MA54200B1 - Procédé industriel pour la préparation d'estétrol de pureté élevée - Google Patents
Procédé industriel pour la préparation d'estétrol de pureté élevéeInfo
- Publication number
- MA54200B1 MA54200B1 MA54200A MA54200A MA54200B1 MA 54200 B1 MA54200 B1 MA 54200B1 MA 54200 A MA54200 A MA 54200A MA 54200 A MA54200 A MA 54200A MA 54200 B1 MA54200 B1 MA 54200B1
- Authority
- MA
- Morocco
- Prior art keywords
- estetrol
- preparation
- high purity
- industrial process
- formula
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
- C07J1/0074—Esters
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Immunology (AREA)
- Gynecology & Obstetrics (AREA)
- Dermatology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Transplantation (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne la préparation d'estétrol de formule (i), des dérivés de ceux-ci protégés aux positions 3,15a, 16a, 17ß de formule générale (iii), et des dérivés 3-hydroxy de ceux-ci protégés aux positions 15a, 16a, 17ß de formule générale (iv), et des intermédiaires des formules générales (iii) et (iv) appliqués dans le procédé. Un autre aspect de l'invention concerne l'utilisation d'estétrol de formule (i) obtenu par le procédé de l'invention pour la préparation d'une composition pharmaceutique.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU1900315A HU231240B1 (hu) | 2019-09-03 | 2019-09-03 | Ipari eljárás nagytisztaságú ösztetrol hatóanyag előállítására |
| PCT/IB2020/058148 WO2021044302A1 (fr) | 2019-09-03 | 2020-09-02 | Procédé industriel pour la préparation d'estétrol de pureté élevée |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MA54200A MA54200A (fr) | 2022-04-27 |
| MA54200B1 true MA54200B1 (fr) | 2023-02-28 |
Family
ID=89992977
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MA54200A MA54200B1 (fr) | 2019-09-03 | 2020-09-02 | Procédé industriel pour la préparation d'estétrol de pureté élevée |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US11633406B2 (fr) |
| EP (1) | EP3877395B1 (fr) |
| JP (1) | JP7265087B2 (fr) |
| KR (1) | KR102871606B1 (fr) |
| CN (1) | CN114302889B (fr) |
| AU (1) | AU2020343497B2 (fr) |
| CA (1) | CA3147815C (fr) |
| CL (1) | CL2022000492A1 (fr) |
| CO (1) | CO2022003769A2 (fr) |
| CU (1) | CU24692B1 (fr) |
| DK (1) | DK3877395T3 (fr) |
| EC (1) | ECSP22022403A (fr) |
| ES (1) | ES2855923T3 (fr) |
| FI (1) | FI3877395T3 (fr) |
| GE (1) | GEP20247626B (fr) |
| HR (1) | HRP20230230T1 (fr) |
| HU (2) | HU231240B1 (fr) |
| IL (1) | IL290973B2 (fr) |
| JO (1) | JOP20220041A1 (fr) |
| LT (1) | LT3877395T (fr) |
| MA (1) | MA54200B1 (fr) |
| MD (1) | MD3877395T2 (fr) |
| MX (1) | MX2022002603A (fr) |
| MY (1) | MY206905A (fr) |
| PE (1) | PE20221418A1 (fr) |
| PH (1) | PH12022550388A1 (fr) |
| PL (1) | PL3877395T3 (fr) |
| PT (1) | PT3877395T (fr) |
| RS (1) | RS63966B1 (fr) |
| SI (1) | SI3877395T1 (fr) |
| WO (1) | WO2021044302A1 (fr) |
| ZA (1) | ZA202203557B (fr) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE112020004564T5 (de) * | 2019-09-27 | 2022-06-15 | Industriale Chimica S.R.L. | VERFAHREN ZUM HERSTELLEN VON (15α,16α,17β)-ESTRA-1,3,5(10)-TRIEN-3,15,16,17-TETROL (ESTETROL) UND ZWISCHENSTUFEN DES VERFAHRENS |
| HU231651B1 (hu) * | 2021-10-01 | 2025-05-28 | Industriale Chimica S.R.L. | Eljárás (15alfa,16alfa,17béta)-ösztra-1,3,5(10)-trién-3,15,16,17-tetrol (esztetrol) és esztetrol-monohidrát előállítására |
