BR112017013476A2 - produtos para o fornecimento de compostos de diagnóstico/terapêuticos para o coração - Google Patents
produtos para o fornecimento de compostos de diagnóstico/terapêuticos para o coraçãoInfo
- Publication number
- BR112017013476A2 BR112017013476A2 BR112017013476-4A BR112017013476A BR112017013476A2 BR 112017013476 A2 BR112017013476 A2 BR 112017013476A2 BR 112017013476 A BR112017013476 A BR 112017013476A BR 112017013476 A2 BR112017013476 A2 BR 112017013476A2
- Authority
- BR
- Brazil
- Prior art keywords
- solution
- range
- diagnostic
- cap
- product
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title abstract 3
- 230000001225 therapeutic effect Effects 0.000 title abstract 3
- 239000000243 solution Substances 0.000 abstract 4
- 229910000389 calcium phosphate Inorganic materials 0.000 abstract 3
- 239000001506 calcium phosphate Substances 0.000 abstract 3
- 235000011010 calcium phosphates Nutrition 0.000 abstract 3
- 239000002105 nanoparticle Substances 0.000 abstract 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 abstract 3
- 238000000034 method Methods 0.000 abstract 2
- 239000000203 mixture Substances 0.000 abstract 2
- 239000000725 suspension Substances 0.000 abstract 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract 1
- 208000024172 Cardiovascular disease Diseases 0.000 abstract 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 abstract 1
- 229910019142 PO4 Inorganic materials 0.000 abstract 1
- 239000007864 aqueous solution Substances 0.000 abstract 1
- 229910052791 calcium Inorganic materials 0.000 abstract 1
- 239000011575 calcium Substances 0.000 abstract 1
- 150000002500 ions Chemical class 0.000 abstract 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract 1
- 239000010452 phosphate Substances 0.000 abstract 1
Classifications
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5115—Inorganic compounds
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/42—Phosphorus; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/03—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
-
- 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
- A61K47/51—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
- A61K47/52—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 inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
-
- 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
-
- 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
- A61K9/007—Pulmonary tract; Aromatherapy
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate 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
- A61K9/143—Intimate 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 inorganic compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
- C12N2310/141—MicroRNAs, miRNAs
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2320/00—Applications; Uses
- C12N2320/30—Special therapeutic applications
- C12N2320/32—Special delivery means, e.g. tissue-specific
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Biomedical Technology (AREA)
- Physics & Mathematics (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Pulmonology (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Cardiology (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
a invenção refere-se a um processo para a preparação de um produto compreendendo uma ou mais nanopartículas de fosfato de cálcio (cap-np) com carga superficial negativa tendo um potencial-¿ na faixa de -41.0 mv a -27.0 mv compreendendo as etapas de: a) manter uma mistura tendo um ph na faixa de 7 a 10 e compreendendo uma solução aquosa de cálcio, uma solução aquosa de fosfato e uma solução de íons de citrato em uma temperatura na faixa de 20ºc a 40ºc por um tempo na faixa de 30 segundos a 10 minutos; b) remover íons não reagidos da solução da etapa a), desse modo obtendo uma suspensão de uma ou mais nanopartículas de fosfato de cálcio (cap-np); c) recuperar o produto de uma ou mais nanopartículas de fosfato de cálcio (cap-np) a partir da suspensão da etapa b). em uma modalidade vantajosa, o processo da invenção provê na mistura da etapa a), também uma solução aquosa de um ou mais compostos de diagnóstico/terapêuticos. o produto da invenção pode ser usado como um veículo para um ou mais compostos terapêuticos/de diagnóstico para o tratamento de doenças cardiovasculares através de administração por inalação.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI20142207 | 2014-12-22 | ||
ITMI2014A002207 | 2014-12-22 | ||
PCT/EP2015/080991 WO2016102576A1 (en) | 2014-12-22 | 2015-12-22 | Products for the delivery of therapeutic/diagnostic compounds to the heart |
Publications (2)
Publication Number | Publication Date |
---|---|
BR112017013476A2 true BR112017013476A2 (pt) | 2018-01-09 |
