular injection, oral administration, intravenous injection or eye drops. Can be prevented or treated.
  • the composition of the present invention is not limited thereto, but the solubility of UDCA in the composition may be at least about 3,000 times (0.15 M vs. 0.05 mM) of the solubility of crystalline UDCA in water, and at least about 300 times as compared to tUDCA. (0.15 M vs. 0.45 mM). Accordingly, Applicant has completed the present invention using a solubilized UDCA.
  • the composition is intravitreal injection
  • the UDCA of the composition can be delivered to the retina by intraocular injection and does not cause skin redness or inflammation in the eye after injection. .
  • the intraocular injection composition of the present invention can significantly inhibit choroidal neovascularization of the retina, promote retinal cell regeneration and down-regulate expression of vascular endothelial growth factor protein at the genetic level. have.
  • the composition when the composition is injected into the mouse eye, it is equivalent to the VEGF antibody injection Eylea (Eylea ® ) currently used as a standard macular degeneration agent. It was clearly confirmed that there was more effect.
  • the single dose of UDCA of the composition may be 50-100 ⁇ l at a concentration of 0.1-1.5 mg / ml.
  • concentration of UDCA once injected into the eye may be 0.1-3.0 mg / ml, and 0.1-1.5 mg / ml may be more suitable.
  • the UDCA concentration of the single injection is above 0.1, the effect is more evident, and when it exceeds 1.5 mg / ml, the effect is substantially equivalent to 1.5 mg / ml, thereby providing an economically efficient amount.
  • the amount of once injected daily 50 ⁇ 100 ⁇ l may be suitable.
  • the composition is intended for oral administration (Oral administration), to deliver the UDCA to the blood, and then to deliver a therapeutically active amount to the eye across the blood-retinal barrier.
  • Oral administration Oral administration
  • UDCA When orally administered in the form of tablets or capsules in the form of conventional UDCA formulations, about 30 to 60% of the total dose is absorbed along the intestines and dolma by nonionic passive diffusion, and in small amounts in the colon because crystalline UDCA is insoluble Only (20% of the intake capacity) is absorbed by the dolmen by an active transport mechanism.
  • UDCA Once UDCA is absorbed by hepatocytes, it can be conjugated to tUDCA and gUDCA, and tUDCA and gUDCA combined with UDCA are excreted by the first pass clearance in the liver as bile acids secreted in humans, so the concentration of UDCA in blood after oral administration is very high. Will be low. Therefore, there is no example provided as a composition for the prevention or treatment of visual disorders such as macular degeneration by carrying the UDCA to the eye with the existing UDCA formulation.
  • the composition when the composition is orally administered to the mouse (125 mg / Kg, Example 11), as a result of the pharmacokinetics study, unlike the conventional crystalline UDCA formulations (tablets, capsules)
  • the highest blood concentration of UDCA was 36.56 ⁇ 3.30 ⁇ g / mL, which was 12.7 times higher, and Tmax was 48 times faster at 5 minutes, resulting in higher concentrations of UDCA in the blood at the same dose of oral administration compared to conventional formulations. Prophylactic or therapeutic effects of disorders can be achieved.
  • the composition for oral administration of the present invention can significantly inhibit the choroidal neovascularization of the retina, promote regeneration of retinal cells and down-regulate expression of vascular endothelial growth factor protein at the gene level.
  • the experimental results of the embodiment related to the oral administration of the present invention and Figures 12a to 15 it was clearly confirmed that when the composition is orally administered to the mouse eye compared to the control has a significant effect.
  • the daily oral dose of UDCA of the composition may be 5 ⁇ 30 mg / kg.
  • the daily oral dose of the UDCA is more efficacious at 5 mg / kg or more, and if it exceeds 30 mg / kg is substantially equivalent to the 30 mg / kg effect, it can provide an economically efficient amount.
  • the daily oral dose of UDCA of the composition is 10 to 30 mg / kg, 15 to 30 mg / kg, 20 to 30 mg / kg, 25 to 30 mg / kg, 5 to 25 mg / kg, 10 to 25 mg / kg, 15 to 25 mg / kg, 20 to 25 mg / kg, 5 to 20 mg / kg, 10 to 20 mg / kg, 15 to 20 mg / kg, 5 to 15 mg / kg , 10-15 mg / kg.
  • the oral administration interval of UDCA may be administered at intervals of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and 7 days depending on symptoms.
  • the dosage is suitable for the human body, but is not limited thereto.
  • the composition may be orally administered 20 or more days and once a day. It is not limited to this.
  • the UDCA of the composition may start to be distributed in the eye between 5 to 10 minutes after oral administration, and stay for a predetermined time, that is, about 1 hour and then be washed out.
  • the composition is administered intravenously, and is directly administered to the blood so as not to block blood vessels and to cause skin irritation.
  • the composition may be administered as eye drops.
  • the UDCA of the composition administered with the eye drop may be transported from the outside of the eye to the eye without causing skin redness and adverse reactions around the eyes or the eyes.
  • the dose amount of UDCA of the composition may be 30 to 50 ⁇ l at a concentration of 0.1 mg / ml to 2.0 mg / ml.
  • the concentration of the UDCA of the eye drop once in the eye may be 0.1 mg / ml-2.0 mg / ml, and 0.1 mg / ml-1.5 mg / ml may be more suitable.
  • the UDCA concentration of the one eye drop is more than 0.1 mg / ml effect is more evident, and when it exceeds 2.0 mg / ml, 2.0 mg / ml and the effect is substantially equivalent, it can provide an economically efficient amount.
