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WO2021253681A1 - Composition de favipiravir et son procédé de préparation - Google Patents

Composition de favipiravir et son procédé de préparation Download PDF

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Publication number
WO2021253681A1
WO2021253681A1 PCT/CN2020/118723 CN2020118723W WO2021253681A1 WO 2021253681 A1 WO2021253681 A1 WO 2021253681A1 CN 2020118723 W CN2020118723 W CN 2020118723W WO 2021253681 A1 WO2021253681 A1 WO 2021253681A1
Authority
WO
WIPO (PCT)
Prior art keywords
favipiravir
composition
povidone
composition according
disintegrant
Prior art date
Application number
PCT/CN2020/118723
Other languages
English (en)
Chinese (zh)
Inventor
章正赞
徐彪
娄贵川
张津州
赵周明
郭晓迪
Original Assignee
浙江华海药业股份有限公司
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 浙江华海药业股份有限公司 filed Critical 浙江华海药业股份有限公司
Priority to CN202080100612.1A priority Critical patent/CN115551484A/zh
Publication of WO2021253681A1 publication Critical patent/WO2021253681A1/fr

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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
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a favipiravir composition and a preparation method thereof.
  • Favipiravir was developed by Fujifilm Toyama Chemical Co., Ltd., and its chemical name is 6-fluoro-3-hydroxypyrazine-2-carboxamide.
  • the drug has broad-spectrum antiviral activity, and has antiviral effects against RNA viruses such as influenza virus, Ebola virus, yellow fever virus, arena virus, bunya virus, and West Nile virus.
  • Fapilavir was sold under the trade name in Japan in 2014 Conditionally approved and marketed for the treatment of new or recurrent influenza in adults (only used when other anti-influenza drugs are ineffective or ineffective).
  • the marketed dosage form is a tablet, each with a specification of 200 mg favipiravir.
  • the usual course of treatment for adults is 5 days. On day 1, 1600 mg of favipiravir is taken once, twice a day; from day 2 to day 5, 600 mg of favipiravir is taken once, twice a day. Each administration requires multiple oral tablets.
  • the plasma concentration reaches its peak in about 30 minutes and exerts its efficacy. Therefore, the developed formulation requires rapid dissolution capability, that is, it can dissolve ⁇ 85% of the drug in 15 minutes in an in vitro dissolution test.
  • the content of favipiravir in the developed tablets must be as high as possible, so that the weight of each tablet is reduced, thereby reducing the size and making it easier to take.
  • the reduction in the weight of each tablet means that fewer excipients need to be used, which will slow down the release of the drug. Therefore, the difficulty in the development of the drug is to achieve rapid dissolution under the condition of lower tablet weight (15 minutes dissolution ⁇ 85% Drug).
  • the patent CN201080011876.6 of the original research Toyama Chemical Co., Ltd. discloses a favipiravir tablet and a preparation method thereof, by using low-substituted hydroxypropyl cellulose or croscarmellose sodium to achieve the effect of improving the dissolution rate , And maintain a low film weight.
  • sodium carboxymethyl starch was used as a disintegrant.
  • the weight of sodium carboxymethyl starch in the preparation of Comparative Example 5 was 5.6 mg, the total mass of the preparation was 260.0 mg, and the sodium carboxymethyl starch accounted for 2.15% by weight of the total mass of the preparation.
  • the dissolution rate of Comparative Example 5 using sodium carboxymethyl starch as the disintegrant was only 63.6%. It can be seen that the patent actually teaches that the use of sodium carboxymethyl starch as a disintegrant cannot achieve the rapid dissolution of favipiravir (ie, the dissolution of ⁇ 85% of the drug in 15 minutes), that is, the avoidance of the use of carboxymethyl
  • the opposite teaching of sodium starch as a disintegrant is 5.6 mg, the total mass of the preparation was 260.0 mg, and the sodium carboxymethyl starch accounted for 2.15% by weight of the total mass of the preparation.
  • the dissolution rate of Comparative Example 5 using sodium carboxymethyl starch as the disintegrant was only 63.6%. It can be seen that the patent actually teaches that the
  • Patent 201510755106.7 describes the effect of increasing the dissolution rate by adding silicified microcrystalline cellulose 50.
  • the content of favipiravir in a single tablet formulation is 55-70%, and the total weight of a single tablet is even as high as 400 mg, which is too high. .
  • the patent requires that the particle size distribution D90 of favipiravir must be between 40 ⁇ m and 160 ⁇ m, otherwise the rapid dissolution of favipiravir cannot be achieved.
  • the patent also pointed out that in the case of using silicified microcrystalline cellulose 50 as a disintegrant, the amount of binder must be controlled so that the weight percentage relative to the tablet is 4% to 7%.
  • Patent 201610163419.8 achieves the effect of increasing the dissolution rate by adding a large amount of microcrystalline cellulose PH-102 and a solubilizer, and the content of favipiravir in a single tablet preparation is less than 67%.
  • the amount of microcrystalline cellulose PH-102 relative to the amount of favipiravir is 0.5-1:1, that is, 200 mg of favipiravir needs to add 100-200 mg of microcrystalline cellulose PH-102,
  • the total weight of the prepared single favipiravir tablet is greatly increased. Therefore, although these two methods can improve the dissolution rate, they need to add more excipients, and the content of favipiravir is less than 74%.
