WO2019132120A1 - 알라린을 주성분으로 하는 요독증 치료제 - Google Patents
알라린을 주성분으로 하는 요독증 치료제 Download PDFInfo
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- WO2019132120A1 WO2019132120A1 PCT/KR2018/003601 KR2018003601W WO2019132120A1 WO 2019132120 A1 WO2019132120 A1 WO 2019132120A1 KR 2018003601 W KR2018003601 W KR 2018003601W WO 2019132120 A1 WO2019132120 A1 WO 2019132120A1
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- Prior art keywords
- alarin
- present
- uremic
- uremia
- therapeutic agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- GLP gallinin-like peptide
- Uremia refers to syndromes that exhibit various clinical symptoms resulting from functional organs abnormalities of various organs or tissues caused by harmful components of urine accumulated in the blood.
- the urine disease is caused by the breakdown of renal function, If it can not be excreted in vitro, symptoms will develop.
- Clinical symptoms of uremia include, for example, digestive system abnormalities such as anorexia, vomiting, vomiting, bad breath, stomatitis, enteritis, nervous system disorders such as insomnia, indifference, depressed state, depressed state, mirror face, coma, anemia, erythropoiesis , Hypertension, ischemic heart disease, pericarditis, myocarditis and other abnormalities of the circulatory system, pigmentation, pruritus, and skin abnormality such as subcutaneous bleeding, and uremic symptoms are caused by uremic substances accumulating in the blood.
- the uremic materials are various, for example, more than a dozen such as methyl guanidine, indole compounds, malondialdehyde, creatinine,?
- uremic substances are essentially involved in the onset of uremia, and it is not known whether or not the uremic syndrome is a sole substance or a complex action caused by these plural substances. It is reported to be large. These facts clearly show the difficulty of treating uremia by drugs. Whatever its onset, uremic patients can face a deadly condition, unless they release the uremic substance out of the body or lower the concentration of the uremic substance by appropriate means.
- therapies that are effective in the treatment of uremia include kidney transplantation, dialysis therapy and activated carbon formulation therapy. The advantage of the latter two treatments is that, by physical means, a plurality of uremic substances Can be removed or diluted nonspecifically.
- the active carbon formulation is used as an underwear.
- the action mechanism of the active carbon formulation is due to the adsorption of various kinds of uremic substances produced in the digestive system, and the excretion of the substances in the body. Therefore, although the activated carbon preparation therapy is called internal replication, it can be regarded as a physical treatment means as well as dialysis therapy.
- the active carbon formulation is not a satisfactory treatment method because it has difficulty in taking the active carbon formulation and has a tendency to cause constipation.
- dialysis has been the most effective treatment for uremia.
- the efficacy of dialysis therapy for withdrawing uremic substances from the body even if renal function has been abolished, has the advantage of avoiding patient death due to uremic substances, Complications due to therapy are becoming a new problem.
- anemia, renal osteodystrophy, renal cancer, extramedullary membrane, aluminum osteoporosis, amyloidosis, crystalline arthritis and multiple cystic neoplasia are complications of long-term dialysis.
- there is a problem in the medical economy such as a deterioration in the social life of a patient who frequently goes to a dialysis facility and a high treatment cost.
- Patent Document 1 Korean Patent Publication No. 1989-0001535
- a pharmaceutical composition containing a mixture of several salts of an alpha -keto analog of basic < RTI ID 0.0 > a-amino < / RTI > and essential amino acids of branched chain, in the form of a poorly soluble or topically soluble coated tablet. It is only starting.
- Patent Document 1 still has a problem that it is difficult to provide a satisfactory uremic treatment effect, and there is still a demand for a therapeutic agent which can be used for a long period of time without exerting any other adverse effects and excellent in the treatment of uremia.
- Alarin derived from a splice variant of GalNAn-like peptide (GALP) RNA is biosynthesized in vivo and synthesized genetically, which is a peptide having the amino acid sequence of APAHRSSTFPKWVTKTERGRQPLRS .
- GALP GalNAn-like peptide
- the Patent Document 2 merely suggests the use of alarin as a therapeutic agent for neurogenic keratitis, retinol disease, acute and chronic inflammatory and autoimmune diseases, obesity or growth deficit, wound healing, uterine leiomyoma, endometriosis, and anorexia.
