PL3466425T3 - Zastosowanie pochodnych glutarimidu w leczeniu chorób eozynofilowych - Google Patents

Zastosowanie pochodnych glutarimidu w leczeniu chorób eozynofilowych

Info

Publication number
PL3466425T3
PL3466425T3 PL18206980T PL18206980T PL3466425T3 PL 3466425 T3 PL3466425 T3 PL 3466425T3 PL 18206980 T PL18206980 T PL 18206980T PL 18206980 T PL18206980 T PL 18206980T PL 3466425 T3 PL3466425 T3 PL 3466425T3
Authority
PL
Poland
Prior art keywords
treatment
eosinophilic diseases
glutarimide derivatives
glutarimide
derivatives
Prior art date
Application number
PL18206980T
Other languages
English (en)
Polish (pl)
Inventor
Vladimir Evgenievich Nebolsin
Tatyana Alexandrovna Kromova
Anastasia Vladimirovna RYDLOVSKAYA
Alexander Grigorievich Chuchalin
Original Assignee
Obschestvo S Ogranichennoi Otvetstvennostiyu "Pharmenterprises"
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Obschestvo S Ogranichennoi Otvetstvennostiyu "Pharmenterprises" filed Critical Obschestvo S Ogranichennoi Otvetstvennostiyu "Pharmenterprises"
Publication of PL3466425T3 publication Critical patent/PL3466425T3/pl

Links

Classifications

    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Otolaryngology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PL18206980T 2013-11-14 2014-11-12 Zastosowanie pochodnych glutarimidu w leczeniu chorób eozynofilowych PL3466425T3 (pl)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
RU2013150861/15A RU2552929C1 (ru) 2013-11-14 2013-11-14 Фармацевтическая композиция, содержащая производные глутаримидов, и их применение для лечения эозинофильных заболеваний
PCT/RU2014/000855 WO2015072893A1 (ru) 2013-11-14 2014-11-12 Фармацевтическая композиция, содержащая производные глутаримидов, и их применение для лечения эозинофильных заболеваний
EP18206980.7A EP3466425B1 (en) 2013-11-14 2014-11-12 Use of glutarimide derivatives in the treatment of eosinophilic diseases
EP14861410.0A EP3069720B1 (en) 2013-11-14 2014-11-12 Pharmaceutical composition containing glutarimide derivatives, and application thereof for treating eosinophilic diseases

Publications (1)

Publication Number Publication Date
PL3466425T3 true PL3466425T3 (pl) 2021-04-06

Family

ID=53057723

Family Applications (2)

Application Number Title Priority Date Filing Date
PL18206980T PL3466425T3 (pl) 2013-11-14 2014-11-12 Zastosowanie pochodnych glutarimidu w leczeniu chorób eozynofilowych
PL14861410T PL3069720T3 (pl) 2013-11-14 2014-11-12 Kompozycja farmaceutyczna zawierająca pochodne glutarimidu i jej zastosowanie w leczeniu chorób eozynofilowych

Family Applications After (1)

Application Number Title Priority Date Filing Date
PL14861410T PL3069720T3 (pl) 2013-11-14 2014-11-12 Kompozycja farmaceutyczna zawierająca pochodne glutarimidu i jej zastosowanie w leczeniu chorób eozynofilowych

Country Status (23)

Country Link
US (2) US9949962B2 (enExample)
EP (2) EP3069720B1 (enExample)
JP (4) JP2016540749A (enExample)
KR (2) KR102312013B1 (enExample)
CN (2) CN110200968A (enExample)
AU (2) AU2014349246C1 (enExample)
BR (1) BR112016010515B1 (enExample)
CA (1) CA2930231C (enExample)
CY (1) CY1122500T1 (enExample)
DK (1) DK3069720T3 (enExample)
EA (4) EA032940B1 (enExample)
ES (2) ES2836887T3 (enExample)
HU (1) HUE046671T2 (enExample)
IL (2) IL245429B (enExample)
LT (1) LT3069720T (enExample)
MX (2) MX365781B (enExample)
PL (2) PL3466425T3 (enExample)
PT (1) PT3069720T (enExample)
RU (1) RU2552929C1 (enExample)
SG (1) SG10201900504XA (enExample)
SI (1) SI3069720T1 (enExample)
UA (1) UA118687C2 (enExample)
WO (1) WO2015072893A1 (enExample)

