WO2023025220A1 - Composition pharmaceutique d'ibuprofène et d'antagoniste d'ions calcium, et application - Google Patents

Composition pharmaceutique d'ibuprofène et d'antagoniste d'ions calcium, et application Download PDF

Info

Publication number
WO2023025220A1
WO2023025220A1 PCT/CN2022/114659 CN2022114659W WO2023025220A1 WO 2023025220 A1 WO2023025220 A1 WO 2023025220A1 CN 2022114659 W CN2022114659 W CN 2022114659W WO 2023025220 A1 WO2023025220 A1 WO 2023025220A1
Authority
WO
WIPO (PCT)
Prior art keywords
arni
amlodipine
pharmaceutical composition
calculated
composition according
Prior art date
Application number
PCT/CN2022/114659
Other languages
English (en)
Chinese (zh)
Inventor
孙晶超
肖瑛
邢伟
吴继纲
Original Assignee
深圳信立泰药业股份有限公司
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 深圳信立泰药业股份有限公司 filed Critical 深圳信立泰药业股份有限公司
Priority to CN202280006430.7A priority Critical patent/CN116157119A/zh
Publication of WO2023025220A1 publication Critical patent/WO2023025220A1/fr

Links

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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the invention belongs to the technical field of pharmaceutical compositions, and relates to a pharmaceutical composition and application of ARNi and a calcium ion antagonist.
  • WO2007056546A1 discloses a sodium salt complex (LCZ696) of Valsartan (Sacubitril, AHU377) and its preparation method, which was approved for marketing in China in 2017. The trade name is: (Commodities listed abroad are named 2015) for heart failure. Its molecular structure unit is as follows:
  • WO2017125031A1 discloses a series of complexes composed of metabolites of angiotensin receptor antagonist (EXP3174) and NEP inhibitor (Sacubitril), the molecular structural units of which are as follows:
  • Amlodipine is a calcium ion antagonist that acts directly on peripheral arterial smooth muscle to reduce peripheral vascular resistance, thereby lowering blood pressure. Its existing forms include racemic amlodipine, levamlodipine, dexamlodipine, or a mixture of levamlodipine and dexamlodipine in any ratio; and, amlodipine can exist in the form of a salt, Including amlodipine besylate, amlodipine maleate, etc.
  • the object of the present invention is to provide a pharmaceutical composition, characterized in that the pharmaceutical composition is composed of ARNi and a calcium ion antagonist, wherein the structural unit of ARNi is as follows:
  • ARNi The structural formula of ARNi is as follows:
  • n is selected from 1, 1.5, 2, 2.5 and 3.
  • ARNi can be obtained through the preparation methods of WO2017125031A1 and WO2021143898A1, and the related preparation methods and obtained substances are introduced into this patent.
  • ARNi is preferably selected from:
  • the calcium ion antagonist is selected from amlodipine.
  • the mass ratio of the ARNi (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) to amlodipine (calculated as C 20 H 25 N 2 O 5 Cl) is 240: 1.25 ⁇ 20.
  • the mass ratio of the ARNi (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) to amlodipine (calculated as C 20 H 25 N 2 O 5 Cl) is 240: 1.25, 240:2.5, 240:5, 240:7.5 and 240:10, preferably 240:5.
  • ARNi (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) in the pharmaceutical composition is selected from 60-480 mg.
  • the ARNi (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) is selected from 60, 120, 240, 300, 360, 420 and 480 mg.
  • the amlodipine (calculated as C 20 H 25 N 2 O 5 Cl) in the pharmaceutical composition is selected from 2.5-10 mg.
  • the amlodipine (calculated as C 20 H 25 N 2 O 5 Cl) is selected from 2.5, 5, 7.5 and 10 mg.
  • the pharmaceutical composition is composed of ARNi and a calcium ion antagonist, including:
  • ARNi (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) 120 mg, amlodipine (calculated as C 20 H 25 N 2 O 5 Cl) 2.5 mg;
  • ARNi (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) 240 mg, amlodipine (calculated as C 20 H 25 N 2 O 5 Cl) 5 mg;
  • ARNi (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) 360 mg, amlodipine (calculated as C 20 H 25 N 2 O 5 Cl) 7.5 mg;
  • ARNi (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) 480 mg, amlodipine (calculated as C 20 H 25 N 2 O 5 Cl) 10 mg.
  • amlodipine Selected from racemic amlodipine, levamlodipine Dexamlodipine, or a mixture of levamlodipine and dexamlodipine in any proportion; amlodipine is in the form of a salt, selected from amlodipine besylate Amlodipine maleate, and levamlodipine besylate, levamlodipine maleate wait.
  • the pharmaceutical composition also contains more than one pharmaceutically acceptable carrier, and the pharmaceutical composition is prepared into a suitable pharmaceutical dosage form by preparation means, and the dosage form includes solid oral dosage forms and the like.
  • the present invention further provides the use of a pharmaceutical composition, wherein the pharmaceutical composition is used in the preparation of medicines for the treatment of heart failure and/or hypertension, and the hypertension includes essential hypertension, so
  • the above-mentioned heart failure includes heart failure with reduced ejection fraction and heart failure with preserved ejection fraction.
  • the use includes the application of ARNi as a drug for hypertension/heart failure patients poorly controlled by single drug, or the application of calcium ion antagonist as a drug for patients with hypertension/heart failure poorly controlled by single drug.
  • the present invention has the following advantages and beneficial effects:
  • the present invention provides a combination of ARNi and calcium ion antagonist, the combination achieves synergistic effect through the specific mass ratio of ARNi and calcium ion antagonist, which is beneficial to improve the effect of treating heart failure and/or hypertension.
  • the combination of amlodipine and the drug of the present invention increases the exposure of the angiotensin receptor antagonist ARB (the EXP3174 of the ARNi complex of the present invention compared to the valsartan of LCZ696) obvious.
  • the use of the drug combination further includes the application of ARNi single-drug poorly controlled hypertension/heart failure patients, or the drug of calcium ion antagonist single-drug poorly controlled hypertension/heart failure patients applications have better results.
  • the raw materials used in the present invention can be obtained by known preparation methods in the prior art, including the methods described in WO2017125031A1 and WO2021143898A1.
  • ARNi in the embodiment of the present invention is a compound of the following formula, and its usage amount is based on anhydrous free acid C 46 H 50 ClN 7 O 7 :
  • amlodipine used is amlodipine besylate, and the usage amount is based on free concentration C 20 H 25 N 2 O 5 Cl:
  • ARNi Accurately weigh ARNi, LCZ696 and amlodipine besylate, add 0.5% CMC-Na and vortex dispersion respectively, so that the concentration of ARNi or LCZ696 is 48 mg/mL, and the concentration of amlodipine (free concentration) is 0.125, 0.25, 0.5, 1.0, 2.0 and 4.0 mg/mL.
  • EXP3174 after oral administration of ARNi and amlodipine in different ratios to rats showed different changes compared with the single drug administration of the same dose of ARNi. Compared with 240mg/kg ARNi single drug, the exposure decreased (about 11.5%), but with the increase of ARNi and amlodipine ratio, the exposure of EXP3174 increased compared with the ARNi single drug group, Among them, ARNi and amlodipine administered at a ratio of 240:5 increased the exposure of EXP3174 with the highest ratio (increased ratio was 35.8%).
  • the rat PK experiment shows that the combination of ARNi and amlodipine of the present invention is better than ARNi alone, and also better than the combination of LCZ696 and amlodipine.
  • EXP3174 and AHU377 achieve a synergistic effect of EXP3174 exposure through the combination of the complex ARNi composed of 1.5Ca and amlodipine (according to the free concentration mass ratio of 240:1.25-20, especially the mass ratio of 240:5). Use can enhance the effect for hypertension and/or heart failure.
  • WKY rats and SHR rats were purchased from Beijing Weitong Lihua Biotechnology Co., Ltd., and they entered the animal room at the age of 13 weeks, and the experiments were carried out after about 2 weeks of pot life.
  • Test substances ARNi, amlodipine and LCZ696 were provided by Shenzhen Xinlitai Pharmaceutical Co., Ltd.
  • Drug preparation 0.5% CMC-Na is used for preparation, and the concentration of the prepared drugs is calculated in anhydrous free form.
  • mice On the day before the administration, the animals were randomly divided into 4 groups according to their basal blood pressure and body weight. See Table 3 for the specific grouping and administration scheme.
  • group 3 and group 4 selected rats with poor blood pressure control (SBP ⁇ 140mmHg) according to the 24h blood pressure control situation to continue the experiment, and group 4 was randomly divided into three groups (group 4, group 5, group 6), see Table 4 for the specific grouping and dosing regimen.
  • the amount of ARNi complex used in this example is based on anhydrous free acid C 46 H 50 ClN 7 O 7 .
  • the amlodipine used is amlodipine besylate, and its usage amount is calculated by free concentration C 20 H 25 N 2 O 5 Cl.
  • WKY rats and SHR rats were purchased from Beijing Weitong Lihua Biotechnology Co., Ltd., and they entered the animal room at the age of 13 weeks, and the experiments were carried out after about 2 weeks of pot life.
  • Test substances ARNi and amlodipine were provided by Shenzhen Xinlitai Pharmaceutical Co., Ltd.
  • Drug preparation 0.5% CMC-Na is used for preparation, and the concentration of the prepared drugs is calculated in anhydrous free form.
  • mice On the day before the administration, the animals were randomly divided into 4 groups according to their basal blood pressure and body weight. See Table 6 for the specific grouping and administration scheme.
  • group 3 and group 4 selected rats with poor blood pressure control (SBP ⁇ 140mmHg) according to the 24h blood pressure control situation to continue the experiment, group 3 was randomly divided into two groups (group 3, group 5), See the table for specific groups and dosing regimens. .
  • the amount of ARNi complex used in this example is based on anhydrous free acid C 46 H 50 ClN 7 O 7 .
  • the amlodipine used is amlodipine besylate, and its usage amount is calculated by free concentration C 20 H 25 N 2 O 5 Cl.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition pharmaceutique d'ARNi et d'un antagoniste d'ions calcium, et une application. La composition pharmaceutique peut être utilisée pour des maladies telles que l'hypertension et l'insuffisance cardiaque.
PCT/CN2022/114659 2021-08-26 2022-08-25 Composition pharmaceutique d'ibuprofène et d'antagoniste d'ions calcium, et application WO2023025220A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280006430.7A CN116157119A (zh) 2021-08-26 2022-08-25 一种ARNi与钙离子拮抗剂的药物组合物与应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110985830.4 2021-08-26
CN202110985830 2021-08-26