  • the proper number of eye drops per day of the UDCA of the composition is once to 10 times, but is characterized in that the number is not limited.
  • An eye drop according to an embodiment of the present invention may include a chelating agent, but is not limited thereto.
  • the chelating agent is not particularly limited as long as it is a compound that chelates metal ions.
  • ede such as edetic acid (ethylenediamine tetraacetic acid), monosodium edate, disodium edate, trisodium edate, tetrasodium edate, dipotassium edate, tripotassium edate, tetrapotassium edate Triacid or its salts;
  • Citric acid or salts thereof such as citric acid, monosodium citrate, disodium citrate, trisodium citrate, monopotassium citrate, dipotassium citrate and tripotassium citrate;
  • Metaphosphoric acid or salts thereof such as metaphosphoric acid, sodium metaphosphate and potassium metaphosphate; Pyrophosphoric acid or salts thereof, such as pyrophosphoric acid, t
  • the said edetic acid, citric acid, metaphosphoric acid, pyrophosphoric acid, polyphosphoric acid, malic acid, tartaric acid, phytic acid, and salts thereof shall also include the hydrates and organic solvates of each entity or salts thereof.
  • preferred chelating agents are edetic acid, salts of edetic acid (edate), citric acid, salts of citric acid (citrate), metaphosphoric acid, salts of metaphosphoric acid (methphosphate), polyphosphoric acid, polyphosphoric acid Salts (polyphosphates), sodium salts of edetic acid (including hydrates such as disodium edetate hydrate), citric acid (including hydrates such as citric acid monohydrate), sodium salts of sodium metaphosphate (sodium methacrylate), Sodium salt of polyphosphoric acid (sodium polyphosphate) may be more suitable.
  • the eye drop may further contain a preservative.
  • a preservative benzalkonium chloride, benzetonium chloride, chlorhexidine gluconate, paraben, sorbic acid, chlorobutanol, boric acid, chlorite, and the like, but benzalkonium chloride is more suitable.
  • a pharmaceutically acceptable additive can be added, if necessary, using a technique that is widely used, and for example, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium acetate, epsilon-aminocaproic acid, and the like. Buffering agents; Tonicity agents, such as sodium chloride, potassium chloride, and concentrated glycerin; Surfactants, such as polyoxyethylene sorbitan monooleate, polyoxyl stearate 40, and polyoxyethylene hardened castor oil, etc. can be selected and added as needed.
  • the visual impairment disease may be selected from the group consisting of macular degeneration, glaucoma and diabetic retinal disease.
  • the visual impaired disease may be macular degeneration.
  • the visually impaired disease may be wet-type age-related macular degeneration.
  • the composition may function at least one of inhibition of choroidal neovascularization, promotion of retinal function, and expression control of vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • the UDCA may be solubilized as a UDCA selected from soluble UDCA, water soluble UDCA derivatives, UDCA salts, and UDCA conjugated with amines.
  • a UDCA selected from soluble UDCA, water soluble UDCA derivatives, UDCA salts, and UDCA conjugated with amines.
  • water-soluble metal salts and water-soluble O-sulfonated bile acids of UDCA may also be included in the soluble UDCA salts.
  • the UDCA is solubilized with at least one UDCA selected from ursodeoxycholic acid (UDCA), taurusodeoxycholic acid (tUDCA) and glycoursodeoxycholic acid (gUDCA). It may be.
  • the taurusodeoxycholic acid (tUDCA) and glycoursodeoxycholic acid (gUDCA) are in vivo metabolites or derivatives of UDCA, tUDCA is a UDCA derivative conjugated with taurine, and gUDCA is a ur conjugated with glycine Means sodeoxycholic acid derivatives.
  • the UDCA may be present in a therapeutically active amount.
  • Existing amount in the therapeutically active amount indicates the extent to which the effect can be obtained as a composition for preventing or treating a visual disorder, an intraocular injection composition, an oral dosage form, and an eye drop, for example, a prophylactic effect, a therapeutic effect, and the like. It means to contain as much as possible.
  • the UDCA may include 0.01 to 5 parts by weight based on the total weight of the composition.
  • the UDCA may be less than 0.01 part by weight based on the total weight of the composition, the effect of preventing or treating a visual impairment disease may be insignificant, and when it exceeds 5 parts by weight, it may be difficult to prepare a clean aqueous solution.
  • the present invention is not limited thereto. However, when a precipitate is generated without a clear aqueous solution, it may be difficult to use as an intraocular injection, an oral administration, and an eye drop.
  • UDCA may be present as crystalline UDCA without dissolving in water, and if used as eye drops or intraocular injections, skin redness is likely due to crystalline UDCA.
  • Preparation with a clear aqueous solution is particularly intended to eliminate all crystalline UDCAs that cause skin flaws in the preparation of intraocular injections, eye drops, and intravenous injections.
  • UDCA may be used in an amount of 0.01 to 5 parts by weight, 0.1 to 5 parts by weight, 1 to 5 parts by weight, 2 to 5 parts by weight, 3 to 5 parts by weight, 4 to 5 parts by weight, based on the total weight of the composition, 0.01 to 3 parts by weight, 0.1 to 3 parts by weight, 1 to 3 parts by weight, 2 to 3 parts by weight, 0.01 to 2.5 parts by weight, 0.1 to 2.5 parts by weight, may be included as 1 to 2.5 parts by weight.
