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WO2020171374A1 - Composition pharmaceutique comprenant rivoceranib pour l'inhibition de la néovascularisation oculaire et procédé d'inhibition de la néovascularisation oculaire à l'aide de celle-ci - Google Patents

Composition pharmaceutique comprenant rivoceranib pour l'inhibition de la néovascularisation oculaire et procédé d'inhibition de la néovascularisation oculaire à l'aide de celle-ci Download PDF

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Publication number
WO2020171374A1
WO2020171374A1 PCT/KR2020/000155 KR2020000155W WO2020171374A1 WO 2020171374 A1 WO2020171374 A1 WO 2020171374A1 KR 2020000155 W KR2020000155 W KR 2020000155W WO 2020171374 A1 WO2020171374 A1 WO 2020171374A1
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WIPO (PCT)
Prior art keywords
corneal
neovascularization
pharmaceutical composition
group
ocular neovascularization
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Ceased
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PCT/KR2020/000155
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English (en)
Korean (ko)
Inventor
윤경철
우제문
김낙성
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Industry Foundation of Chonnam National University
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Industry Foundation of Chonnam National University
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition for suppressing ocular neovascularization comprising riboceranib and apatinib in the past, and a method for suppressing ocular neovascularization using the same, and more particularly, to a method for suppressing ocular neovascularization using the same It relates to a pharmaceutical composition comprising riboseranib, which can inhibit blood vessels and prevent and treat related eye diseases.
  • the cornea is the only avascular tissue in the human body and must be maintained without blood vessels to maintain the transparency of the eye.
  • an angiogenesis factor and an angiogenesis inhibitor are in balance in the cornea, but when angiogenesis factors increase, blood vessels grow.
  • corneal neovascularization occurs due to various causes such as corneal infection, inflammation and immune response, swelling, and limbic cell deficiency, not only serious visual impairment occurs, but also the prognosis of secondary corneal transplantation is poor.
  • Angiogenesis factors include vascular endothelial growth factor (VEGF), basic fibroblast growth factor, matrix metalloproteinase, and insulin-like growth factor. factor), but the most important factor is VEGF, an endothelial factor.
  • VEGF vascular endothelial growth factor
  • VEGFR-2 is known as the most important receptor mediating most cellular responses to VEGF in corneal neovascularization.
  • angiogenesis inhibitors such as substrate P (substance P)
  • procedures such as laser photocoagulation or photodynamic therapy have been attempted, but they have not been used since they have been clearly proven.
  • VEGF inhibitors which can inhibit angiogenesis in macular degeneration of the eye
  • they have also been applied to the treatment of corneal neovascularization.
  • bevacizumab Avastin
  • ranicizumab Ranicizumab
  • aflibercept Eylea
  • riboceranib YN968D1 is a tyrosine kinase inhibitor selectively targeting Vascular Endothelial Growth Factor-2 (VEGF-2), which can be administered orally and is VEGF in cancer cells. It has been reported that it can inhibit the formation of new blood vessels by inhibiting mediated endothelial cell migration and proliferation, and is currently in clinical trials as an anticancer agent to treat various human cancers. However, little is known about the inhibitory role of riboseranib in the neovascularization of the eye, and no literature has been reported on the results of applying a drug containing riboseranib as an active ingredient to the cornea for ophthalmic treatment purposes.
  • VEGF-2 Vascular Endothelial Growth Factor-2
  • the inventors of the present invention were studying to develop a new substance that inhibits or treats corneal neovascularization, while eye drops containing riboceranib as an active ingredient reduce the corneal neovascularization area and the neovascularization index in an animal model. It was confirmed that the number and area of blood vessels and lymph vessels in tissues can be reduced.
  • an object of the present invention is to provide a pharmaceutical composition for inhibiting ocular neovascularization comprising riboseranib.
  • Another object of the present invention is to provide a method for inhibiting ocular neovascularization, comprising administering a pharmaceutical composition for suppressing ocular neovascularization comprising riboseranib to the eye of an individual other than human.
