WO2019205021A1 - Bromhydrate de ténéligliptine amorphe et son procédé de préparation - Google Patents

Bromhydrate de ténéligliptine amorphe et son procédé de préparation Download PDF

Info

Publication number
WO2019205021A1
WO2019205021A1 PCT/CN2018/084459 CN2018084459W WO2019205021A1 WO 2019205021 A1 WO2019205021 A1 WO 2019205021A1 CN 2018084459 W CN2018084459 W CN 2018084459W WO 2019205021 A1 WO2019205021 A1 WO 2019205021A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrobromide
amorphous
temperature
solvent
amorphous form
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2018/084459
Other languages
English (en)
Chinese (zh)
Inventor
张�杰
王磊鑫
陈勇
罗忠华
黄芳芳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
RUYUAN HEC PHARM CO Ltd
Sunshine Lake Pharma Co Ltd
Original Assignee
RUYUAN HEC PHARM CO Ltd
Sunshine Lake Pharma Co Ltd
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 RUYUAN HEC PHARM CO Ltd, Sunshine Lake Pharma Co Ltd filed Critical RUYUAN HEC PHARM CO Ltd
Priority to PCT/CN2018/084459 priority Critical patent/WO2019205021A1/fr
Priority to JP2021508035A priority patent/JP2021522332A/ja
Publication of WO2019205021A1 publication Critical patent/WO2019205021A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the technical field of organic and pharmaceutical synthesis, and particularly relates to an amorphous form of tigeaglin hydrobromide and a preparation method thereof.
  • Tiglipstatin hydrobromide English name: Teneligliptin Hydrobromide Hydrate, chemical name: 3- ⁇ (2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazole-5- Peptazin-1-yl]pyrrolidin-2-ylcarbonyl ⁇ thiazolidine 2.5 hydrobromide hydrate
  • Formula (I) Original research company Japan's Mitsubishi Tanabe Pharmaceutical Co., Ltd., listed in Japan in 2012, is suitable for the treatment of type 2 diabetes.
  • Mechanism of action DPP-IV inhibitor.
  • CN101119991B reports a 1.0-2.0 hydrate crystal form of tiglistatin 2.5 hydrobromide salt, which has many impurities in the process of preparing its hydrate crystal form, and has a patent barrier.
  • the present invention overcomes the patent barrier problem existing in the prior art method for preparing ticagrelor 2.5 hydrobromide hydrate, and provides a method for preparing tigelastine 2.5 hydrobromide salt and a preparation method thereof. It is simple, efficient and economical, and the quality of the intermediate is controllable, which is suitable for industrial preparation.
  • the amorphous form prepared by the invention has been successfully applied to the preparation product and has good stability.
  • the present invention provides an amorphous form of tiglietine 2.5 hydrobromide.
  • the technical feature of the present invention is that the crystal form of the crystal form is characterized by X-ray powder diffraction analyzer (PXRD) diffraction detection, and the result proves to be amorphous.
  • PXRD X-ray powder diffraction analyzer
  • thermogravimetric spectrum is detected by differential scanning calorimetry (DSC): the decomposition temperature is about 239.39 °C.
  • the tigeraceine 2.5 hydrobromide amorphous has a moisture content of from 0 to 8%.
  • the invention provides a method for the amorphous form of tiglietine 2.5 hydrobromide, which is prepared by dissolving tiglietine 2.5 hydrobromide hydrate in a certain amount of solvent, using a rotary evaporator for rotary steaming, in a certain water bath. The mixture was steamed under reduced pressure at a temperature to finally obtain an amorphous form of tiglistatin 2.5 hydrobromide.
  • the solvent is water, C 1 -C 5 alcohols or mixtures thereof.
  • the solvent is water or an alcohol in C 1 -C 5.
  • the alcohol is, but not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol.
  • the mass-to-volume ratio of the amount of ticastatin 2.5 hydrobromide hydrate to solvent is from about 1 g/100 ml to 1 g/1 ml.