  • each administration of favipiravir requires multiple oral tablets. Therefore, the content of favipiravir in the developed tablets needs to be as high as possible, so that the weight of each tablet is reduced and the size is reduced. Easy to take. However, the reduction in the weight of each tablet means that fewer excipients need to be used, which will slow down the release of the drug. Therefore, the difficulty in the development of the drug is that it can achieve rapid drug dissolution under the condition of lower tablet weight.
  • the present invention provides a favipiravir composition, which contains:
  • the favipiravir composition can dissolve more than 85% in 15 minutes in an in vitro dissolution test.
  • the present invention also provides a favipiravir composition, which contains:
  • a disintegrant of 2.5%-15% by weight of the composition is selected from one or a combination of sodium carboxymethyl starch or calcium carboxymethyl cellulose;
  • the favipiravir composition can also achieve rapid release, wherein the favipiravir composition can dissolve ⁇ 85% in 15 minutes in an in vitro dissolution test.
  • the dissolution method can be determined according to the second method of the Chinese Pharmacopoeia (paddle method). The specific conditions of the method are: the rotating speed of the stirring blade is 50 rpm, the dissolution medium is pH 4.5 acetate buffer, the medium volume is 900 ml, and the medium temperature is 37°C ⁇ 0.5°C.
  • the weight ratio of favipiravir to the composition is more than 60%, preferably more than 70%, more preferably 70%-85%, even more preferably 75%-82%.
  • the disintegrant is selected from one or a combination of two of sodium carboxymethyl starch or calcium carboxymethyl cellulose, and the disintegrant accounts for a weight percentage of the composition 2.5%-15%, more preferably 3-12%.
  • the favipiravir composition provided by the present invention may further contain a filler.
  • Fillers suitable for the composition of the present invention include but are not limited to: mannitol, xylitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, sucrose, glucose, maltitol, calcium hydrogen phosphate, dihydrogen phosphate One of calcium and calcium silicate or any combination thereof, preferably mannitol and/or microcrystalline cellulose, more preferably microcrystalline cellulose.
  • the weight percentage of the filler in the composition is ⁇ 15%, preferably ⁇ 12%.
  • Binders suitable for the composition of the present invention include but are not limited to: hypromellose, hydroxypropyl cellulose, methyl cellulose, copovidone, povidone, etc., preferably copovidone and/or povidone , More preferably povidone, povidone is preferably selected from povidone K30, povidone K25, povidone K17, povidone K90 and the like.
  • the weight percentage of the binder in the composition is 0.5-5%, preferably 2-5%.
  • the favipiravir composition provided by the present invention may further contain an anti-sticking agent.
  • Anti-sticking agents suitable for the composition of the present invention include, but are not limited to, silicon dioxide, diatomaceous earth, etc., preferably silicon dioxide.
  • the weight percentage of the anti-sticking agent in the composition is 0.5-5%, preferably 2-5%.
  • composition of the present invention based on the weight percentage of the composition, includes the following components:
  • Favipiravir or its salt is more than 60%, preferably more than 70%, more preferably 70%-85%;
  • Disintegrant selected from one or a combination of sodium carboxymethyl starch or calcium carboxymethyl cellulose 2.5%-15%, more preferably 3-12%;
  • Anti-sticking agent 0.5-5%, preferably 2-5%;
  • the composition is powdered granules.
  • the invention provides a method for preparing a favipiravir composition in the form of powdered granules, which comprises: obtaining powdered granules by wet granulation.
  • the method for preparing favipiravir in the form of powdered particles includes: dissolving a binder (such as povidone) in water, and then adding an anti-sticking agent (such as silicon dioxide) to obtain a binder solution ; Then Favipiravir or its salt, filler (such as microcrystalline cellulose) and one or a combination of disintegrant sodium carboxymethyl starch or calcium carboxymethyl cellulose, add the above binder solution Wet granulation, selective drying, and sieving to obtain favipiravir powder granules.
  • a binder such as povidone
  • an anti-sticking agent such as silicon dioxide
  • the present invention also provides a favipiravir tablet, which contains the following components based on the weight percentage of the tablet:
  • Favipiravir or its salt is more than 60%, preferably more than 70%, more preferably 70%-85%;
  • Anti-sticking agent 0.5-5%, preferably 2-5%;
  • Lubricant and optional other additives 0.1-5%, preferably 0.5%-2%;
  • an external disintegrant is added by 1-4%, preferably 1.5-3%.
  • the external disintegrant suitable for the tablet of the present invention includes but is not limited to: crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, etc., preferably crospovidone.
  • the weight percentage of the external disintegrant in the preparation is 1-4%, preferably 1.5-3%.
  • the external lubricant includes but is not limited to: stearic acid, magnesium stearate, sodium stearyl fumarate, talc, etc., preferably sodium stearyl fumarate.
  • additives include coloring agents, coating agents, flavoring agents, surfactants, plasticizers or fragrances and the like.
  • the favipiravir tablet of the present invention can be optionally film-coated.
  • the coating film is usually about 1.5-5% of the total weight of the tablet, and the coating film is composed of film-forming agents, plasticizers, pigments, and the like.