  • the UDCA content may be 0.05 to 0.2 parts by weight, more appropriately 0.04 to 0.16 parts by weight, and 0.04 to 0.07 parts by weight relative to the total weight of the composition.
  • the UDCA content is suitable for the total weight of the composition is 0.1 to 2.5 parts by weight, and 1 to 2.5 parts by weight may be more suitable.
  • the water-soluble starch preparation is maltodextrin
  • the maltodextrin may comprise 1 to 70 parts by weight based on the total weight of the composition.
  • maltodextrin may not be dissolved in water in an effective amount if less than 1 part by weight of maltodextrin may have a negligible effect of preventing or treating visual impairment, and in the case of more than 70 parts by weight, precipitation occurs due to UDCA or maltodextrin. Precipitating out of this aqueous solution may cause skin redness.
  • the maltodextrin is 1 to 60 parts by weight, 5 to 60 parts by weight, 10 to 60 parts by weight, 20 to 60 parts by weight, 30 to 60 parts by weight, 40 to 60 parts by weight based on the total weight of the composition.
  • the water-soluble starch compound is maltodextrin
  • the minimum weight ratio of maltodextrin to UDCA may be 1:30, but is not limited thereto, 1:25, 1:20, 1 : 15, 1:12, 1: 6.
  • the amount of high molecular weight, water soluble starch integrant used in the composition can be defined as the amount that is soluble in the selected concentration of ursodeoxycholic acid and in the pH ranges described herein.
  • the minimum amount of maltodextrin can be equally applied to tUDCA and gUDCA.
  • the pH value is 3 to 9
  • the water-soluble starch invert is maltodextrin
  • the minimum weight ratio of maltodextrin to UDCA is characterized in that 1:16 ⁇ 1:30
  • a composition for preventing or treating a blind disorder is provided.
  • the minimum weight ratio of maltodextrin to UDCA is 1:16 to 1:20, 1:16 to 1:25, 1:16 to 1:30, 1:20 to 1:25, 1: 20 to 1:30, 1:25 to 1:30.
  • the pH value is 6 to 9
  • the water-soluble starch invert is maltodextrin
  • the minimum weight ratio of maltodextrin to UDCA is 1:13 to 1:30, characterized in that
  • a composition for preventing or treating a blind disorder is provided.
  • the water-soluble starch inverts of the present invention comprise carbohydrates obtained directly from a portion or incomplete hydrolysis of starch under various pH conditions.
  • Non-limiting examples can be maltodextrin, dextrin, liquid glucose, corn syrup solids (dry powder of liquid glucose).
  • the corn syrup solids are Maltrin M200, and the maltodextrin may be Maltrin M700, but are not limited thereto, and may be manufactured under the trade name GPC of Grain Processing Corporation of Muscutin, Iowa, USA.
  • the starch invert When the starch invert is made of a polymer, the polymer may have at least one reducing end and at least one non-reducing end, and may be straight or branched chain.
  • the molecular weight may be at least about 100 mass units, or at least 106 mass units.
  • high molecular weight water-soluble starch inverts may have a molecular weight of at least 105 mass units.
  • the water-soluble non-starch polysaccharides can be obtained under various pH conditions by various hydrolysis or synthesis mechanisms. Non-limiting examples include dextran, guar gum, pectin, indigestible soluble fibers and the like.
  • the polymer When made of a polymer, the polymer has at least one reducing end and at least one non-reducing end.
  • the polymer may be straight or branched chain.
  • the molecular weight of the polysaccharide of the present invention may be at least about 100 mass units, or at least 106 mass units. Although not limited to this, the molecular weight is preferably at least 105 mass units.
  • the composition may be provided with a composition that is an aqueous solution comprising a combination of water soluble starch inverts and / or soluble non-starch polysaccharides.
  • the minimum weight ratio of liquid glucose (e.g. corn syrup) to UDCA required to prevent precipitation of the composition is about 1:25 (i.e., about 12.5 per 500 mg of UDCA in 100 ml of water). g, and about 25 g per gram of UDCA in 200 ml of water).
  • the minimum amount of dry powder of liquid glucose (corn syrup solids, such as Maltrin M200) required to prevent precipitation may be about 30 g per 1 g of UDCA in 100 ml of water and , About 60 g per 2 g of ursodeoxycholic acid in 200 ml of water, but is not limited thereto.
  • the minimum amount of soluble non-starch polysaccharides required to prevent precipitation may be about 50 g of guar rubber per 500 mg of ursodeoxycholic acid in 100 ml of water and in 100 ml of water 80 g of pectin per 500 mg of ursodeoxycholic acid.
  • the minimum required amount of high molecular weight water soluble starch inverts or soluble non-starch polysaccharides can be determined primarily by the absolute amount of UDCA in the solution formulation rather than by concentration.
  • composition of the present invention may further comprise dietary fiber when formulated for oral administration.
  • dietary fiber include, but are not limited to, guar rubber, pectin, psyllium, oat rubber, soy fiber, oat bran, corn cob, cellulose and wheat bran.
  • composition of the present invention may further comprise an emulsifier and suspending agent.
  • emulsifiers include guar gum, pectin, acacia, carrageenan, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol, povidone, tragacanth rubber, xanthan gum and sorbitan Ester is mentioned.
  • composition of the present invention may further include a pharmaceutically acceptable additive, and the pharmaceutically acceptable additive may include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose, Mannitol, malt, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, opiodry, sodium starch glycolate, lead carnauba, aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, White sugar, dextrose, sorbitol, talc and the like can be used.