Publications (1)

Publication Number Publication Date
WO2023025220A1 true WO2023025220A1 (fr) 2023-03-02

Family

ID=85322511

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/114659 WO2023025220A1 (fr) 2021-08-26 2022-08-25 Composition pharmaceutique d'ibuprofène et d'antagoniste d'ions calcium, et application

Country Status (4)

Country Link
CN (1) CN116157119A (fr)
AR (1) AR126886A1 (fr)
TW (1) TW202327582A (fr)
WO (1) WO2023025220A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024027779A1 (fr) * 2022-08-04 2024-02-08 深圳信立泰药业股份有限公司 Nouvelle forme cristalline de composé arni, son procédé de préparation et son utilisation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102702119A (zh) * 2005-11-09 2012-10-03 诺瓦提斯公司 血管紧张素受体拮抗剂和nep抑制剂的药物组合产品
WO2017125031A1 (fr) * 2016-01-20 2017-07-27 深圳信立泰药业股份有限公司 Métabolite antagoniste du récepteur de l'angiotensine ii et composite inhibiteur de la nep, et procédé de préparation associé
CN109865139A (zh) * 2017-12-04 2019-06-11 深圳信立泰药业股份有限公司 一种阿利沙坦酯或其盐与钙离子通道拮抗剂的复方药物组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102702119A (zh) * 2005-11-09 2012-10-03 诺瓦提斯公司 血管紧张素受体拮抗剂和nep抑制剂的药物组合产品
WO2017125031A1 (fr) * 2016-01-20 2017-07-27 深圳信立泰药业股份有限公司 Métabolite antagoniste du récepteur de l'angiotensine ii et composite inhibiteur de la nep, et procédé de préparation associé
CN109865139A (zh) * 2017-12-04 2019-06-11 深圳信立泰药业股份有限公司 一种阿利沙坦酯或其盐与钙离子通道拮抗剂的复方药物组合物