  • it is from about 1 g/10 ml to 1 g/20 ml.
  • the water bath temperature is between about 20 ° C and 100 ° C.
  • it is between about 40 ° C and 60 ° C.
  • the invention provides a method for the amorphous form of tiglietine 2.5 hydrobromide, which is prepared by dissolving tiglietine 2.5 hydrobromide hydrate in a certain amount of solvent, spray drying the solution by a spray dryer, and setting a certain amount. Inlet air temperature, outlet air temperature, pumping rate, and peristaltic pump speed. Final spray drying gave an amorphous form of tiglistatin 2.5 hydrobromide salt.
  • the solvent is water, C 1 -C 5 alcohols or mixtures thereof.
  • the solvent is water or an alcohol in C 1 -C 5.
  • the alcohol is, but not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol.
  • the quantity by volume ratio of the amount of tiguletine 2.5 hydrobromide hydrate to solvent is from about 1 g/1000 ml to 1 g/1 ml.
  • it is from about 1 g/10 ml to 1 g/20 ml.
  • the inlet air temperature is between about 50 ° C and 300 ° C.
  • it is between about 140 °C and 170 °C.
  • the outlet temperature is between about 50 ° C and 150 ° C.
  • it is from about 92 °C to 87 °C.
  • the pumping rate is between 20% and 100%.
  • the peristaltic pump has a rotational speed of 5% to 100%.
  • the present invention provides a method for the amorphous form of tiglietine 2.5 hydrobromide, which is prepared by dissolving tiguletine 2.5 hydrobromide hydrate in a certain amount of solvent, lyophilizing the solution, setting a certain freezing temperature, One drying temperature and one dry vacuum, and analytical drying temperature and analytical vacuum. Final freeze-drying gave an amorphous form of tiglistatin 2.5 hydrobromide.
  • the solvent is water, C 1 -C 5 alcohols or mixtures thereof.
  • the solvent is water or an alcohol in C 1 -C 5.
  • the solvent is water.
  • the quantity by volume ratio of the amount of tiguletine 2.5 hydrobromide hydrate to solvent is from about 1 g/1000 ml to 1 g/1 ml.
  • it is from about 1 g/10 ml to 1 g/20 ml.
  • the freezing temperature is from about -50 ° C to the point of solidification of the solvent.
  • it is about -35 °C.
  • the primary drying temperature is between -20 ° C and 20 ° C.
  • the primary dry vacuum is from 0.2 mpar to 1 mpar. .
  • the analytical drying temperature is from -5 °C to 20 °C.
  • the analytical dry vacuum is from 0.05 mpar to 1 mpar.
  • the present invention provides the results of the influencing factors of tiguestatine 2.5 hydrobromide salt, the conditions are as follows (the hydrate given in the table refers to the hydrate crystal form (1.0-2.0H 2 O) in the patent US2011282058A1):
  • tigestatin 2.5 hydrobromide amorphous was unstable under high temperature (60 ° C) and high humidity (93%) conditions, and was easily converted into hydrate crystal form; in light (UV + light) and sealed dry conditions Under the amorphous type, no change occurred, indicating that the amorphous type is relatively stable under light conditions and sealed dry conditions. This amorphous type is recommended for storage at room temperature and under sealed dry conditions.
  • the invention provides the results of long-term stability determination of tigelastine 2.5 hydrobromide salt, and the conditions are as follows: a sample of the cisplatin hydrobromide (2.5HBr) amorphous drug substance is sealed in a PE bag, and then placed in an aluminum foil bag. The desiccant was added at the same time, and finally vacuum sealed, placed in a 25 ° C incubator to investigate the long-term stability.
  • a sample of the cisplatin hydrobromide (2.5HBr) amorphous drug substance is sealed in a PE bag, and then placed in an aluminum foil bag.
  • the desiccant was added at the same time, and finally vacuum sealed, placed in a 25 ° C incubator to investigate the long-term stability.