  • the pharmaceutically acceptable additive may include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose, Mannitol, malt, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose,
  • compositions of the present invention can be administered in various parenteral formulations during actual clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. that are commonly used are used. Can be prepared.
  • Formulations for non-oral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, suppositories, injections.
  • the pH of the composition may be 1 to 10, and the pH may be in a clear aqueous solution in which the composition is dissolved.
  • the composition may be solubilized in water and may be in a clean aqueous solution without precipitation at the pH. That is, the composition may be in a clean aqueous state without precipitation of UDCA even after several months (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months).
  • the selected pH range that does not precipitate the compound is not limited thereto, but may be between about pH 1 and about pH 10, and about pH 3 to about pH 9 is suitable, but is not limited to, pH 6-8 More suitable, pH 6.5-8 is more suitable. It may also contain acids, bases and buffers if necessary to maintain the pH.
  • the pH adjusting material is not limited thereto, but HCl, H 3 PO 4 , H 2 SO 4 , HNO 3 , CH 3 COOH, citric acid, malic acid, tartaric acid, lactic acid, phosphate, and edetic acid ) And alkalis.
  • the nature and manner of use of such pH adjusting materials are well known in the art.
  • the pH range is any subset of pH levels that can be obtained in the water system, depending on the method of administration, that the various formulations remain in solution from the formulation and are injected into the eye or absorbed into the blood by oral administration.
  • the composition can be used as a formulation in solution without the composition according to the present invention being precipitated at prevailing pH levels in the oral cavity, stomach and intestine.
  • the UDCA remains free under acidic conditions as a free state despite being generally insoluble under acidic conditions.
  • the composition may further include a composition in the form of being soluble when added to the formulation.
  • the composition may provide a transparent and stable solution in order to provide a composition for the prevention and treatment of visual disorders such as macular degeneration in the form of intraocular injection, oral administration, eye drops or intravenous injection.
  • the composition may be a syrup, cream, paste or dried formulation.
  • the syrup is not limited thereto, but may be general syrup or thick syrup.
  • the composition may be formulated to dry powder.
  • the powder form of the composition is easy to store and handle, there is an advantage in the preparation of the composition of the desired form of the formulation.
  • the composition may be administered in combination with other macular degeneration diseases.
  • the other macular degeneration agent may be an anti-vascular endothelial growth factor antibody.
  • the agent for treating macular degeneration is not limited thereto, but may be Eylea ® , Avastin ® , Macugen ® , Lucentis ® , or a combination thereof.
  • the composition is not limited thereto, but may be co-administered with Visudyne drug treatment.
  • the agent for treating macular degeneration may be for intraocular injection.
  • compositions and methods may be used.
  • compounds have been described as being capable of being administered with solubilized ursodeoxycholic acid, other compounds may also be included.
  • Administration of the medicament may be performed at the same time as the administration of the aqueous solubilized UDCA composition, or the two may be the same or overlapping time periods (eg, the same time, the same date or the same). May be administered briefly.
  • mice were housed in cages for 3 mice.
  • the animal room environment was set at a temperature of 19 ⁇ 20 °C, humidity of 40 ⁇ 60%, and illuminance of 150 ⁇ 300 Lux.
  • mice (Orient Bio, Korea) were image-guided laser (Phoenix, USA) at 3, 6, 9, 12 o'clock.
  • the laser was irradiated in the direction, where the laser conditions were 532 nm, 100 ms / 70 ms, 200 mW and the spot size was 50 ⁇ m.
  • CNV laser-induced choroidal neovascularization
  • FFA Fundus Fluorescein Angiography
  • CNV mice Both eyes of CNV mice were shaken and blood vessels were stained by intraperitoneal injection of 1% Fluorescein (Sigma, USA). Mice were anesthetized and laser-induced neovascularization 5 minutes after fluorescein injection was taken with a Micron IV image equipment. CNV lesions were expressed by calculating the corrected total fluorescence (CTF) using the Image J program, and the equation for obtaining the CTF is as follows.
  • CTF corrected total fluorescence
  • mice were injected with a mixture of ketamine (30 mg / kg) and xylazine hydrochloride (2.5 mg / kg) into the abdominal cavity for general anesthesia, and the electrodes were contacted with the skin, tail and cornea, respectively, to retina.
  • An electrical potential test was performed. The response was obtained by stimulating the retina with mono-white light, and the amplitude measured from the bone of A wave to the peak of B wave was measured and evaluated as an index of retinal function.
  • mice After 15 days of laser injury, the mice were euthanized and the eyeballs were removed to remove the sclera, cornea and lens, and the choroid and retinal layers were separated. After washing the choroid and the retina twice with PBS, Pro-PREP (iNtRON, Korea) was added and homogenized tissue was extracted and extracted protein was quantified using BCA protein assay kit (Thermo scientific, USA) and 20 ⁇ g Protein was used for Western blot. After blocking for 1 hour in 5% skim milk, the primary antibody was diluted 1: 1000 to TBS-T and overnight at 4 ° C. After washing with TBS-T, the secondary antibody was diluted 1: 5000 in 3% skim milk, treated at room temperature for 1 hour, and then detected using a Chemi Image System.
  • Pro-PREP iNtRON, Korea
  • the YSB201-4 test substance was orally administered to the C57BL / 6 mouse model, and the pharmacokinetic trends in the plasma and biological organs of drug components were analyzed over time.