- the present inventors have recognized and solved the above-mentioned conventional problems, and as a result, they have found that a peptide, which can be simply provided, exhibits excellent improvement effects in cisplatin-induced uremic lysis,
- the inventors of the present invention have found that the present invention can be used as a therapeutic agent for uremia by paying attention to the fact that it can be used as a therapeutic agent that can be used for a long period of time without causing side effects of the conventional therapeutic agents which burden patients such as gastrointestinal disorders, .
- the main object of the present invention is to solve the problems of the prior art based on the background of the above-mentioned conventional uremia treatment agents, and it is an object of the present invention to provide a therapeutic agent
- the present invention is not limited to the treatment of uremic disease and does not cause side effects such as anemia, renal osteodystrophy, extramedullary inflammation, aluminum osteoarthritis, amyloidosis, crystalline arthritis, multiple cystic neoplasia and diarrhea, And to provide a therapeutic agent for uremia which can be used for a long period of time without causing a high treatment cost.
- Another object of the present invention is to provide a method which can more easily provide a uremic treatment agent having the above-mentioned characteristics.
- the invention may also be directed to achieving other objects, which may be easily derived by those skilled in the art, from these objects and from the overall description of the present specification, in addition to the above-mentioned and obvious objects.
- the inventors of the present invention have recognized and solved the problems in the conventional uremic treatment as described above. As a result of studying to solve the above problems, the inventor of the present invention found that the neural peptide, alarin cisplatin-induced uremic disease, The present invention has been accomplished on the basis of this finding that it is possible to provide a therapeutic agent for uremic disease based on alarin.
- the uremic treatment agent of the present invention is characterized by containing alarin as a main component.
- the above-mentioned Alarin is a human-derived allyl trifluoroacetate salt having the following amino acid sequence:
- the above-mentioned Alarin has a molecular weight of 2894.29 and is characterized by having the following molecular formula:
- the uremic treatment agent of the present invention is characterized in that 0.5 mg to 10 mg of Alarin is formulated to be administered on the basis of 60 kg of an adult.
- the formulation is an injection.
- the formulation is injected by subcutaneous muscle injection.
- Figure 1 shows the gene splice variant of galenic-like peptides (GALPs) from Murine.
- Fig. 2 shows the result of comparison of amino acid sequences of allalanin according to a preferred embodiment of the present invention from Muirring, rat, short-tailed monkey and human.
- FIG. 3 is a graph showing the blood urea nitrogen (BSA) concentration in the cisplatin-induced urease Sprague-Dawley rat model according to the embodiment of the present invention in the control and the group treated with the therapeutic agent of the present invention.
- BSA blood urea nitrogen
- FIG. 4 is a graph showing the concentration of creatinine (CRE) in a cisplatin-induced urease Sprague-Dawley rat model according to an embodiment of the present invention in a group administered with the control and the therapeutic agent of the present invention
- CRE creatinine
- FIG. 5 is a graph showing histopathological examination results in the control group and the group treated with the therapeutic agent of the present invention in a cisplatin-induced urease Sprague-Dawley rat model according to an embodiment of the present invention , Where 1 point is the occurrence of less than 25% tubular necrosis between the cortex and cortical junction, 2 points 25% to 50% tubular necrosis, 3 points between 50% and 75% Necrosis occurred in 4 patients and tubular necrosis occurred in 75% of patients.
- Figure 6 is a micrograph of histopathological examination results in the control group and in the group treated with the therapeutic agent of the present invention in a cisplatin-induced urease Sprague-Dawley rat model according to an embodiment of the present invention to be.
- the uremic treatment agent according to the preferred embodiment of the present invention contains alarin as a main component.
- Alarin used in the uremic treatment of the present invention may be human-derived allalan having the following amino acid sequence:
- Alarin used as a uremic treatment agent of the present invention may be a pharmaceutically acceptable salt of a human-derived allalan having the above amino acid sequence.
- Such pharmaceutically acceptable salts are those salts which possess the biological effects of the free acids and bases of the particular compound and which are not biologically or otherwise undesirable.