BR112017013476B1 BR112017013476B1 (pt) | 2023-02-07 |
Family
ID=52574296
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
BR112017013476-4A BR112017013476B1 (pt) | 2014-12-22 | 2015-12-22 | Produtos para o fornecimento de compostos de diagnóstico/terapêuticos para o coração |
Country Status (15)
Country | Link |
---|---|
US (1) | US10729660B2 (pt) |
EP (1) | EP3236947B1 (pt) |
JP (1) | JP6781712B2 (pt) |
KR (1) | KR102532139B1 (pt) |
CN (1) | CN107205934B (pt) |
AU (1) | AU2015370986B2 (pt) |
BR (1) | BR112017013476B1 (pt) |
CA (1) | CA2971519C (pt) |
ES (1) | ES2956684T3 (pt) |
IL (1) | IL253141B (pt) |
MX (1) | MX379568B (pt) |
PL (1) | PL3236947T3 (pt) |
RU (1) | RU2721778C2 (pt) |
SG (1) | SG11201705128VA (pt) |
WO (1) | WO2016102576A1 (pt) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3756024A1 (en) * | 2018-02-19 | 2020-12-30 | BRUKER FRANCE (Société par Actions Simplifiée) | Nuclear spin hyperpolarization in a porous matrix |
IT201800006753A1 (it) * | 2018-06-28 | 2019-12-28 | Calcio fosfato amorfo stabilizzato dopato con ioni fluoruro e un procedimento per produrlo | |
CN111870582B (zh) * | 2020-06-28 | 2022-03-18 | 苏州天微肽生物医药科技有限公司 | 正硅酸乙酯-利拉鲁肽复合微球制剂及其制备方法和应用 |
IT202000021292A1 (it) | 2020-09-09 | 2022-03-09 | Consiglio Nazionale Ricerche | Composizione in forma di polvere a base di microparticelle incorporanti nanoparticelle per la veicolazione di composti terapeutici/diagnostici |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030185892A1 (en) * | 2001-08-17 | 2003-10-02 | Bell Steve J. D. | Intraocular delivery compositions and methods |
ATE538776T1 (de) * | 2003-02-14 | 2012-01-15 | Childrens Hosp & Res Ct Oak | Träger zur freisetzung lipophilisches wirkstoffes und desen verwendungsverfahren |
EP1605752B1 (en) * | 2003-03-27 | 2011-09-14 | Cytokinetics, Inc. | Sulfonamides for the treatment of congestive heart failure, their compositions and uses. |
TW200745163A (en) * | 2006-02-17 | 2007-12-16 | Syntonix Pharmaceuticals Inc | Peptides that block the binding of IgG to FcRn |
JP2012501966A (ja) * | 2008-06-16 | 2012-01-26 | バインド バイオサイエンシズ インコーポレイテッド | ビンカアルカロイド含有治療用ポリマーナノ粒子並びにその製造方法及び使用方法 |
US8309134B2 (en) * | 2008-10-03 | 2012-11-13 | Southwest Research Institute | Modified calcium phosphate nanoparticle formation |
US8771741B2 (en) | 2009-01-23 | 2014-07-08 | The Penn State Research Foundation | In vivo photodynamic therapy of cancer via a near infrared agent encapsulated in calcium phosphate nanoparticles |
ES2557183B1 (es) * | 2014-07-21 | 2016-11-03 | Consejo Superior De Investigaciones Científicas (Csic) | Procedimiento de obtención de nanopartículas de fosfato de calcio amorfo recubiertas de citrato y dopadas con flúor |
-
2015
- 2015-12-22 PL PL15825795.6T patent/PL3236947T3/pl unknown
- 2015-12-22 RU RU2017126093A patent/RU2721778C2/ru active
- 2015-12-22 ES ES15825795T patent/ES2956684T3/es active Active
- 2015-12-22 CA CA2971519A patent/CA2971519C/en active Active
- 2015-12-22 MX MX2017008330A patent/MX379568B/es unknown
- 2015-12-22 US US15/538,663 patent/US10729660B2/en active Active
- 2015-12-22 CN CN201580073751.9A patent/CN107205934B/zh active Active
- 2015-12-22 WO PCT/EP2015/080991 patent/WO2016102576A1/en active Application Filing
- 2015-12-22 BR BR112017013476-4A patent/BR112017013476B1/pt active IP Right Grant
- 2015-12-22 JP JP2017551362A patent/JP6781712B2/ja active Active
- 2015-12-22 AU AU2015370986A patent/AU2015370986B2/en active Active
- 2015-12-22 KR KR1020177019912A patent/KR102532139B1/ko active Active
- 2015-12-22 SG SG11201705128VA patent/SG11201705128VA/en unknown
- 2015-12-22 EP EP15825795.6A patent/EP3236947B1/en active Active
-
2017
- 2017-06-22 IL IL253141A patent/IL253141B/en unknown
Also Published As
Publication number | Publication date |
---|---|
EP3236947A1 (en) | 2017-11-01 |
PL3236947T3 (pl) | 2023-12-27 |
AU2015370986A1 (en) | 2017-07-27 |
CA2971519A1 (en) | 2016-06-30 |
EP3236947B1 (en) | 2023-06-28 |
WO2016102576A1 (en) | 2016-06-30 |
RU2017126093A (ru) | 2019-01-24 |
CN107205934A (zh) | 2017-09-26 |
JP6781712B2 (ja) | 2020-11-04 |
BR112017013476B1 (pt) | 2023-02-07 |
AU2015370986B2 (en) | 2021-02-04 |
RU2017126093A3 (pt) | 2019-06-06 |
MX2017008330A (es) | 2018-04-24 |
US10729660B2 (en) | 2020-08-04 |
IL253141A0 (en) | 2017-08-31 |
KR102532139B1 (ko) | 2023-05-12 |
EP3236947C0 (en) | 2023-06-28 |
IL253141B (en) | 2022-04-01 |
CN107205934B (zh) | 2023-06-30 |
KR20170108954A (ko) | 2017-09-27 |
RU2721778C2 (ru) | 2020-05-22 |
ES2956684T8 (es) | 2024-03-27 |
SG11201705128VA (en) | 2017-07-28 |
MX379568B (es) | 2025-03-11 |
JP2018505211A (ja) | 2018-02-22 |
CA2971519C (en) | 2023-04-11 |
ES2956684T3 (es) | 2023-12-26 |
US20170348245A1 (en) | 2017-12-07 |
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