  • Various bile acids used as standard materials include gUDCA, tUDCA, UDCA, GCA (Glycocholic acid hydrate), TCA (Taurocholic acid sodium salt hydrate), CA (Cholic acid), GCDCA (Glycochenodeoxycholic acid), TCDCA (Taurochenodeoxycholic acid) , Sigma-Aldrich with Glycodeoxycholic acid (GDCA), Taurodeoxycholic acid (TDCA), Chenodeoxycholic acid (CDC), Deoxycholic acid (DCA), Glycolithocholic acid sodium salt (GLCA), Tarololithocholic acid (TLCA), and Lithocholic acid (LCA) It was purchased from Sigma-Aldrich.
  • the analytical instrument is a 2695 Alliance HPLC (high performance liquid chromatography) instrument of Water Corporation of the United States, BilePak II column (4.6125 mm, JASCO, Japan) and EnzymePak 3 ⁇ -HSD column (4.635 mm, JASCO, Japan) of JASCO, Japan. Used together.
  • HPLC high performance liquid chromatography
  • the amount of individual dose was converted to oral doses based on the measured body weight, and a single syringe was used for oral administration.
  • the solid feed was re-supplied after 4 hours after oral administration.
  • mice C57BL / 6 females
  • mice were weighed from 16 to 18 g and purified for 7 days before being used for the experiment.
  • Animals were used at around ⁇ 20% of total mean body weight at the first dose.
  • KOTEC Proxyeongtaek, Gyeonggi-do, Korea
  • the environment of the animal room was set at a temperature of 19-25 ° C, a humidity of 40-60%, and an illumination intensity of 150-300Lux.
  • the cleaning of the animal room and the cage were carried out according to the standard working instructions of the Institute of Human Biotechnology, Inje University Busan Paik Hospital.
  • composition and dosing schedule of the control and test groups are shown in Table 1.
  • the bile acid analysis system of JASCO, Japan was used for analysis of blood and biological samples of mice.
  • Waters Alliance HPLC system Waters ® 2695 Alliance HPLC system
  • fluorescence detector excitation: 345 nm, emission: 470 nm
  • a clear stock solution of solubilized UDCA was prepared comprising native UDCA and water soluble starch with low glucose equivalents.
  • Ursodeoxycholic acid solution prepared as shown in Table 3 formed a clear aqueous solution without visual precipitation at pH 10.3, 9.2, 6.7, but precipitated at pH 5.4.
  • a clear stock solution of solubilized UDCA was prepared comprising native UDCA and water soluble starch with low glucose equivalents.
  • Example 2 it was prepared according to the same guidelines as in Example 1 except that 720 g of maltodextrin as one high molecular weight water-soluble starch integer per 60 g of UDCA was used. As shown in Table 3, the prepared UDCA solution formed a clean aqueous solution without visual precipitation at pH 9.6, 7.3, 6.5, 6.1, but precipitated at pH 5.5.
  • a clear stock solution of solubilized UDCA was prepared comprising native UDCA and water soluble starch with low glucose equivalents.
  • Example 2 it was prepared according to the same guidelines as in Example 1 except that 750 g of maltodextrin as one high molecular weight water-soluble starch invert per 50 g of UDCA was used. At this time, 5.7 g of sodium hydroxide pellets were dissolved in 400 ml of purified water and used. Ursodeoxycholic acid solution prepared as shown in Table 3 to form a clear aqueous solution without visual precipitation at pH 9.5, 8.9, 7.9, 7.1, 6.0. However, at pH 5.5, a precipitate formed. 1 is a photograph showing whether a clean aqueous solution is generated by putting a UDCA solution at each pH value in a test tube.
  • a clear stock solution of solubilized UDCA was prepared comprising native UDCA and water soluble starch with low glucose equivalents.
  • Example 2 it was prepared according to the same guidelines as in Example 1 except that 350 g of maltodextrin as one high molecular weight water-soluble starch invert per 17.5 g of UDCA was used. At this time, 2.0 g of sodium hydroxide pellets were dissolved in 400 ml of purified water and used.
  • the prepared UDCA solution as shown in Table 3 formed a clear aqueous solution without visual precipitation at pH 9.4, 7.1, 6.1, 5.5. However, at pH 5.1, a precipitate formed.
  • 2 is a photograph showing whether a clean aqueous solution is generated by putting a UDCA solution at each pH value in a test tube.
  • a clear stock solution of solubilized UDCA was prepared comprising native UDCA and water soluble starch with low glucose equivalents.
  • Example 2 it was prepared according to the same guidelines as in Example 1 except that 350 g of maltodextrin as one high molecular weight water-soluble starch invert per 14 g of UDCA was used. At this time, 1.7 g of sodium hydroxide pellets were dissolved in 400 ml of purified water and used. As prepared in Table 3, the prepared UDCA solution formed a clear aqueous solution without visual precipitation at pH 9.6, 6.1, 5.1. However, at pH 4.0, a precipitate formed. 3 is a photograph showing whether a clean aqueous solution is generated by putting a UDCA solution at each pH value in a test tube.
  • a clear stock solution of solubilized UDCA was prepared comprising native UDCA and water soluble starch with low glucose equivalents.
  • Example 2 it was prepared according to the same guidelines as in Example 1 except that 750 g of maltodextrin was used as one high molecular weight water-soluble starch invertant per 25 g of UDCA. At this time, 2.8 g of sodium hydroxide pellets were dissolved in 400 ml of purified water and used. As prepared in Table 3, the prepared UDCA solution formed a clear aqueous solution without visual precipitation at pH 9.0, 8.0, 7.0, 6.0, 5.1, 4.1, 2.9. 4 is a photograph showing whether a clean aqueous solution is generated by putting a UDCA solution at each pH value in a test tube.