| JP2026503158A (ja) * | 2023-02-02 | 2026-01-27 | インダストリアーレ キミカ エッセ.エッレ.エッレ. | (15α,16α,17β)-エストラ-1,3,5(10)-トリエン-3,15,16,17-テトロール(エステトロール)一水和物の調製方法 |
| CN117088928B (zh) * | 2023-08-16 | 2025-09-09 | 湖北共同甾体药物研究院有限公司 | 用于制备高纯度雌四醇的工艺 |
| CN119569803B (zh) * | 2023-09-05 | 2025-09-16 | 秦皇岛紫竹药业有限公司 | 一种制备高纯度雌四醇的方法 |
| HUP2400151A1 (hu) | 2024-02-28 | 2025-09-28 | Richter Gedeon Nyrt | Ösztetrol-monohidrát kristályosítási eljárás |
| CN119112905B (zh) * | 2024-09-10 | 2026-07-28 | 武汉九珑人福药业有限责任公司 | 含雌孕激素的药物组合物、药物制剂及其制备方法、应用 |
Family Cites Families (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60217324T2 (de) | 2001-05-18 | 2007-04-26 | Pantarhei Bioscience B.V. | Pharmazeutische zusammensetzung für die hormonersatztherapie |
| EP1260225A1 (fr) | 2001-05-18 | 2002-11-27 | Pantarhei Bioscience B.V. | Compositions pharmaceutiques pour le traitement hormonal substitutif |
| DK1390042T3 (da) | 2001-05-23 | 2008-03-31 | Pantarhei Bioscience Bv | System for administration af et lægemiddel omfattende tetrahydroxyleret östrogen til anvendelse i hormonal svangerskabsforebyggelse |
| DE60234515D1 (de) | 2001-05-23 | 2010-01-07 | Pantarhei Bioscience Bv | Tetrahydroxylierte estrogen enthaltendes arzneistoffverabreichungssystem zur verwendung in hormonalen kontrazeption |
| DE60216630T2 (de) | 2001-11-15 | 2007-09-20 | Pantarhei Bioscience B.V. | Verwendung von östrogen in kombination mit progestogen für die hormonsubstitutiionstherapie |
| SI1511496T1 (sl) | 2002-06-11 | 2007-04-30 | Pantarhei Bioscience Bv | Metoda zdravljenja ali prevencije imunsko mediiranih motenj in farmacevtska formulacija za njeno uporabo |
| ES2399423T3 (es) | 2002-06-11 | 2013-04-01 | Pantarhei Bioscience B.V. | Método para tratar la piel humana y una composición para el cuidado de la piel para su uso en tal método |
| EP1526856B1 (fr) | 2002-07-12 | 2008-01-02 | Pantarhei Bioscience B.V. | Composition pharmaceutique comprenant des derives d'estetrol utilises dans la therapie anticancereuse |
| WO2004037269A1 (fr) | 2002-10-23 | 2004-05-06 | Pantarhei Bioscience B.V. | Compositions pharmaceutiques comprenant des derives d'estetrol a utiliser dans le traitement du cancer |
| CN100343269C (zh) * | 2002-11-08 | 2007-10-17 | 潘塔希生物科学股份有限公司 | 通过雌酮衍生的甾体化合物合成雌四醇 |
| US20090221540A1 (en) | 2006-01-09 | 2009-09-03 | Pantarhei Bioscience B.V. | Method of Treating An Acute Vascular Disorder |
| DE602008001783D1 (de) | 2007-01-08 | 2010-08-26 | Pantarhei Bioscience Bv | Verfahren zur behandlung oder prävention von unfruchtbarkeit bei weiblichen säugern und pharmazeutisches kit zur anwendung dieses verfahrens |
| EP2383279A1 (fr) * | 2011-07-19 | 2011-11-02 | Pantarhei Bioscience B.V. | Procédé de préparation d'estetrol |
| CA2843951C (fr) | 2011-08-11 | 2019-08-06 | Wout WOUTERS | Utilisation d'estetrol comme contraceptif d'urgence |
| AU2012320423C1 (en) * | 2011-10-07 | 2018-01-25 | Estetra Srl | Process for the production of estetrol |
| EP2653163A1 (fr) | 2012-04-19 | 2013-10-23 | Université de Liège | Constituants estrogènes pour l'utilisation dans le traitement de troubles neurologiques |
| WO2013034780A2 (fr) * | 2012-12-20 | 2013-03-14 | Crystal Pharma, S.A.U. | Procédé de préparation de l'estétrol et de composés analogues |
| ES2624667T3 (es) * | 2013-09-18 | 2017-07-17 | Crystal Pharma, S.A.U. | Procedimiento para la preparación de estetrol |