- the compounds of the present invention may have functional groups that are sufficiently acidic, sufficiently basic, or both, and thus may react with any of a number of inorganic or organic bases, and inorganic and organic acids to produce pharmaceutically acceptable salts.
- Exemplary pharmaceutically acceptable salts include salts prepared by reaction of a compound of the invention with an inorganic or organic acid or inorganic base, for example, salts including: trifluoroacetate, sulfate, But are not limited to, sulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, But are not limited to, maleic anhydride, maleic anhydride, maleic anhydride, maleic anhydride, maleic anhydride, maleic anhydride, maleic anhydride, Maleic anhydride, Diolate, hexa-l, 6-diolate, benzoate, chlorobenzoate, methyl benzoate, di Hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,
- Alarin used in the uremic treatment of the present invention may be a human-derived allyl trifluoroacetate salt having the following amino acid sequence:
- said Alarin has a molecular weight of 2894.29 and has the following molecular formula:
- the above-mentioned Alarin can be stably stored at -20 ⁇ 5 ° C.
- the uremic treatment agent of the present invention may be administered with 0.5 to 10 mg of Alarin based on an adult having a body weight of 60 kg in order to provide a therapeutic effect on uremia.
- the uremic treatment agent of the present invention may be administered 1.0 to 5.0 mg of allalin on the basis of an adult having a body weight of 60 kg to provide a therapeutic effect on uremia.
- the uremic treatment agent of the present invention may be administered with 2.0 to 5.0 mg of allergen on the basis of an adult weighing 60 kg in order to provide a therapeutic effect on uremia.
- the uremic treatment agent of the present invention can administer 3.0 mg to 5.0 mg of allalan on the basis of an adult weighing 60 kg to provide a therapeutic effect of uremia.
- the uremic treatment agent of the present invention may be administered with 4.0 to 5.0 mg of allaline on the basis of an adult weighing 60 kg to provide a therapeutic effect on uremia.
- the uremic treatment agent of the present invention is administered in an amount of 0.5 mg to 10 mg, preferably 1.0 mg to 5.0 mg, based on an adult of 60 kg body weight, mg, more preferably 2.0 mg to 5.0 mg, more preferably 3.0 mg to 5.0 mg, and most preferably 4.0 mg to 5.0 mg.
- the formulation can be, but is not limited to, preferably an injection.
- the formulation may be one which is preferably injected by subcutaneous injection, although not exclusively.
- a solvent, a solubilizing agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid esters of sorbitan can be used.
- Cisplatin-induced uremia evaluated the effect of test substance administration on the improvement of uremia in a Sprague-Dawley rat model.
- G1 is a normal control group to which excipient is administered
- G2 is an excipient-induced control group
- G3 is a test substance at a dose of 10 ⁇ g / 1 mL / head
- G4 is a test substance at 20 ⁇ g / 1 mL / head.
- the test substance is the Alarin (human) trifluoroacetate salt of the present invention.
- Cisplatin was administered intraperitoneally (IP) and intravenous (IV) in the case of test substances.
- test substance (G3-G4) was administered once at 8 hours (day 0) after cisplatin administration and at 5 mg / 10 mL / kg.
- the animal was fixed in a correction frame, and slowly injected at a rate of 1 mL / min through a vein using a syringe equipped with a 26-gauge needle.
- the intraperitoneal administration was carried out by fixing the animal by the adriamycin fixation method and intraperitoneally using a syringe equipped with a 26-gauge needle
- Body weight was measured on the day of the test substance, on the day of induction and on the day of the autopsy (Day 7). As a result, the body weight of all the test substance - administered group on the day of the autopsy showed no significant difference from the normal control group.
- Blood samples were taken from the jugular vein of all surviving animals prior to the administration of the test substance, before and after the cisplatin administration, and then injected into a tube containing the coagulant. The mixture was allowed to stand at room temperature for about 15 minutes and then coagulated for 10 minutes at 3,000 rpm (BUN) and creatine (CRE) in the blood using a blood biochemical analyzer (7180 Hitachi, Japan). Blood biochemical test results showed significantly lower BUN and CRE levels in the high dose group than in the induced control group.