  • the present invention also provides a method for preparing favipiravir tablets, which includes: dissolving a binder (such as povidone) in water, and then adding an anti-sticking agent (such as silicon dioxide) to obtain a binder solution ; Then Favipiravir or its salt, filler (such as microcrystalline cellulose) and one or a combination of disintegrant sodium carboxymethyl starch or calcium carboxymethyl cellulose are mixed, and the binder solution is added Wet granulation, selective drying, sieving and sieving to obtain favipiravir powdered granules; then adding lubricants such as sodium stearyl fumarate and optionally disintegrating agents such as crospovidone, Perform total mixing and compression to prepare favipiravir tablets.
  • a binder such as povidone
  • an anti-sticking agent such as silicon dioxide
  • the favipiravir composition provided by the present invention is prepared by adding one or both of the disintegrating agent sodium carboxymethyl starch or calcium carboxymethyl cellulose, which accounts for 2.5%-15% of the weight percentage of the preparation, Unexpected technical effects are obtained. In the in vitro dissolution test, it can dissolve ⁇ 85% in 15 minutes.
  • the favipiravir composition provided by the present invention has moderate hardness of the tablet, smooth tablet surface, good appearance, and no scratches or spots.
  • the preparation method of the favipiravir composition provided by the present invention has simple operation and good reproducibility, and the obtained favipiravir composition product has stable quality and is suitable for large-scale industrial production.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir, microcrystalline cellulose and sodium carboxymethyl starch evenly, add the binder solution to wet Method of granulation and drying, the dry granules are sieved and granulated, and then sodium stearyl fumarate is added for total mixing and tableting.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir and sodium carboxymethyl starch evenly, add the binder solution for wet granulation and drying, The dry granules are sieved and granulated, then crospovidone and sodium stearyl fumarate are added for total mixing and then compressed.
  • Favipiravir tablet composition :
  • Dissolve copovidone VA64 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir and sodium carboxymethyl starch evenly, add the binder solution for wet granulation and drying, The dry granules are sieved and granulated, then crospovidone and sodium stearyl fumarate are added for total mixing and then compressed.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir, microcrystalline cellulose and sodium carboxymethyl starch evenly, add the binder solution to wet Method of granulation and drying, the dry granules are sieved and granulated, then cross-linked povidone and sodium stearyl fumarate are added for total mixing and then compressed.
  • Favipiravir tablet composition :
  • Favipiravir tablet composition :
  • Dissolve 2/3 povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir, mannitol, sodium carboxymethyl starch and 1/3 povidone K30 Evenly, the binder solution is added for wet granulation and drying, the dry granules are sieved and granulated, and crospovidone and sodium stearyl fumarate are added for total mixing and tableting.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir and carboxymethyl cellulose calcium evenly, add the binder solution for wet granulation and drying , The dry granules are sieved and granulated, then cross-linked povidone and sodium stearyl fumarate are added for total mixing and then compressed.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir to obtain a binder solution; mix favipiravir, silicified microcrystalline cellulose and carboxymethyl cellulose calcium, and add the binder solution
  • Wet granulation and drying are carried out, the dry granules are sieved and granulated, and crospovidone and sodium stearyl fumarate are added for total mixing and then compressed.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir and corn starch uniformly, add the binder solution for wet granulation and drying, and dry granules for After sieving and granulating, add cross-linked povidone and sodium stearyl fumarate for total mixing and then press tablets.
  • Favipiravir tablet composition :
  • Dissolve povidone K30 in purified water then add silicon dioxide and stir evenly to obtain a binder solution; mix favipiravir, microcrystalline cellulose and the internally added crospovidone evenly, and add the adhesive
  • the agent solution is subjected to wet granulation and drying, and the dry granules are sieved and granulated, and then an additional part of cross-linked povidone and sodium stearyl fumarate are added for total mixing and tableting.
  • Favipiravir tablet composition :
  • the comparative example 3 is the comparative example 4 of the patent CN201080011876.6. As shown in Comparative Example 4 of Patent CN201080011876.6, the favipiravir tablet only dissolves 76.3% in 15 minutes in the in vitro dissolution test.
  • Favipiravir tablet composition :
  • the comparative example 4 is the comparative example 5 of the patent CN201080011876.6. As shown in Comparative Example 5 of Patent CN201080011876.6, the favipiravir tablet only dissolves 63.6% in 15 minutes in the in vitro dissolution test.
  • the favipiravir tablets prepared in Examples 1-7 and the favipiravir tablets in Comparative Examples 1-3 were subjected to the determination of the dissolution profile according to the second method of the Chinese Pharmacopoeia (paddle method).
  • the rotating speed of the stirring blade is 50rpm
  • the dissolution medium is pH4.5 acetate buffer
  • the volume of the medium is 900ml
  • the temperature of the medium is 37°C ⁇ 0.5°C.
  • Example 1 63 81 89 94 98
  • Example 2 70 82 89 93 97
  • Example 3 72 84 90 94 97
  • Example 4 66 80 88 93 97
  • Example 5 73 84 90 94 98
  • Example 6 69 78 85 89 95
  • Example 7 73 83 88 92 96
  • Example 8 60 77 87 93 99 Comparative Example 1 63 72 79 83 89 Comparative Example 2 51 68 78 86 94

