MX2020000807A - Proceso para preparar una composicion de entrega de farmaco. - Google Patents

Proceso para preparar una composicion de entrega de farmaco.

Info

Publication number
MX2020000807A
MX2020000807A MX2020000807A MX2020000807A MX2020000807A MX 2020000807 A MX2020000807 A MX 2020000807A MX 2020000807 A MX2020000807 A MX 2020000807A MX 2020000807 A MX2020000807 A MX 2020000807A MX 2020000807 A MX2020000807 A MX 2020000807A
Authority
MX
Mexico
Prior art keywords
polymer
preparing
drug delivery
delivery composition
drug
Prior art date
Application number
MX2020000807A
Other languages
English (en)
Inventor
Philippe Pouletty
Frédérique Guillamot
Original Assignee
PK Med SAS
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 PK Med SAS filed Critical PK Med SAS
Publication of MX2020000807A publication Critical patent/MX2020000807A/es

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46Hydrolases (3)
    • A61K38/47Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • A61K9/1694Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2095Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06At least partially resorbable materials
    • A61L17/10At least partially resorbable materials containing macromolecular materials
    • A61L17/12Homopolymers or copolymers of glycolic acid or lactic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001Use of materials characterised by their function or physical properties
    • A61L24/0015Medicaments; Biocides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/046Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/18Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04Macromolecular materials
    • A61L31/06Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29CSHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C48/00Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
    • B29C48/022Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor characterised by the choice of material
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241Tumor Necrosis Factors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A61L2300/254Enzymes, proenzymes
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29KINDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2067/00Use of polyesters or derivatives thereof, as moulding material
    • B29K2067/04Polyesters derived from hydroxycarboxylic acids
    • B29K2067/043PGA, i.e. polyglycolic acid or polyglycolide
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29KINDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2067/00Use of polyesters or derivatives thereof, as moulding material
    • B29K2067/04Polyesters derived from hydroxycarboxylic acids
    • B29K2067/046PLA, i.e. polylactic acid or polylactide
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29KINDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2105/00Condition, form or state of moulded material or of the material to be shaped
    • B29K2105/0005Condition, form or state of moulded material or of the material to be shaped containing compounding ingredients
    • B29K2105/0035Medical or pharmaceutical agents
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29KINDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2105/00Condition, form or state of moulded material or of the material to be shaped
    • B29K2105/0085Copolymers

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Surgery (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Vascular Medicine (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Materials Engineering (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Mechanical Engineering (AREA)
  • Inorganic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Processes Of Treating Macromolecular Substances (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La presente invención se refiere al proceso para preparar una composición de entrega de fármaco que comprende las etapas de a) preparar una mezcla madre que comprende un fármaco y un primer polímero (i) extruyendo el primer polímero, en donde dicho primer polímero tiene una temperatura de fusión inferior a 140 ºC; y (ii) introduciendo el fármaco durante la extrusión del primer polímero, con un contenido de fármaco de entre el 0,1 % y el 90 %, basándose en el peso total de la mezcla madre; y b) introducir la mezcla madre en una matriz a base de polímero durante la producción de la composición de entrega de fármaco, en donde la etapa a) se realiza a una temperatura a la que el primer polímero está en un estado parcial o totalmente fundido y la etapa b) se realiza a una temperatura a la que tanto el primer polímero como al menos un polímero de la matriz a base de polímero están en un estado parcial o totalmente fundido.
MX2020000807A 2017-07-25 2018-07-25 Proceso para preparar una composicion de entrega de farmaco. MX2020000807A (es)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP17305993 2017-07-25
PCT/EP2018/070139 WO2019020678A1 (en) 2017-07-25 2018-07-25 PROCESS FOR PREPARING A DRUG DELIVERY COMPOSITION

Publications (1)

Publication Number Publication Date
MX2020000807A true MX2020000807A (es) 2020-08-17

Family

ID=59579573

Family Applications (1)

Application Number Title Priority Date Filing Date
MX2020000807A MX2020000807A (es) 2017-07-25 2018-07-25 Proceso para preparar una composicion de entrega de farmaco.