- the animals were anesthetized with ether on an autopsy day, the animals were euthanized, the kidneys were harvested and fixed in 10% neutral buffered formalin solution, and the fixed tissues were subjected to anesthesia, dehydration, paraffin embedding and hematoxylin & eosin After staining and other tissue treatments, specimens for histopathological examination were prepared and examined by optical microscope (Olympus BX53, Japan). Histopathological examination results showed that the lesion level in the high dose group of the test substance was significantly lower than that in the induced control group.
- test substance when the test substance was administered in a single dose of 10 ⁇ g / 1 mL / head and 20 ⁇ g / 1 mL / head in the urachal-daury rat model in which uremic effect was induced by administering cystine under the test conditions, BUN and CRE levels in the test substance 20 ⁇ g / 1 mL / head group showed a significant difference compared to the vehicle control group. Histopathologic examination showed a dose - related change trend and a significant change in lesion level. Therefore, it is considered that the alanine (alarin) of the present invention has an effect on the improvement of uremia in the cisplatin-induced urea model.
- the therapeutic agent for uremic dysgenesis comprising allantoin as a main component of the present invention having the above-mentioned structure is characterized in that alarin, which is a kind of peptide which exists in vivo and can be simply synthesized, is the main component, , Nephrotic dystrophy, epicarditis, aluminum osteoporosis, amyloidosis, crystalline arthritis, multiple cystic neoplasms, diarrhea, etc., and does not result in quality deterioration and high treatment costs in patients' social life due to treatment
- the present invention provides an excellent uremic treatment agent which can be used over a long period of time, and provides an excellent action and effect for solving the problems associated with the above-mentioned conventional uremic treatment.
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Abstract
Description
Claims (6)
- 알라린(Alarin)을 주성분으로 포함함을 특징으로 하는 요독증 치료제.
- 제1항에 있어서, 상기 알라린(Alarin)은 하기 아미노산 서열을 갖는 인간 유래 알라린 트리플루오로아세테이트 염(trifluoroacetate salt)임을 특징으로 하는 요독증 치료제:H-Ala-Pro-Ala-His-Arg-Ser-Ser-Thr-Phe-Pro-Lys-Trp-Val-Thr-Lys-Thr-Glu-Arg-Gly-Arg-Gln-Pro-Leu-Arg-Ser-OH-트리플루오로아세테이트 염.
- 제1항에 있어서, 상기 알라린(Alarin)은 분자량 2894.29로, 다음 분자식을 갖는 것임을 특징으로 하는 요독증 치료제:C127H206N43O38
- 제1항에 있어서, 상기 요독증 치료제는 알라린(Alarin) 0.5mg 내지 10mg을 성인 60kg 기준에 투여되도록 제형화된 것임을 특징으로 하는 요독증 치료제.
- 제4항에 있어서, 상기 제형은 주사제임을 특징으로 하는 요독증 치료제.
- 제4항에 있어서, 상기 제형은 피하근육 주사에 의해 투입되는 것임을 특징으로 하는 요독증 치료제.