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US7608693B2 (en) 2006-10-02 2009-10-27 Regeneron Pharmaceuticals, Inc. High affinity human antibodies to human IL-4 receptor
CN118286417A (zh) 2012-09-07 2024-07-05 瑞泽恩制药公司 以il-4r拮抗剂治疗特应性皮炎的方法
EP3722290B1 (en) * 2013-04-12 2023-06-21 VALENTA-INTELLEKT Limited Glutarimide derivative, use thereof, pharmaceutical composition based thereon and methods for producing the glutarimide derivative
TWI634900B (zh) 2013-07-11 2018-09-11 再生元醫藥公司 藉由投與il-4r抑制劑治療嗜酸性食道炎的方法
PT3110848T (pt) 2014-09-24 2024-03-05 Regeneron Pharma Métodos para tratamento de infeção cutânea por administração de um antagonista do il-4r
KR102872485B1 (ko) 2016-09-01 2025-10-20 리제너론 파아마슈티컬스, 인크. Il-4r 길항제를 투여함에 의해 알레르기를 예방하거나 치료하기 위한 방법
CN106539792B (zh) * 2016-11-07 2017-08-25 王晓旭 一种治疗高血脂症的药物
GEAP202115467A (en) 2017-09-07 2021-10-11 Obschestvo S Ogranichennoi Otvetstvennostiyu Pharmenterprises Use of a glutarimide derivative to treat diseases related to the aberrant activity of cytokines
RU2712281C1 (ru) * 2018-11-23 2020-01-28 Общество С Ограниченной Ответственностью "Хемиммьюн Терапьютикс" Применение производного глутаримида для преодоления резистентности к стероидам и терапии заболеваний, ассоциированных с аберрантным сигналингом интерферона гамма
KR20210143246A (ko) 2019-03-21 2021-11-26 리제너론 파아마슈티컬스, 인크. 알레르기 치료용 il-4/il-13 경로 억제제 및 형질 세포 절제의 병용
JP7736667B2 (ja) 2019-08-05 2025-09-09 リジェネロン・ファーマシューティカルズ・インコーポレイテッド Il-4rアンタゴニストを投与することによるアトピー性皮膚炎の治療方法
US11504426B2 (en) 2019-08-05 2022-11-22 Regeneron Pharmaceuticals, Inc. Methods for treating allergy and enhancing allergen-specific immunotherapy by administering an IL-4R antagonist
BR112022019244A2 (pt) * 2020-04-07 2022-11-08 Hofseth Biocare Asa Método para reduzir a função efetora de eosinófilos, artigo de fabricação e kit
TN2022000350A1 (en) * 2020-06-26 2024-07-04 Ltd “Valenta Intellekt” Use of a glutarimide derivative for treating diseases associated with aberrant interleukin-6 activity
WO2023113650A1 (ru) * 2021-12-15 2023-06-22 Владимир Евгеньевич НЕБОЛЬСИН Фармацевтическая композиция 1-[2-(1-метилимидазол-4-ил)-этил]пергидроазин-2,6-дион для терапии заболеваний верхних дыхательных путей