  • Another object of the present invention relates to the use of riboseranib to inhibit ocular neovascularization.
  • the present invention relates to a pharmaceutical composition for inhibiting ocular neovascularization comprising riboceranib, and the pharmaceutical composition according to the present invention exhibits an effect of inhibiting angiogenesis of the cornea.
  • eye drops containing riboseranib as an active ingredient can reduce the corneal neovascular area and the neovascular index in an animal model, and reduce the number and area of blood vessels and lymph vessels in corneal tissue.
  • One aspect of the present invention is a pharmaceutical composition for inhibiting ocular neovascularization comprising riboseranib.
  • the inhibition of angiogenesis may be achieved through a decrease in an area of an angiogenesis, a decrease in an angiogenesis index, an area of a blood vessel, or an area of a lymphatic vessel.
  • neovascular area refers to a value expressed as a percentage of the area corresponding to the neovascularization within a specific area range.
  • neovascularization index refers to a value expressed by scoring vascularization according to the degree of length within a specific range.
  • blood vessel area herein can be measured through immunohistochemical staining using a blood vessel marker antibody.
  • Anti-CD31 may be used as the vascular marker antibody, but is not limited thereto.
  • lymphatic vessel area herein can be measured through immunohistochemical staining using a lymphatic vessel marker antibody.
  • Anti-LYVE-1 may be used as the lymphatic marker antibody, but is not limited thereto.
  • the eyeball may be selected from the group consisting of a cornea, a sclera, and a retina, and may be, for example, a cornea, but is not limited thereto.
  • the composition includes diabetic retinopathy, macular degeneration, retinopathy of prematurity, corneal graft rejection, retrolental fibroplasia, glaucoma, retinal vein obstruction, ischemic retinopathy, and It may be to prevent or treat a disease selected from the group consisting of hypoxia, but is not limited thereto.
  • the composition may be any one formulation selected from the group consisting of eye drops, injections, granules, tablets, pills, capsules, gels, syrups, suspensions, emulsions, drops and solutions, for example, may be eye drops. However, it is not limited thereto.
  • the composition contains riboseranib from 0.01 to 2.00% (w/v), 0.01 to 1.80% (w/v), 0.01 to 1.60% (w/v), 0.01 to 1.40% (w/v), 0.01 to 1.20 % (w/v), 0.01 to 1.00% (w/v), 0.01 to 0.80% (w/v), 0.01 to 0.60% (w/v), 0.05 to 2.00% (w/v), 0.05 to 1.80 % (w/v), 0.05 to 1.60% (w/v), 0.05 to 1.40% (w/v), 0.05 to 1.20% (w/v), 0.05 to 1.00% (w/v), 0.05 to 0.80 % (w/v), 0.05 to 0.60% (w/v), 0.10 to 2.00% (w/v), 0.10 to 1.80% (w/v), 0.10 to 1.60% (w/v), 0.10 to 1.40 % (w/v), 0.10 to 1.20% (w/v), 0.10 to 1.00% (w/v), 0.10 to
  • the pharmaceutical composition of the present invention can be used as a pharmaceutical composition comprising a pharmaceutically effective amount of riboseranib and/or a pharmaceutically acceptable carrier.
  • the term "pharmaceutically effective amount” means an amount sufficient to achieve the above-described efficacy or activity of riboseranib.
  • Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used in formulation, and are lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate. , Microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, etc., but are limited thereto. no.
  • the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like in addition to the above components.
  • the pharmaceutical composition according to the present invention can be administered to mammals including humans by various routes.
  • the mode of administration may be any method commonly used, for example, may be administered by oral, dermal, intravenous, intramuscular, subcutaneous, or the like, and preferably parenterally.
  • a suitable dosage of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, mode of administration, age, weight, sex, pathological condition, food, administration time, route of administration, excretion rate and response sensitivity of the patient, and is usually As such, a skilled physician can easily determine and prescribe an effective dosage for the desired treatment or prophylaxis.
