RU2016144055A - Конъюгаты лекарственного средства с наночастицами - Google Patents
Конъюгаты лекарственного средства с наночастицами Download PDFInfo
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- RU2016144055A RU2016144055A RU2016144055A RU2016144055A RU2016144055A RU 2016144055 A RU2016144055 A RU 2016144055A RU 2016144055 A RU2016144055 A RU 2016144055A RU 2016144055 A RU2016144055 A RU 2016144055A RU 2016144055 A RU2016144055 A RU 2016144055A
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- Prior art keywords
- conjugate according
- fragment
- drug
- paragraphs
- linker
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- 239000002105 nanoparticle Substances 0.000 title claims 10
- 239000012634 fragment Substances 0.000 claims 20
- 229940079593 drug Drugs 0.000 claims 13
- 239000003814 drug Substances 0.000 claims 13
- 125000005647 linker group Chemical group 0.000 claims 9
- 125000006850 spacer group Chemical group 0.000 claims 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 4
- 239000002202 Polyethylene glycol Substances 0.000 claims 3
- 229920001223 polyethylene glycol Polymers 0.000 claims 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims 3
- 108091005804 Peptidases Proteins 0.000 claims 2
- 239000004365 Protease Substances 0.000 claims 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 2
- 239000007850 fluorescent dye Substances 0.000 claims 2
- 230000002285 radioactive effect Effects 0.000 claims 2
- 239000000377 silicon dioxide Substances 0.000 claims 2
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 claims 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 claims 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 claims 1
- 235000001014 amino acid Nutrition 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 claims 1
- 238000003776 cleavage reaction Methods 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 229960002448 dasatinib Drugs 0.000 claims 1
- 229960002584 gefitinib Drugs 0.000 claims 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 229920000620 organic polymer Polymers 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 claims 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 claims 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 claims 1
- 102000005962 receptors Human genes 0.000 claims 1
- 108020003175 receptors Proteins 0.000 claims 1
- 230000007017 scission Effects 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 claims 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0089—Particulate, powder, adsorbate, bead, sphere
- A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
- A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
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- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
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- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
- A61K47/6931—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
- A61K47/6935—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
- A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
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- A61P35/00—Antineoplastic agents
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- Animal Behavior & Ethology (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Nanotechnology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Optics & Photonics (AREA)
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- Ceramic Engineering (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Claims (29)
1. Конъюгат лекарственного средства с наночастицами (NDC), включающий
наночастицу;
линкерный фрагмент; и
фрагмент лекарственного средства,
в котором наночастица покрыта органическим полимером, и
в котором фрагмент лекарственного средства и линкерный фрагмент образуют расщепляемую конструкцию линкер-лекарственное средство, которая ковалентно связана с наночастицей.
2. Конъюгат по п. 1, отличающийся тем, что указанная наночастица имеет диаметр в диапазоне от 1 нм до 25 нм.
3. Конъюгат по п. 1 или 2, отличающийся тем, что указанный фрагмент лекарственного средства содержит дазатиниб или гефитиниб, включая любые их аналоги.
4. Конъюгат по п. 1 или 2, отличающийся тем, что указанное среднее соотношение фрагмента лекарственного средства и наночастиц находится в диапазоне от 1 до 20.
5. Конъюгат по п. 1, отличающийся тем, что линкерный фрагмент содержит одну или более аминокислот.
6. Конъюгат по п. 2, отличающийся тем, что линкерный фрагмент содержит (амино-(спейсер)x)y-пептид или (спейсер)z-пептид,
где спейсер содержит от 2 до 50 атомов,
где x представляет собой целое число от 1 до 5,
где y представляет собой целое число от 1 до 5,
где z представляет собой целое число от 5 до 15, и
где линкерный фрагмент содержит разлагаемый фрагмент между линкерным фрагментом и фрагментом лекарственного средства.
7. Конъюгат по любому из пп. 1-6, отличающийся тем, что указанный линкерный фрагмент позволяет отщепление фрагмента лекарственного средства в присутствии протеазы.
8. Конъюгат по любому из пп. 1-7, отличающийся тем, что линкерный фрагмент содержит спейсер между пептидом и фрагментом лекарственного средства.
9. Конъюгат по п. 8, отличающийся тем, что указанный спейсер содержит полиэтиленгликоль (ПЭГ), ПЭГ2, пара-аминобензилоксикарбамат (РАВС).
10. Конъюгат по любому из пп. 1-9, дополнительно содержащий флуоресцентное соединение.
11. Конъюгат по любому из пп. 1-10, дополнительно содержащий радиоактивную метку.
12. Конъюгат по любому из пп. 1-11, отличающийся тем, что линкерный фрагмент способен подвергаться гидролизу на С-конце при связывании с протеазой, таким образом высвобождая фрагмент лекарственного средства из наночастицы.
13. Конъюгат по любому из пп. 1-12, отличающийся тем, что фрагмент лекарственного средства содержит ингибитор рецепторной тирозинкиназы (RTK).
14. Конъюгат по любому из пп. 1-13, дополнительно содержащий от 1 до 20 нацеливаемых фрагментов, при этом нацеливаемые фрагменты связываются с рецепторами на опухолевых клетках.
15. Конъюгат по п. 14, отличающийся тем, что указанные нацеливаемые фрагменты содержат циклическую аргинилглициласпарагиновую кислоту (cRGD).
16. Конъюгат по п. 13, отличающийся тем, что указанный конъюгат лекарственного средства с наночастицами (NDC) является лечебно-диагностическим средством.
17. Конъюгат по любому из пп. 11-16, отличающийся тем, что флуоресцентное соединение представляет собой Cy5.5.
18. Конъюгат по любому из пп. 11-17, отличающийся тем, что фрагмент лекарственного средства присоединен к радиоактивной метке.
19. Конъюгат по любому из пп. 1-18, отличающийся тем, что наночастица дополнительно содержит ядро на основе диоксида кремния и оболочку из диоксида кремния вокруг по меньшей мере части ядра.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462004738P | 2014-05-29 | 2014-05-29 | |
US62/004,738 | 2014-05-29 | ||
US201462094923P | 2014-12-19 | 2014-12-19 | |
US62/094,923 | 2014-12-19 | ||
PCT/US2015/032565 WO2015183882A1 (en) | 2014-05-29 | 2015-05-27 | Nanoparticle drug conjugates |
Publications (1)
Publication Number | Publication Date |
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RU2016144055A true RU2016144055A (ru) | 2018-07-02 |
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EP3693026A1 (en) | 2020-08-12 |
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CA2947895C (en) | 2023-08-08 |
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ES2788865T3 (es) | 2020-10-23 |
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BR112016027624A8 (pt) | 2021-07-20 |
CA3201974A1 (en) | 2015-12-03 |
CA2947895A1 (en) | 2015-12-03 |
PL3148591T3 (pl) | 2020-11-02 |
DK3148591T3 (da) | 2020-04-14 |
JP6573633B2 (ja) | 2019-09-11 |
JP2017521371A (ja) | 2017-08-03 |
CN106659797A (zh) | 2017-05-10 |
CN106659797B (zh) | 2021-04-27 |
AU2015267200B2 (en) | 2019-01-03 |
WO2015183882A1 (en) | 2015-12-03 |
US10111963B2 (en) | 2018-10-30 |
US20190070310A1 (en) | 2019-03-07 |
US10485881B2 (en) | 2019-11-26 |
EP3148591B1 (en) | 2020-03-11 |
CN113082225A (zh) | 2021-07-09 |
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