  • the ml is milliliters
  • min is minutes
  • g is grams
  • room temperature is 10 ° C to 30 ° C
  • the English code in the instrumentation is the specific model of the device.
  • Example 1 is an XRPD characterization spectrum of an amorphous crystalline form of ticagrelor 2.5 hydrobromide salt prepared in Example 1;
  • Example 2 is an amorphous crystalline form DSC characterization chart of ticastatin 2.5 hydrobromide salt prepared in Example 1;
  • Example 3 is a graph showing the amorphous TGA characterization of tiguletine 2.5 hydrobromide salt prepared in Example 1;
  • Figure 4 is an XRD spectrum of tigestatin 2.5 hydrobromide salt after 5 days of amorphous high temperature, light, sealed dry storage;
  • Figure 5 is a DSC chart of tigeglitin 2.5 hydrobromide salt after 5 days of amorphous high temperature, light, sealed dry storage;
  • Figure 6 is a TGA diagram of tigestatin 2.5 hydrobromide salt after 5 days of amorphous high temperature, light, sealed dry storage;
  • Figure 7 is an XRD spectrum of tiguestatine 2.5 hydrobromide salt after 10 days of amorphous high temperature, light, sealed dry storage;
  • Figure 8 is a DSC chart of tigeglitin 2.5 hydrobromide salt after 10 days of amorphous high temperature, light, sealed dry storage;
  • Figure 9 is a TGA diagram of tigeglitin 2.5 hydrobromide salt after 10 days of amorphous high temperature, light, sealed dry storage;
  • Figure 10 is an XRD spectrum of tiguestatine 2.5 hydrobromide salt after 15 days of amorphous high temperature, light, sealed dry storage;
  • Figure 11 is a DSC chart of tigeglitin 2.5 hydrobromide salt after 15 days of amorphous high temperature, light, sealed dry storage;
  • Figure 12 is a TGA diagram of tigestatin 2.5 hydrobromide salt after 15 days of amorphous high temperature, light, sealed dry storage.
  • reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
  • the present invention can monitor the degree of reaction of the raw materials by TLC or HPLC, as monitored by HPLC, and the reaction is completed when the peak area is less than 1.0%.
  • the method for preparing an amorphous crystalline form of tiglietine 2.5 hydrobromide hydrate provided by the present invention has the advantages of simplicity, high efficiency, economy, and the like.
  • the parameters of the DSC method are as follows:
  • the TGA method parameters are as follows:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un bromhydrate (2,5) de ténéligliptine amorphe et son procédé de préparation. Le procédé comprend : l'évaporation rotative d'un hydrate de bromhydrate (2,5) de ténéligliptine à une certaine température du bain-marie à l'aide d'un évaporateur rotatif ; ou la dissolution d'un hydrate de bromhydrate (2,5) de ténéligliptine dans un solvant, et le séchage par pulvérisation de la solution à l'aide d'un séchoir par pulvérisation ; ou la lyophilisation d'une solution d'hydrate de bromhydrate (2,5) de ténéligliptine pour préparer le bromhydrate (2,5) de ténéligliptine amorphe. Le procédé est simple, efficace et économique, la qualité de l'intermédiaire peut être contrôlée, et le procédé est approprié pour une préparation industrielle. Le produit de préparation préparé est stable.
PCT/CN2018/084459 2018-04-25 2018-04-25 Bromhydrate de ténéligliptine amorphe et son procédé de préparation Ceased WO2019205021A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2018/084459 WO2019205021A1 (fr) 2018-04-25 2018-04-25 Bromhydrate de ténéligliptine amorphe et son procédé de préparation
JP2021508035A JP2021522332A (ja) 2018-04-25 2018-04-25 テネリグリプチン臭化水素酸塩アモルファス及びその調製方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2018/084459 WO2019205021A1 (fr) 2018-04-25 2018-04-25 Bromhydrate de ténéligliptine amorphe et son procédé de préparation