  • the daily dosage of the pharmaceutical composition of the present invention is 1 to 20 ul, 1 to 18 ul, 1 to 16 ul, 1 to 14 ul, 1 to 12 ul, 1 to 10 ul, 2 to 20 ul, 2 to 18 ul, 2 to 16 ul, 2 to 14 ul, 2 to 12 ul, 2 to 10 ul, 5 to 20 ul, 5 to 18 ul, 5 to 16 ul, 5 to 14 ul, It may be 5 to 12 ul or 5 to 10 ul, for example, 8 ul, but is not limited thereto.
  • the pharmaceutical composition of the present invention is prepared in unit dosage form by formulating using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person having ordinary knowledge in the technical field to which the present invention belongs, or It can be manufactured by placing it in a multi-volume 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 extract, powder, granule, tablet, capsule, or gel (eg, hydrogel), and may additionally include a dispersant or a stabilizer. .
  • Another aspect of the present invention is a method for inhibiting ocular neovascularization, comprising administering a pharmaceutical composition for suppressing ocular neovascularization comprising riboseranib to the eyes of animals other than humans.
  • the inhibition of angiogenesis may be achieved through a decrease in an area of angiogenesis, a decrease in the vascularization index, a decrease in the corneal vascularization index, a decrease in the number of blood vessels, or a decrease in the number of lymphatic vessels.
  • the eyeball may be selected from the group consisting of a cornea, a sclera, and a retina, and may be, for example, a cornea, but is not limited thereto.
  • the method may be to prevent or treat a disease selected from the group consisting of diabetic retinopathy, macular degeneration, retinopathy of prematurity, corneal graft rejection, posterior lens fibrosis, glaucoma, retinal vein obstruction, ischemic retinopathy, and hypoxia. It is not limited.
  • the composition may be any one formulation selected from the group consisting of eye drops, injections, granules, tablets, pills, capsules, gels, syrups, suspensions, emulsions, drops and solutions, for example, may be eye drops. However, it is not limited thereto.
  • the composition contains riboseranib from 0.01 to 2.00% (w/v), 0.01 to 1.80% (w/v), 0.01 to 1.60% (w/v), 0.01 to 1.40% (w/v), 0.01 to 1.20 % (w/v), 0.01 to 1.00% (w/v), 0.01 to 0.80% (w/v), 0.01 to 0.60% (w/v), 0.05 to 2.00% (w/v), 0.05 to 1.80 % (w/v), 0.05 to 1.60% (w/v), 0.05 to 1.40% (w/v), 0.05 to 1.20% (w/v), 0.05 to 1.00% (w/v), 0.05 to 0.80 % (w/v), 0.05 to 0.60% (w/v), 0.10 to 2.00% (w/v), 0.10 to 1.80% (w/v), 0.10 to 1.60% (w/v), 0.10 to 1.40 % (w/v), 0.10 to 1.20% (w/v), 0.10 to 1.00% (w/v), 0.10 to
  • the present invention relates to a pharmaceutical composition for suppressing ocular neovascularization including riboceranib and a method for suppressing ocular neovascularization using the same, wherein the eye drops containing riboceranib as an active ingredient include corneal neovascularization area and Since it reduces the neovascular index and reduces the number and area of blood vessels and lymphatic vessels in the corneal tissue, it can be effectively used to suppress corneal neovascularization.
  • FIG. 1 is a graph showing the effect of reducing corneal vascular area of an eye drop-administered group after induction of corneal neovascularization according to an embodiment of the present invention.
  • FIG. 2 is a photograph showing the effect of inhibiting corneal neovascularization of an eye drop-administered group after induction of corneal neovascularization according to an embodiment of the present invention.
  • FIG. 3 is a graph showing the effect of reducing the vascularization index of an eye drop-administered group after induction of corneal neovascularization according to an embodiment of the present invention.
  • Figure 4a is a photograph showing the blood vessel suppression of the eye drop-administered group using immunohistochemical staining in which a vascular marker antibody is treated in a flat mount of a corneal tissue after induction of corneal neovascularization according to an embodiment of the present invention.