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201880070679.8A CN111278452B (zh) | 2017-12-26 | 2018-03-27 | 以阿林肽为活性成分的尿毒症药物 |
JP2020543435A JP6991615B2 (ja) | 2017-12-26 | 2018-03-27 | アラリンを主成分とする尿毒症治療剤 |
US16/758,022 US20200254059A1 (en) | 2017-12-26 | 2018-03-27 | Therapeutic agent of uremia containing alarin as the main ingredient |
US17/400,629 US11642392B2 (en) | 2017-12-26 | 2021-08-12 | Therapeutic agent of uremia containing alarin as the main ingredient |
Applications Claiming Priority (2)
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KR10-2017-0179309 | 2017-12-26 | ||
KR1020170179309A KR101827245B1 (ko) | 2017-12-26 | 2017-12-26 | 알라린을 주성분으로 하는 요독증 치료제 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
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US16/758,022 A-371-Of-International US20200254059A1 (en) | 2017-12-26 | 2018-03-27 | Therapeutic agent of uremia containing alarin as the main ingredient |
US17/400,629 Continuation US11642392B2 (en) | 2017-12-26 | 2021-08-12 | Therapeutic agent of uremia containing alarin as the main ingredient |
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WO2019132120A1 true WO2019132120A1 (ko) | 2019-07-04 |
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PCT/KR2018/003601 WO2019132120A1 (ko) | 2017-12-26 | 2018-03-27 | 알라린을 주성분으로 하는 요독증 치료제 |
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US (2) | US20200254059A1 (ko) |
JP (1) | JP6991615B2 (ko) |
KR (1) | KR101827245B1 (ko) |
CN (1) | CN111278452B (ko) |
WO (1) | WO2019132120A1 (ko) |
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KR101827245B1 (ko) * | 2017-12-26 | 2018-02-08 | (주)제이유타이드 | 알라린을 주성분으로 하는 요독증 치료제 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20080024203A (ko) * | 2005-07-08 | 2008-03-17 | 도레이 가부시끼가이샤 | 요독증 개선을 위한 치료제 및 처치방법 |
US20090149374A1 (en) * | 2005-03-07 | 2009-06-11 | Barbara Kofler | Neuropeptides |
US20110070211A1 (en) * | 2009-08-14 | 2011-03-24 | Allergan, Inc. | Methods of Treating Cancer Using Galanin Retargeted Endopepidases |
US20120251519A1 (en) * | 2011-03-29 | 2012-10-04 | Allergan, Inc. | Endopeptidase Treatment of Smooth Muscle Disorders |
KR101827245B1 (ko) * | 2017-12-26 | 2018-02-08 | (주)제이유타이드 | 알라린을 주성분으로 하는 요독증 치료제 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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ES2336575T3 (es) * | 2005-09-22 | 2010-04-14 | Biocompatibles Uk Limited | Polipeptidos de fusion glp-1 (peptido-1 similar al glucagon) con resistencia aumentada a la peptidasa. |
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2017
- 2017-12-26 KR KR1020170179309A patent/KR101827245B1/ko active IP Right Grant
-
2018
- 2018-03-27 US US16/758,022 patent/US20200254059A1/en not_active Abandoned
- 2018-03-27 WO PCT/KR2018/003601 patent/WO2019132120A1/ko active Application Filing
- 2018-03-27 CN CN201880070679.8A patent/CN111278452B/zh active Active
- 2018-03-27 JP JP2020543435A patent/JP6991615B2/ja active Active
-
2021
- 2021-08-12 US US17/400,629 patent/US11642392B2/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090149374A1 (en) * | 2005-03-07 | 2009-06-11 | Barbara Kofler | Neuropeptides |
KR20080024203A (ko) * | 2005-07-08 | 2008-03-17 | 도레이 가부시끼가이샤 | 요독증 개선을 위한 치료제 및 처치방법 |
US20110070211A1 (en) * | 2009-08-14 | 2011-03-24 | Allergan, Inc. | Methods of Treating Cancer Using Galanin Retargeted Endopepidases |
US20120251519A1 (en) * | 2011-03-29 | 2012-10-04 | Allergan, Inc. | Endopeptidase Treatment of Smooth Muscle Disorders |
KR101827245B1 (ko) * | 2017-12-26 | 2018-02-08 | (주)제이유타이드 | 알라린을 주성분으로 하는 요독증 치료제 |
Non-Patent Citations (1)
Title |
---|
ZHANG, ZHENWEN ET AL.: "Intracerebroventricular Injection of Alarm Increased Glucose Uptake in Skeletal Muscle of Diabetic Rats", PLOS ONE, vol. 10, no. 10, 2015, pages 1 - 13, XP055623260 * |
Also Published As
Publication number | Publication date |
---|---|
CN111278452A (zh) | 2020-06-12 |
KR101827245B1 (ko) | 2018-02-08 |
JP6991615B2 (ja) | 2022-02-03 |
KR101827245B9 (ko) | 2021-07-14 |
JP2021500408A (ja) | 2021-01-07 |
CN111278452B (zh) | 2023-08-29 |
US20200254059A1 (en) | 2020-08-13 |
US11642392B2 (en) | 2023-05-09 |
US20220031804A1 (en) | 2022-02-03 |
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