Publications (1)

Publication Number Publication Date
WO2019205021A1 true WO2019205021A1 (fr) 2019-10-31

Family

ID=68294358

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/084459 Ceased WO2019205021A1 (fr) 2018-04-25 2018-04-25 Bromhydrate de ténéligliptine amorphe et son procédé de préparation

Country Status (2)

Country Link
JP (1) JP2021522332A (fr)
WO (1) WO2019205021A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20210121421A (ko) 2020-03-30 2021-10-08 코오롱생명과학 주식회사 테네리글리프틴 2.5브롬화수소산염 무정형의 제조방법
JP2021161096A (ja) * 2020-04-03 2021-10-11 金剛化学株式会社 テネリグリプチン塩のアモルファス形態及びその製造方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117379383A (zh) * 2023-11-01 2024-01-12 上海旭东海普药业有限公司 一种注射用右雷佐生冻干粉针的生产工艺

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102372705A (zh) * 2005-02-18 2012-03-14 田边三菱制药株式会社 脯氨酸衍生物的盐，其溶剂合物，及其生产方法
CN103649055A (zh) * 2011-06-01 2014-03-19 田边三菱制药株式会社 用于制备吡唑衍生物的方法
CN104230917A (zh) * 2013-06-24 2014-12-24 南京华威医药科技开发有限公司 一种脯氨酸衍生物盐的水合物及其生产方法
WO2015019239A1 (fr) * 2013-08-06 2015-02-12 Ranbaxy Laboratories Limited Procédé pour la préparation de 1-(3-méthyl-1-phényl-1h-pyrazolo-5-yl)pipérazine
WO2015063709A1 (fr) * 2013-10-31 2015-05-07 Ranbaxy Laboratories Limited Procédé pour la préparation de la 1-(3-méthyl-1-phényl-1h-pyrazol-5-yl)pipérazine
CN104650065A (zh) * 2013-11-22 2015-05-27 天津市汉康医药生物技术有限公司 一种替格列汀化合物
US20150203484A1 (en) * 2012-08-31 2015-07-23 Glenmark Generics Limited Process for the preparation of teneligliptin
CN105294673A (zh) * 2014-06-18 2016-02-03 四川科伦药物研究院有限公司 一种氢溴酸替格列汀的合成方法
CN108727364A (zh) * 2017-04-18 2018-11-02 乳源东阳光药业有限公司 一种氢溴酸替格列汀无定型及其制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200510362A (en) * 2003-04-01 2005-03-16 Plus Chemicals Bv Amorphous simvastatin calcium and methods for the preparation thereof
EP2631234A1 (fr) * 2012-02-23 2013-08-28 Esteve Química, S.A. Formes solides de mesylate d'étexilate de dabigatran et leurs procédés de préparation