  • FIG. 4B is a graph showing the blood vessel suppression of an eye drop-administered group using immunohistochemical staining that treats a vascular marker antibody in a flat mount of corneal tissue after induction of corneal neovascularization according to an embodiment of the present invention.
  • 5A is a photograph showing the suppression of lymphatic vessels in an eye drop-administered group using immunohistochemical staining for treating a lymphatic marker antibody in a flat mount of corneal tissue after induction of corneal neovascularization according to an embodiment of the present invention.
  • 5B is a graph showing the suppression of lymphatic vessels in an eye drop-administered group using immunohistochemical staining for treating a lymphatic marker antibody in a flat mount of a corneal tissue after induction of corneal neovascularization according to an embodiment of the present invention.
  • a pharmaceutical composition for inhibiting ocular neovascularization comprising riboceranib.
  • % used to indicate the concentration of a specific substance is (weight/weight)% for solids/solids, (weight/volume)% for solids/liquids, and Liquid/liquid is (vol/vol)%.
  • Riboceranib eye drops were prepared using a commercialized powder (past name Afatinib, Apatinib mesylate, Selleckchem.com). For dilution, 0.1% (1 mg/ml, w/v) and 0.5% (5 mg/ml, w/v) riboseranib eye drop formulations were prepared using carboxymethycellulose.
  • ketamine hydrochloride For anesthesia of the animals, 50 mg/kg of ketamine hydrochloride and 10 mg/kg of xylazine were injected intramuscularly, and proparacaine eye drops were instilled in the eyes.
  • An 8-week-old C57BL/6 mouse (Daehan Biolink, Eumseong, South Korea) contacted a 2 mm diameter paper soaked with 0.1 N NaOH on the corneal surface of the right eye for 10 seconds to induce neovascularization by corneal burns. After 10 seconds, the corneal surface was washed with 15 ml sterile saline.
  • the cornea and the epithelium of the corneal limbus were removed while rotating parallel to the corneal limbus using a corneal knife. After removal of the corneal epithelium, moxifloxacin (Vigamox, Alcon, US) eye drops were immediately instilled.
  • moxifloxacin Vigamox, Alcon, US
  • mice Animal behavior, food and water intake were not restricted during the experiment. Mice were divided into the following 6 groups according to the method of eye drop treatment one week after induction of corneal neovascularization: control group without eye drop solution; Physiological saline (PBS) eye drops administration group; 0.1% (w/v) riboceranib eye drops administration group; 0.5% (w/v) riboseranib eye drops administration group; And 0.5% (5 mg/ml, w/v) bevacizumab eye drops administration group.
  • PBS Physiological saline
  • riboseranib and bevacizumab eye drops were prepared by diluting in carboxymethycellulose. 2 ul of eye drop was administered 3 times a day to the mouse inducing corneal neovascularization.
  • biomicroscopy was performed by taking pictures of 10 mice at a standardized magnification of 10 times, respectively, on the 7th day of treatment (DAY 7) and the 14th day after treatment (DAY 14) after induction of corneal neovascularization.
  • a picture of corneal neovascularization was taken using a camera attached to a slit lamp biological microscope (F-801s, Nikon, Japan). The photo was converted to a file (tagged information file format) with a resolution of 624 X 480 pixels.
  • R corneal diameter
  • L length of new blood vessels from the limbus to the central cornea.
  • the 0.5% (w/v) bevacizumab-treated group and the 0.5% (w/v) riboseranib-treated group compared to the control group, the PBS-treated group, and the 0.1% (w/v) riboseranib group. Equally, the corneal neovascular area was significantly suppressed.
  • mice after induction of corneal neovascularization on the 7th day of treatment (DAY 7), on the 14th day after treatment (DAY 14), physiological saline (PBS) administration group, 0.1% (w/v) riboseranib eye drops administration group, 0.5% (w/ v) The corneal angiogenesis index of the riboseranib eye drops administration group and 0.5% (w/v) bevacizumab eye drop administration group was analyzed.