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JPH02196767A (ja) * 1988-10-11 1990-08-03 Kyowa Hakko Kogyo Co Ltd ヒドロキサム酸誘導体
EP0564520A1 (en) 1990-12-24 1993-10-13 Merrell Dow Pharmaceuticals Inc. Use of certain glutarimide derivatives in the treatment of depression and mania
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AUPO005496A0 (en) 1996-05-24 1996-06-13 Bresagen Limited An interleukin-5 antagonist
RU2141483C1 (ru) 1997-07-04 1999-11-20 Небольсин Владимир Евгеньевич Производные пептидов или их фармацевтически приемлемые соли, способ их получения, применение и фармацевтическая композиция
DE60230656D1 (de) 2001-11-07 2009-02-12 Cytos Biotechnology Ag Antigenraster welche il-5, il-13 oder eotaxin präshilen erkrankungen
EP1741709A1 (en) 2005-06-28 2007-01-10 Sanofi-Aventis Deutschland GmbH Heteroaryl-substituted amides comprising a saturated linker group, and their use as pharmaceuticals
WO2007007054A1 (en) 2005-07-08 2007-01-18 Cancer Research Technology Limited Phthalamides, succinimides and related compounds and their use as pharmaceuticals
PT3072525T (pt) 2007-05-14 2018-04-20 Astrazeneca Ab Métodos para reduzir os níveis de basófilos
RU2406727C2 (ru) * 2008-02-13 2010-12-20 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Фармацевтическая композиция, содержащая n-ацильные производные аминокислот, и их применение в качестве противоаллергических, антианафилактических и противовоспалительных средств
RU2378284C2 (ru) * 2008-02-13 2010-01-10 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Способы получения n-ацильных производных аминокислот (варианты)
EP3722290B1 (en) * 2013-04-12 2023-06-21 VALENTA-INTELLEKT Limited Glutarimide derivative, use thereof, pharmaceutical composition based thereon and methods for producing the glutarimide derivative

Also Published As

Publication number Publication date
LT3069720T (lt) 2020-01-10
AU2018264084A1 (en) 2018-12-06
US10220029B2 (en) 2019-03-05
JP2020002152A (ja) 2020-01-09
BR112016010515A2 (enExample) 2017-08-08
DK3069720T3 (da) 2019-11-25
EA032955B1 (ru) 2019-08-30
RU2552929C1 (ru) 2015-06-10
EP3466425B1 (en) 2020-10-07
KR20160078400A (ko) 2016-07-04
US20160279114A1 (en) 2016-09-29
JP2019055953A (ja) 2019-04-11
BR112016010515B1 (pt) 2022-09-27
ES2759530T3 (es) 2020-05-11
MX2019006881A (es) 2019-08-01
IL245429B (en) 2020-02-27
AU2014349246B2 (en) 2018-10-18
EP3069720A1 (en) 2016-09-21
EA201891262A1 (ru) 2018-10-31
AU2014349246C1 (en) 2019-02-21
MX2016006330A (es) 2016-09-06
PL3069720T3 (pl) 2020-05-18
EA037447B1 (ru) 2021-03-30
ES2836887T3 (es) 2021-06-28
KR102312013B1 (ko) 2021-10-15
CA2930231A1 (en) 2015-05-21
EA201891261A1 (ru) 2018-10-31
CA2930231C (en) 2022-06-14
EA032955B3 (ru) 2020-02-27
JP2019214606A (ja) 2019-12-19
IL271352B (en) 2021-04-29
KR20200053639A (ko) 2020-05-18
SI3069720T1 (sl) 2020-02-28
SG10201900504XA (en) 2019-02-27
EA030961B1 (ru) 2018-10-31
AU2014349246A9 (en) 2018-09-20
CY1122500T1 (el) 2021-01-27
EP3466425A1 (en) 2019-04-10
EA201690798A1 (ru) 2016-08-31
PT3069720T (pt) 2019-12-02
UA118687C2 (uk) 2019-02-25
KR102312294B1 (ko) 2021-10-15
EA201990529A1 (ru) 2019-07-31
JP6589251B2 (ja) 2019-10-16
CN110200968A (zh) 2019-09-06
EP3069720A4 (en) 2017-06-21
WO2015072893A1 (ru) 2015-05-21
CN105722511B (zh) 2019-09-17
EP3069720A8 (en) 2017-10-04
EA032940B1 (ru) 2019-08-30
IL245429A0 (en) 2016-06-30
RU2013150861A (ru) 2015-05-20
MX386887B (es) 2025-03-19
AU2018264084C1 (en) 2020-08-27
MX365781B (es) 2019-06-13
IL271352A (en) 2020-01-30
US9949962B2 (en) 2018-04-24
AU2014349246A1 (en) 2016-05-19
EP3069720B1 (en) 2019-10-30
HUE046671T2 (hu) 2020-03-30
CN105722511A (zh) 2016-06-29
AU2018264084B2 (en) 2020-05-14
JP6758677B2 (ja) 2020-09-23
JP2016540749A (ja) 2016-12-28
US20180104230A1 (en) 2018-04-19

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