  • 0.3 g of sodium hydroxide pellets were dissolved in 500 ml of purified water.
  • 1.0 g of UDCA, 0.5 g of tUDCA, and 0.5 g of gUDCA were dissolved in the sodium hydroxide solution under stirring at room temperature.
  • 60 g of maltodextrin was added to the transparent solution little by little and stirred.
  • the preservative was then added to the clear solution obtained with sonication at high throughput (750 W, 20 kHz) in an amount suitable for pharmaceutical formulation and the pH was adjusted by dropwise addition of HCl.
  • Purified water was added to adjust to a total of 1,000 ml.
  • the prepared UDCA solution formed a clear aqueous solution without visual precipitation at pH 10.2, 9.0, 8.1, 7.1, 6.1, 5.1, 4.1, 2.9. 5 is a photograph showing whether a clean aqueous solution is generated by putting the UDCA solution at each pH value in a test tube.
  • a stock solution of YSB201 was prepared by first dissolving UDCA (25 g) in 400 mL NaOH (2.7 g) solution. Next, 745 g of maltodextrin was added little by little to the obtained clear solution under vigorous stirring. Subsequently, the pH was adjusted to 6.8 by dropwise addition of HCl while performing ultrasonic decomposition (750 W, 20 kHz) at high throughput. Next, the obtained solution was adjusted to 1.0 L with pharmaceutical grade water. The stock solution of YSB201 was diluted with medical water to reach a desired UDCA concentration and filtered and sterilized using a 0.2 ⁇ m filterware filtration device under sterile conditions.
  • YSB201-1 (Example 8) and YSB201-2 (Example 9)
  • YSB201-3 (Example 10)
  • YSB201-4 (Example 11)
  • YSB201-5 (Example 12) test materials were prepared.
  • the filtration is important for sterilization but is not intended to remove particulate matter since the solution is already transparent.
  • Positive control Eilia (Eylea ® ) of the intraocular administration group was prepared at 10 mg / ml using PBS.
  • test materials were stored at 4 ° C.
  • PURPOSE The aim of this study was to develop a laser-induced choroidal neovascularization (CNV) mouse model that induces choroidal neovascularization, which is characteristic of senile macular degeneration, by irradiating laser to the choroid of the mouse, and intraocular injection of test substance YSB201 to inhibit choroidal neovascularization. To confirm (see FIG. 6).
  • CNV laser-induced choroidal neovascularization
  • mice used for administration were 36 C57BL / 6 females and the body weight ranged from 16 to 18 g / mouse for 6 days and used for the experiment. Animals were used at around ⁇ 20% of the total mean body weight at the first dose.
  • mice were anesthetized by dropping Shandong (Troferin Eye Drop, Hanmi Pharm. Co., Ltd.) into both eyes for 10 minutes, and then injecting ketamine (30 mg / kg) and xylazine hydrochloride (2.5 mg / kg) intraperitoneally. Substances were injected three times, once every two days, 2 ⁇ l each in the mouse's eyes using an Ultra-Micro Pump (35 ⁇ l syringes filled with 100 ⁇ l glass syringes).
  • FFA Fundus Fluorescein Angiography
  • FIG. 7A to 7E show fluorescence of the choroidal neovascularization inhibitory effect according to the choroidal neovascularization and the administered substances produced by injecting Fluorescein after 14 days of laser injury, and FIG. 7F quantifies it.
  • CTF is calculated and graphed after excluding values over 2 ⁇ 10 6 .
  • Positive control Eylea (Eylea ® ) was injected once into each eye 2 ⁇ l
  • test substance YSB201 was injected into each eye 2 ⁇ l 1, 3, 6 days after laser injury (laser injury).
  • choroidal neovascularization was observed in the group treated with YSB201 and Eylea ® .
  • the test substance YSB201-1 (Example 8, Fig. 7c), YSB201-2 (Example 9, Fig. 7d) and Isle Liao (Eylea ®, Fig. 7b) were significantly inhibit CNV statistically (p ⁇ 0001).
  • OCT Optical Coherence Tomography
  • FIG. 8a to 8e are tomography images of the retina to observe choroidal neovascularization
  • FIG. 8f is a graph quantifying the size of CNV lesions.
  • mice choroidal neovascularization was observed in the retinal cross-section after 14 days of laser injury, and in the group in which YSB201 (Examples 8 to 10) fm was administered directly into the eye, compared to the control group (Vehicle, PBS) Small retinal lesions (CNV lesions) were observed.
  • the test substance YSB201-1 (Example 8, Fig. 8c) and YSB201-2 (Example 9, Fig. 8d) and Isle Liao (Eylea ®, Fig. 8b) inhibited significantly the CNV statistically (p ⁇ 0001).
  • 9A to 9F are test results of cancer compliance with the intraocular administration group after 15 days of laser injury and measuring the degree of response of the retina to light.
  • VEGF vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • Eylea ® only blocks the VEGF activity secreted from the choroid and retinal cells due to the nature of the protein antibody and does not prevent the increase of VEGF expression in the choroid and retinal cells.
  • Eylea ® has a disadvantage in that it does not fundamentally and continuously inhibit the intracellular VEGF expression at the gene level.
  • YSB201 treated group (Example 8 and Example 10) for the can be seen that the amount of VEGF expression in the choroid and retina cells much more reduced than Isle Liao (Eylea ®) which, unlike the mechanism of action of the Republic of Liao (Eylea ®)
  • Isle Liao Isle Liao
  • VEGF expression in the choroid and retinal cells is down regulated at the gene level, indicating that angiogenesis can be fundamentally and continuously inhibited.