| DK3079671T3 (en) | 2013-12-12 | 2017-12-11 | Donesta Bioscience B V | Orally disintegrating solid dosage unit containing an estetrol component |
| EP3701944B1 (fr) | 2015-06-18 | 2021-12-08 | Estetra SRL | Unité posologique orodispersible contenant un composant d'estétrol |
| LT3310345T (lt) | 2015-06-18 | 2021-06-25 | Estetra Sprl | Burnoje disperguojama tabletė, turinti estetrolio |
| MA44206B1 (fr) | 2015-06-18 | 2021-04-30 | Estetra Sprl | Comprimé orodispersible comprenant estetrol |
| CA3178291A1 (fr) | 2016-08-05 | 2018-04-12 | Estetra Srl | Methode de prise en charge de la dysmenorrhee et des douleurs menstruelles |
| KR102780201B1 (ko) | 2016-10-28 | 2025-03-12 | 에스테트라, 소시에떼 아 레스폰서빌리떼 리미떼 | 월경통 및 생리통의 관리방법 |
| SG11202000881VA (en) | 2017-08-01 | 2020-02-27 | Fund Sa | Adjuvant therapy for use in prostate cancer treatment |
| IL276584B2 (en) | 2018-02-07 | 2024-10-01 | Estetra Srl | Contraceptive composition with reduced cardiovascular effects |
| DE112020004564T5 (de) | 2019-09-27 | 2022-06-15 | Industriale Chimica S.R.L. | VERFAHREN ZUM HERSTELLEN VON (15α,16α,17β)-ESTRA-1,3,5(10)-TRIEN-3,15,16,17-TETROL (ESTETROL) UND ZWISCHENSTUFEN DES VERFAHRENS |
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2019
- 2019-09-03 HU HU1900315A patent/HU231240B1/hu unknown
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2020
- 2020-09-02 ES ES20768398T patent/ES2855923T3/es active Active
- 2020-09-02 FI FIEP20768398.8T patent/FI3877395T3/fi active
- 2020-09-02 CN CN202080061521.1A patent/CN114302889B/zh active Active
- 2020-09-02 PT PT207683988T patent/PT3877395T/pt unknown
- 2020-09-02 RS RS20230112A patent/RS63966B1/sr unknown
- 2020-09-02 MD MDE20210894T patent/MD3877395T2/ro unknown
- 2020-09-02 IL IL290973A patent/IL290973B2/en unknown
- 2020-09-02 GE GEAP202015920A patent/GEP20247626B/en unknown
- 2020-09-02 CA CA3147815A patent/CA3147815C/fr active Active
- 2020-09-02 KR KR1020227010919A patent/KR102871606B1/ko active Active
- 2020-09-02 MY MYPI2022000866A patent/MY206905A/en unknown
- 2020-09-02 LT LTEPPCT/IB2020/058148T patent/LT3877395T/lt unknown
- 2020-09-02 WO PCT/IB2020/058148 patent/WO2021044302A1/fr not_active Ceased
- 2020-09-02 SI SI202030156T patent/SI3877395T1/sl unknown
- 2020-09-02 MA MA54200A patent/MA54200B1/fr unknown
- 2020-09-02 AU AU2020343497A patent/AU2020343497B2/en active Active
- 2020-09-02 HR HRP20230230TT patent/HRP20230230T1/hr unknown
- 2020-09-02 MX MX2022002603A patent/MX2022002603A/es unknown
- 2020-09-02 CU CU2022000013A patent/CU24692B1/es unknown
- 2020-09-02 JP JP2022511285A patent/JP7265087B2/ja active Active
- 2020-09-02 EP EP20768398.8A patent/EP3877395B1/fr active Active
- 2020-09-02 PE PE2022000348A patent/PE20221418A1/es unknown
- 2020-09-02 HU HUE20768398A patent/HUE061427T2/hu unknown
- 2020-09-02 DK DK20768398.8T patent/DK3877395T3/da active
- 2020-09-02 PL PL20768398.8T patent/PL3877395T3/pl unknown
- 2020-09-02 US US17/639,206 patent/US11633406B2/en active Active
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2022
- 2022-02-21 JO JOP/2022/0041A patent/JOP20220041A1/ar unknown
- 2022-02-28 CL CL2022000492A patent/CL2022000492A1/es unknown
- 2022-03-24 EC ECSENADI202222403A patent/ECSP22022403A/es unknown
- 2022-03-28 ZA ZA2022/03557A patent/ZA202203557B/en unknown
- 2022-03-29 CO CONC2022/0003769A patent/CO2022003769A2/es unknown
- 2022-09-02 PH PH1/2022/550388A patent/PH12022550388A1/en unknown
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