  • PBS physiological saline
  • the area of blood vessels in the corneal tissue of the bevacizumab ophthalmic solution administration group was compared and analyzed.
  • mice treated with eye drops were fixed in 10% formalin, embedded in paraffin, cut to a thickness of 4 ⁇ m, and fixed on a slide glass. Then, the slide glass was immersed in ethanol, blocked with bovine serum albumin, Normal horse serum, Vector, Burlingame, CA, USA, and then vascular marker antibody (No: sc-18916, FITC- conjugated rat anti-CD31, Santa Cruz, Dallas, TX, USA) were treated at room temperature for 3 hours.
  • vascular marker antibody No: sc-18916, FITC- conjugated rat anti-CD31, Santa Cruz, Dallas, TX, USA
  • the present invention relates to a pharmaceutical composition for suppressing ocular neovascularization including riboceranib and a method for suppressing ocular neovascularization using the same, wherein the eye drops containing riboceranib as an active ingredient include corneal neovascularization area and Since it reduces the neovascular index and reduces the number and area of blood vessels and lymphatic vessels in the corneal tissue, it can be effectively used to suppress corneal neovascularization.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant Rivocéranib pour l'inhibition de la néovascularisation oculaire et un procédé d'inhibition de la néovascularisation oculaire à l'aide de celle-ci. Une goutte oculaire comprenant Rivocéranib en tant que principe actif réduit une zone cornéenne néovascularisée et un indice de vascularité dans un modèle animal et le nombre et la surface des vaisseaux et des conduits lymphatiques dans les tissus cornéens et, de ce fait, peut être efficacement utilisé pour inhiber la néovascularisation cornéenne.
PCT/KR2020/000155 2019-02-19 2020-01-06 Composition pharmaceutique comprenant rivoceranib pour l'inhibition de la néovascularisation oculaire et procédé d'inhibition de la néovascularisation oculaire à l'aide de celle-ci Ceased WO2020171374A1 (fr)

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KR10-2019-0019442 2019-02-19
KR1020190019442A KR20200101160A (ko) 2019-02-19 2019-02-19 리보세라닙을 포함하는 안구 신생혈관 억제용 약학 조성물 및 이를 이용한 안구 신생혈관 억제 방법

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016166761A1 (fr) * 2015-04-14 2016-10-20 Tiltan Pharma Ltd. Polythérapies et utilisations associées dans le traitement du cancer
WO2017120601A1 (fr) * 2016-01-08 2017-07-13 Clearside Biomedical, Inc. Méthodes et dispositifs pour le traitement de troubles oculaires postérieurs avec l'aflibercept et d'autres substances biologiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016166761A1 (fr) * 2015-04-14 2016-10-20 Tiltan Pharma Ltd. Polythérapies et utilisations associées dans le traitement du cancer
WO2017120601A1 (fr) * 2016-01-08 2017-07-13 Clearside Biomedical, Inc. Méthodes et dispositifs pour le traitement de troubles oculaires postérieurs avec l'aflibercept et d'autres substances biologiques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JEONG, J. H. ET AL.: "Therapeutic effect of apatinib-loaded nanoparticles on diabetes-induced retinal vascular leakage", INTERNATIONAL JOURNAL OF NANOMEDICINE, vol. 1 1, 2016, pages 3101 - 3109, XP055735340 *
KIM, K. L. ET AL.: "Apatinib, an inhibitor of vascular endothelial growth factor receptor 2, suppresses pathologic ocular neovascularization in mice", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 58, no. 9, 2017, pages 3592 - 3599, XP055735334 *
LEE, J. E. ET AL.: "Apatinib-loaded nanoparticles suppress vascular endothelial growth factor-induced angiogenesis and experimental corneal neovascularization", INTERNATIONAL JOURNAL OF NANOMEDICINE, vol. 12, 2017, pages 4813 - 4822, XP055735338 *

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