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102372705A (zh) * 2005-02-18 2012-03-14 田边三菱制药株式会社 脯氨酸衍生物的盐，其溶剂合物，及其生产方法
CN103649055A (zh) * 2011-06-01 2014-03-19 田边三菱制药株式会社 用于制备吡唑衍生物的方法
US20150203484A1 (en) * 2012-08-31 2015-07-23 Glenmark Generics Limited Process for the preparation of teneligliptin
CN104230917A (zh) * 2013-06-24 2014-12-24 南京华威医药科技开发有限公司 一种脯氨酸衍生物盐的水合物及其生产方法
WO2015019239A1 (fr) * 2013-08-06 2015-02-12 Ranbaxy Laboratories Limited Procédé pour la préparation de 1-(3-méthyl-1-phényl-1h-pyrazolo-5-yl)pipérazine
WO2015063709A1 (fr) * 2013-10-31 2015-05-07 Ranbaxy Laboratories Limited Procédé pour la préparation de la 1-(3-méthyl-1-phényl-1h-pyrazol-5-yl)pipérazine
CN104650065A (zh) * 2013-11-22 2015-05-27 天津市汉康医药生物技术有限公司 一种替格列汀化合物
CN105294673A (zh) * 2014-06-18 2016-02-03 四川科伦药物研究院有限公司 一种氢溴酸替格列汀的合成方法
CN108727364A (zh) * 2017-04-18 2018-11-02 乳源东阳光药业有限公司 一种氢溴酸替格列汀无定型及其制备方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20210121421A (ko) 2020-03-30 2021-10-08 코오롱생명과학 주식회사 테네리글리프틴 2.5브롬화수소산염 무정형의 제조방법
JP2021161096A (ja) * 2020-04-03 2021-10-11 金剛化学株式会社 テネリグリプチン塩のアモルファス形態及びその製造方法
JP2024095748A (ja) * 2020-04-03 2024-07-10 金剛化学株式会社 テネリグリプチン塩のアモルファス形態及びその製造方法
JP7788749B2 (ja) 2020-04-03 2025-12-19 金剛化学株式会社 テネリグリプチン塩のアモルファス形態及びその製造方法

Also Published As

Publication number Publication date
JP2021522332A (ja) 2021-08-30

Similar Documents

Publication Publication Date Title
TWI495472B (zh) Ｓｇｌｔ２抑制劑之晶型與非晶型
US11040961B2 (en) Co-crystals of SGLT2 inhibitors, process for their preparation and pharmaceutical compositions thereof
WO2019205021A1 (fr) Bromhydrate de ténéligliptine amorphe et son procédé de préparation
Díaz-Oltra et al. Study of the effect of polymorphism on the self-assembly and catalytic performance of an l-proline based molecular hydrogelator
JP6491217B2 (ja) シクロペプチド系化合物の結晶およびその製造方法と使用
CN102875531A (zh) 一种(r)-兰索拉唑无水晶型及其制备方法
CN108727364A (zh) 一种氢溴酸替格列汀无定型及其制备方法
CN111303099B (zh) 含笑内酯二甲基胺富马酸盐晶型f及其制备方法
Yu Competing role of water in inclusion of indomethacin and volatile organic compounds by native cyclodextrins
CN106995434A (zh) 一种三唑类抗真菌药的晶型及其制备方法
CN104109159A (zh) 苯磺酰胺噻唑化合物的新晶型及其制备方法
CN103512318A (zh) 胰岛素的冻干工艺
CN110467589B (zh) 一种炎琥宁无菌原料药的制备方法
CN115611921A (zh) 一种苯唑西林酸胺盐及相关晶型
WO2023064480A1 (fr) Sel monohydrate d'acétate de dénatonium
CN102249980B (zh) 一种控制色氨酸中4，5-色氨酸-二酮产生的工艺
CN101591372B (zh) 一种制备钴胺素晶体的耦合干燥工艺
CN118496183A (zh) 一种盐酸胺碘酮杂质f的合成方法及其应用
CN103827078B (zh) 制备阿戈美拉汀的晶型i的方法
CN119119324A (zh) 一种致密度可控的基于反式-2-己烯醛的羧甲基壳聚糖席夫碱及其制备方法和应用
CN108530502B (zh) 一种晶体形式戊柔比星的制备方法
CN104710439A (zh) 一种利福霉素-喹嗪酮双靶标分子的晶型i及其制备方法
CN107586301A (zh) 米尔贝a3肟晶型a及其制备方法
CN106432253A (zh) 一种维帕他韦新晶型及其制备方法
CN117417298A (zh) 一种卡马西平与均苯三甲酸的共晶结构及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18916684

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021508035

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC, EPO FORM 1205A DATED 09.02.2021

122 Ep: pct application non-entry in european phase

Ref document number: 18916684

Country of ref document: EP

Kind code of ref document: A1