  • PURPOSE This study was designed to develop a CNV mouse model that induces choroidal neovascularization, which is characteristic of senile macular degeneration, by irradiating laser to the choroid of the mouse and orally administering test substance YSB201 (Examples 11 and 12). To reach the intraocular across and to see if there is an effect of inhibiting the expression of choroidal neovascularization (see FIG. 11).
  • mice used for administration were 24 C57BL / 6 females, and the body weight ranged from 16 to 18 g of mice and purified for 6 days before being used for the experiment. Animals were used at around ⁇ 20% of the total mean body weight at the first dose.
  • the dose of the individual dose was converted and administered orally by using a sonde in a disposable syringe.
  • Oral administration was performed from 11 AM to 2 PM once a day 10 days before the laser damage treatment. Even after laser damage, oral administration was performed once a day for 10 days between 11 am and 2 pm, and mice were euthanized on day 15 to prepare a sample for measurement.
  • FFA Fundus Fluorescein Angiography
  • FIG. 12a to 12c are photographs showing the neovascularization inhibitory effect according to the choroidal neovascularization and the administered substances generated by injecting Fluorescein after 13 days of laser injury, and FIG. In order to correct the background, the CTF is calculated and graphed except for a value over 2 ⁇ 10 6 .
  • YSB201 As a result, the oral administration of YSB201 (Examples 10 and 11) showed a higher reduction of CNV lesions compared to the control group receiving olive oil. 125 mg / kg / day, Example 11) showed the best efficacy (p ⁇ 0.001). YSB201-5 (250 mg / Kg) showed a decreased tendency of CNV lesions than the control group, but was not statistically significant.
  • OCT Optical Coherence Tomography
  • FIG. 13A to 13C are tomography images of the retina to observe CNV
  • FIG. 13D is a graph showing the numerical value of CNV lesions.
  • choroidal neovascularization was observed in the retinal cross-section after 13 days of laser injury in all mice, and in the group orally administered YSB201-4 (Example 11), the control group (vehicle, olive oil administration) group Much smaller retinal lesions (CNV lesions) were observed.
  • 14A to 14E are test results of dark adaptation of the oral administration group after 14 days of laser injury and measuring the degree of response of the retina to light.
  • FIG. 15 shows Western blot expression of vascular endothelial growth factor (VEGF) in the choroid and retina of the oral administration group after 14 days of laser injury.
  • VEGF vascular endothelial growth factor
  • VEGF protein As a result, the expression of VEGF protein was increased in the eyes of CNV mice without oral administration and mice injected with olive oil, but the amount of VEGF protein expression was increased in the oral administration of YSB201-4 (Example 11). This markedly decreased.
  • YSB201 The purpose of this study is to confirm the possibility of treatment of macular degeneration with a clean solution of solubilized UDCA (YSB201).
  • YSB201 using CNV mouse model that induces choroidal neovascularization characteristic of wet macular degeneration by irradiating laser to the choroid of mouse. It was confirmed that the neovascular inhibition effect of.
  • the laser was irradiated partially to the Bruch membrane of the mouse to induce choroidal neovascularization.
  • the test was conducted 9 days before the laser irradiation, YSB201-4 (Example 11) orally administered at a dose of 125 mg / Kg and YSB201-5 (Example 12) at 250 mg / Kg to confirm the prevention and treatment of macular degeneration.
  • the study was divided into two trials: YSB201 was administered directly to intraocular injection to confirm its potential as a treatment for macular degeneration.
  • YSB201-1 Example 8
  • YSB201-2 Example 9
  • retinal tomography confirmed the pattern of CNV
  • individuals with CNV formation were observed in the PBS-injected group and showed retinal edema, and partial retina degradation was also found.
  • YSB201-4 125 mg / ml, Example 11
  • YSB201-4 Example 11
  • YSB201-5 Example 12
  • the retinal potential test which was performed to test the retinal function of the mouse, resulted in a decrease in amplitude, a typical finding of retinal disease in CNV mice.
  • the retinal potential is divided into a wave and b wave, and a wave (receptor potential) is a negative wave generated in the cell by optical stimulation, and it can be seen that it reflects the function of the cell.
  • the b-wave (Muller cell potential) was generated in Mueller cells during the transmission of cell information and appeared as a sudden positive potential wave. In the normal retina, a wave is negative and b wave is positive, so the potential difference between the two waves can be used to determine the function of the retina. In clinical macular degeneration, a and b waves are not lost, but amplitude is known to decrease. In set-1, YSB201-4 (Example 11) showed the highest efficacy and effectively reduced the expression of VEGF. Laser injury On day 13, fluorescein (fluorescein) was injected intraperitoneally and confirmed by fluorography. As a result, the retinal injury (CNV lesion) was found to be significantly reduced in the group receiving YSB201.
  • fluorescein fluorescein
  • YSB201 is effective in reducing CNV by effectively inhibiting VEGF protein expression when administered orally and directly to the retina.
  • test substance YSB201-4 125 mg / kg, Example 11
  • test substance YSB201-4 125 mg / kg, Example 11
  • drug components are transported into plasma over time and sequentially treated across the retinal vascular barrier to the eye. It is a test to analyze the pharmacokinetic trend that is carried in an active amount and that is implemented in other living tissues.