Country Status (13)

Country Link
US (1) US11911476B2 (es)
EP (1) EP3658117A1 (es)
JP (1) JP7373486B2 (es)
KR (1) KR20200040776A (es)
CN (1) CN111065378A (es)
AU (1) AU2018305160A1 (es)
BR (1) BR112020001262A2 (es)
CA (1) CA3069399A1 (es)
MX (1) MX2020000807A (es)
RU (1) RU2020107391A (es)
SG (1) SG11202000497VA (es)
WO (1) WO2019020678A1 (es)
ZA (1) ZA202001046B (es)

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JP2022526952A (ja) 2019-03-28 2022-05-27 ピーケイ・メッド 多成分熱可塑性製品
CN110237308B (zh) * 2019-06-06 2021-05-18 中南大学湘雅二医院 一种用于修复肿瘤性骨缺损的人工骨及其制备方法
CA3153224A1 (en) * 2019-09-19 2021-03-25 Amw Gmbh Extruded depot form for controlled active substance release
US20230034354A1 (en) 2019-12-19 2023-02-02 Carbios Foamed plastic compositions
WO2023016848A1 (en) * 2021-08-09 2023-02-16 Basf Se Sinter powder (sp) comprising at least one polylactide and at least one polycaprolactone
CN113908267B (zh) * 2021-11-30 2023-12-19 中国科学院长春应用化学研究所 一种疫苗佐剂及其制备方法和应用

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BR0309844A (pt) 2002-05-07 2005-02-15 Control Delivery Sys Inc Processos para formação de um dispositivo para a distribuição de droga
US9555167B2 (en) 2006-12-11 2017-01-31 3M Innovative Properties Company Biocompatible antimicrobial compositions
US8846073B2 (en) * 2006-12-19 2014-09-30 Allergan, Inc. Low temperature processes for making cyclic lipid implants for intraocular use
TWI542338B (zh) 2008-05-07 2016-07-21 壯生和壯生視覺關懷公司 用於活性劑之控制釋放的眼用裝置
ES2527193T3 (es) * 2010-07-09 2015-01-21 Innocore Technologies B.V. Copolímeros multibloque segmentados de fases separadas biodegradables y liberación de polipéptidos biológicamente activos
CN102440966A (zh) * 2010-10-06 2012-05-09 段明华 艾塞那肽缓释制剂的制备工艺研究
FR2984354A1 (fr) * 2011-12-20 2013-06-21 Centre Nat Rech Scient Procede de preparation d'alliage polymere/enzymes
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US20150001020A1 (en) * 2013-06-26 2015-01-01 King Fahd University Of Petroleum And Minerals Luggage sliders
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WO2015051020A1 (en) * 2013-10-03 2015-04-09 Polyone Corporation Antimicrobial polymer concentrates and compounds
EP3065890A2 (en) 2013-11-05 2016-09-14 Carbios A method for degrading a plastic
CN105330956A (zh) * 2014-08-07 2016-02-17 普立万聚合体(上海)有限公司 含对热敏感的功能添加剂的母料
WO2016097325A1 (en) 2014-12-19 2016-06-23 Carbios Plastic compound and preparation process
CA2987842C (en) 2015-06-12 2024-01-02 Carbios Biodegradable polyester composition and uses thereof
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US20200206354A1 (en) * 2017-07-25 2020-07-02 PK Med SAS Drug delivery composition

Also Published As

Publication number Publication date
WO2019020678A1 (en) 2019-01-31
SG11202000497VA (en) 2020-02-27
JP2020528459A (ja) 2020-09-24
ZA202001046B (en) 2022-10-26
RU2020107391A (ru) 2021-08-25
EP3658117A1 (en) 2020-06-03
CA3069399A1 (en) 2019-01-31
KR20200040776A (ko) 2020-04-20
BR112020001262A2 (pt) 2020-07-21
RU2020107391A3 (es) 2021-10-20
CN111065378A (zh) 2020-04-24
US11911476B2 (en) 2024-02-27
JP7373486B2 (ja) 2023-11-02
US20200368357A1 (en) 2020-11-26
AU2018305160A1 (en) 2020-01-30

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