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition de Favipiravir, un comprimé de Favipiravir, et son procédé de préparation. La composition contient du Favipiravir ou un sel de celui-ci, une ou une combinaison de deux d'un carboxyméthyl amidon sodique (CMS) délitant ou d'une carboxyméthylcellulose calcique, constituant 2,5 % à 15 % du poids de la composition, et un adhésif. La teneur en médicament de la composition de Favipiravir est élevée, et la libération rapide de Favipiravir peut être obtenue ; dans des essais de dissolution in vitro, ≥ 85 % a été dissous en 15 minutes.
PCT/CN2020/118723 2020-06-19 2020-09-29 Composition de favipiravir et son procédé de préparation WO2021253681A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080100612.1A CN115551484A (zh) 2020-06-19 2020-09-29 一种法匹拉韦组合物及其制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010565808 2020-06-19
CN202010565808.X 2020-06-19

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Publication Number Publication Date
WO2021253681A1 true WO2021253681A1 (fr) 2021-12-23

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102348458A (zh) * 2009-03-13 2012-02-08 富山化学工业株式会社 含有6-氟-3-羟基-2-吡嗪甲酰胺的片剂和粒状粉剂
CN105687152A (zh) * 2016-03-22 2016-06-22 山东齐都药业有限公司 一种法匹拉韦快速释放药物制剂及制备方法
CN106667926A (zh) * 2015-11-09 2017-05-17 石药集团中奇制药技术（石家庄）有限公司 一种法匹拉韦片剂及其制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112236146A (zh) * 2018-04-24 2021-01-15 盐野义制药株式会社 稳定性优良的固体制剂

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102348458A (zh) * 2009-03-13 2012-02-08 富山化学工业株式会社 含有6-氟-3-羟基-2-吡嗪甲酰胺的片剂和粒状粉剂
CN106667926A (zh) * 2015-11-09 2017-05-17 石药集团中奇制药技术（石家庄）有限公司 一种法匹拉韦片剂及其制备方法
CN105687152A (zh) * 2016-03-22 2016-06-22 山东齐都药业有限公司 一种法匹拉韦快速释放药物制剂及制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHANG PEIMING , LIU LIN , LEI YAOLONG: "Research Progress of Antiviral Drug Favipiravir from the Perspective of Patent", CHINA INVENTION & PATENT, vol. 17, no. 5, 16 May 2020 (2020-05-16), pages 50 - 57, XP055882274, ISSN: 1672-6081 *

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