  • concentration of UDCA in the blood of groups 1, 2, 3, and 4 of the test mice reached the highest blood concentration [36.53 ⁇ 3.32 (standard error value)] ⁇ g / mL between 5 and 10 minutes immediately after oral administration.
  • the degree of loss of blood UDCA concentration tended to decrease (FIGS. 16 and 17).
  • YSB201-4 125 mg / kg, Example 11
  • Pharmacokinetic modeling was performed on orally administered drugs to calculate the main pharmacokinetic parameters (Table 7). As a result, the time to reach the maximum blood concentration appears between 5 and 10 minutes and the half-life is estimated to be about 1.5 to 2 hours.
  • YSB201-4 125 mg / kg, Example 11
  • Intraocular samples were analyzed after oral administration.
  • oral administration of YSB201-4 shows that UDCA and UDCA family bile acids can be delivered to the eye at high concentrations and inhibit choroidal neovascularization while effectively restoring the function of damaged retinal cells.
  • the stomach of the test group was uniformly crushed, and then extracted and analyzed.
  • the amount of UDCA in the stomach of test mice 1, 2, 3, and 4 rapidly increased after 5 minutes and disappeared after 4 hours (FIGS. 20 and 21).
  • UDCA clean water solution (YSB201) was able to deliver high concentrations of UDCA to the plasma and subsequently delivered therapeutically active amounts of UDCA across the retinal vascular barrier to the eye.
  • intraocular UDCA did not immediately disappear and remained effective for about 2 hours, and the UDCA metabolite, tUDCA, was transported into the eye and maintained for 4 hours, thus preventing and treating macular degeneration by oral administration of YSB201.
  • tUDCA UDCA metabolite

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Abstract

La présente invention concerne une composition contenant de l'acide ursodésoxycholique (UDCA) pour la prévention ou le traitement d'une déficience visuelle. Plus spécifiquement, la présente invention concerne une composition pharmaceutique, qui permet une administration orale, une injection intraoculaire ou une administration de gouttes oculaires, par de l'acide ursodésoxycholique solubilisé aqueux, ce qui conduit à d'excellents effets de prévention ou de traitement de maladies provoquant une déficience visuelle, telles que la dégénérescence maculaire, le glaucome et la rétinopathie diabétique.
PCT/KR2018/001770 2017-02-09 2018-02-09 Composition contenant de l'acide ursodésoxycholique pour la prévention ou le traitement d'une déficience visuelle WO2018147685A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
JP2019520858A JP6901739B2 (ja) 2017-02-09 2018-02-09 ウルソデオキシコール酸を含有する視覚障害の予防または治療用組成物
BR112019009202-1A BR112019009202A2 (pt) 2017-02-09 2018-02-09 Composição para a prevenção ou o tratamento de danos visuais compreendendo ácido ursodeoxicólico
EP18751361.9A EP3581185A4 (fr) 2017-02-09 2018-02-09 Composition contenant de l'acide ursodésoxycholique pour la prévention ou le traitement d'une déficience visuelle
GB1904993.1A GB2571644A (en) 2017-02-09 2018-02-09 Composition containing ursodeoxycholic acid for prevention or treatment of visual impairment
MX2019008963A MX2019008963A (es) 2017-02-09 2018-02-09 Composicion para la prevencion o el tratamiento de deterioros visuales que comprenden acido ursodesoxicolico.
CN201880005395.0A CN110177556A (zh) 2017-02-09 2018-02-09 含有熊去氧胆酸的用于预防或治疗视力障碍的组合物
RU2019111077A RU2723988C1 (ru) 2017-02-09 2018-02-09 Композиция для предупреждения или лечения нарушений зрения, содержащая урсодезоксихолевую кислоту
AU2018218696A AU2018218696B2 (en) 2017-02-09 2018-02-09 Composition for the prevention or the treatment of visual impairments comprising ursodeoxycholic acid
CA3039500A CA3039500C (fr) 2017-02-09 2018-02-09 Composition destinee a la prevention ou au traitement de troubles visuels comprenant de l'acide ursodesoxycholique
SG11201906169QA SG11201906169QA (en) 2017-02-09 2018-02-09 Composition for the prevention or the treatment of visual impairments comprising ursodeoxycholic acid
US16/400,969 US20190255074A1 (en) 2017-02-09 2019-05-01 Composition for the prevention or the treatment of visual impairments comprising ursodeoxycholic acid
AU2020204384A AU2020204384B2 (en) 2017-02-09 2020-06-30 Composition for the prevention or the treatment of visual impairments comprising ursodeoxycholic acid
US17/224,731 US20210252022A1 (en) 2017-02-09 2021-04-07 Composition for the prevention or the treatment of visual impairments comprising ursodeoxycholic acid
AU2021204660A AU2021204660A1 (en) 2017-02-09 2021-07-02 Composition for the prevention or the treatment of visual impairments comprising ursodeoxycholic acid

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KR1020180015944A KR102252450B1 (ko) 2017-02-09 2018-02-08 우르소데옥시콜산을 함유하는 시각장애 예방 또는 치료용 조성물

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WO2021099973A1 (fr) * 2019-11-22 2021-05-27 Shilpa Medicare Limited Compositions injectables d'acide ursodésoxycholique

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JP6771698B1 (ja) * 2018-12-18 2020-10-21 参天製薬株式会社 ウルソデオキシコール酸を含有する老視の治療または予防剤
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WO2021099973A1 (fr) * 2019-11-22 2021-05-27 Shilpa Medicare Limited Compositions injectables d'acide ursodésoxycholique

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