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "To evaluate the single center, open, single and combined pharmacokinetics of S086 tablets and amlodipine besylate tablets in healthy subjects", SHENZHEN SALUBRIS PHARMACEUTICALS CO., LTD., 15 June 2022 (2022-06-15), XP093039534, Retrieved from the Internet <URL:http://zy.yaozh.com/linchuangshiyan/pdf/CTR20221444.pdf> [retrieved on 20230417] *
CHEN, SHENJUE; KUANG, ZE-MIN; YUAN, HONG; HUANG, ZHI-JUN; ZUO, XIAO-CONG: "Advances in research on interactions between amlodipine and other drugs", CHINESE JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, CHINESE PHARMACOLOGICAL SOCIETY, CHINA, vol. 19, no. 6, 30 June 2014 (2014-06-30), CHINA , pages 701 - 706, XP009543861, ISSN: 1009-2501 *
JILIN UNIVERSITY HOSPITAL: "Evaluation of the pharmacokinetics of alisartan Ester Tablets and amlodipine besylate tablets in a single-center, open-label, steady state, single dose and combination dose, phase I study for pharmacokinetics of Allisartan tablets and Amlodipine tablets in healthy volunteers", CHINESE CLINICAL TRIAL REGISTRY, CN, no. ChiCTR1900026661, CN, pages 1 - 4, XP009544001, Retrieved from the Internet <URL:http://www.chictr.org.cn/showproj.aspx?proj=44430> *
LI XIULI, SUN JINGCHAO, GUO ZITAO, ZHONG DAFANG, CHEN XIAOYAN: "Carboxylesterase 2 and Intestine Transporters Contribute to the Low Bioavailability of Allisartan, a Prodrug of Exp3174 for Hypertension Treatment in Humans", DRUG METABOLISM AND DISPOSITION, PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, US, vol. 47, no. 8, 1 August 2019 (2019-08-01), US , pages 843 - 853, XP093039535, ISSN: 0090-9556, DOI: 10.1124/dmd.118.085092 *
SUN, JINGCHAO ET AL.: "Pharmacodynamic and pharmacokinetic effects of S086, a novel angiotensin receptor neprilysin inhibitor,", BIOMEDICINE & PHARMACOTHERAPY, vol. 129, 31 December 2020 (2020-12-31), pages 1 - 10, XP055793583, DOI: 10.1016/j.biopha.2020.110410 *
WANG WANG JI-GUANG JI-GUANG, YUKISADA KIMIHIKO, SIBULO ANTONIO, HAFEEZ KUDSIA, JIA YAN, ZHANG JACK: "Efficacy and safety of sacubitril/valsartan (LCZ696) add-on to amlodipine in Asian patients with systolic hypertension uncontrolled with amlodipine monotherapy", JOURNAL OF HYPERTENSION., LIPPINCOTT WILLIAMS & WILKINS, LTD., GB, vol. 35, no. 4, 30 April 2017 (2017-04-30), GB , pages 877 - 885, XP009543891, ISSN: 0263-6352, DOI: 10.1097/HJH.0000000000001219 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024027779A1 (fr) * 2022-08-04 2024-02-08 深圳信立泰药业股份有限公司 Nouvelle forme cristalline de composé arni, son procédé de préparation et son utilisation

Also Published As

Publication number Publication date
CN116157119A (zh) 2023-05-23
TW202327582A (zh) 2023-07-16
AR126886A1 (es) 2023-11-22

Similar Documents

Publication Publication Date Title
JP6738376B2 (ja) 低減された投与容量を必要とする患者におけるベンダムスチン応答性症状の治療方法
JP4846063B2 (ja) 選択的ｓ１ｐ１レセプターアゴニストの投与法
EP3682902A1 (fr) Formulation liquide
CN102133171A (zh) 延缓释放阿立哌唑的可注射组合物
BR112013014642A2 (pt) produto farmacêutico, kit, uso, produtos, métodos e usos inovadores
WO2008122190A1 (fr) Composition comprenant de la l-carnitine ou ses dérivés et son utilisation
TW200815014A (en) Method of improved diuresis in individuals with impaired renal function
WO2023025220A1 (fr) Composition pharmaceutique d&#39;ibuprofène et d&#39;antagoniste d&#39;ions calcium, et application
US20210353648A1 (en) Grapiprant unit dosage forms
TWI341728B (en) Combinations comprising epothilones and anti-metabolites
CN109833481B (zh) 一种阿利沙坦酯或其盐与利尿剂的药物组合物
CN1394601A (zh) 联合化学疗法
EP4364742A1 (fr) Composition pharmaceutique pour le traitement de tumeurs solides
US20080312250A1 (en) Combination Comprising a Bcrp Inhibitor and 4- (4-Methylpiperazin-1-Ylmethyl)-N-[4-Methyl-3- (4-Pyridin-3-Yl) Pyrimidin-2-Ylamino) Phenyl] -Benzamide
EP1518554B1 (fr) Composition pharmaceutique pour le traitement de l&#39;hyperhomocystéinémie
CN116999442A (zh) 一种含有艾沙利酮和氢氯噻嗪的药物组合物
WO2021224494A1 (fr) Nouveaux traitements d&#39;infections virales
JPH02121925A (ja) 腎ドーパミン様作用剤とアンジオテンシン変換酵素抑制剤の相乗作用を有する組成物
Torun Approach to cases with resistant hypertension.
US20030139430A1 (en) Use of organic compounds
JP2023020885A (ja) 透析患者に適用される注射用医薬組成物
US20080108603A1 (en) Combination therapy for the treatment of pain
EP4110326A1 (fr) Combinaison comprenant de l&#39;alpelisib et de l&#39;acide 6-(2,4-dichlorophényle)-5-[4-[(3s)-1-(3-fluoropropyl) pyrrolidin-3-yl] oxyphényl]-8,9-dihydro-7h-benzo[7]annulène-2-carboxylique
WO2023159200A1 (fr) Utilisations d&#39;ivaltinostat pour le traitement du cancer du pancréas
TW200403054A (en) Drug composition for prevention or inhibition of advance of diabetic complication

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: 22860566

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202490366

Country of ref document: EA

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112024003633

Country of ref document: BR

NENP Non-entry into the national phase

Ref country code: DE