JP6672512B2 - 一酸化窒素放出プロスタミドを含有する眼科用組成物 - Google Patents
一酸化窒素放出プロスタミドを含有する眼科用組成物 Download PDFInfo
- Publication number
- JP6672512B2 JP6672512B2 JP2019128085A JP2019128085A JP6672512B2 JP 6672512 B2 JP6672512 B2 JP 6672512B2 JP 2019128085 A JP2019128085 A JP 2019128085A JP 2019128085 A JP2019128085 A JP 2019128085A JP 6672512 B2 JP6672512 B2 JP 6672512B2
- Authority
- JP
- Japan
- Prior art keywords
- ophthalmic
- aqueous
- solution
- hydroxystearate
- composition according
- 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.)
- Active
Links
- 0 CCNC(CCCC=CC[C@@]([C@](C[C@@]1O)O)[C@]1C=C[C@](CCc1ccccc1)OC(CCCCC*)=O)=O Chemical compound CCNC(CCCC=CC[C@@]([C@](C[C@@]1O)O)[C@]1C=C[C@](CCc1ccccc1)OC(CCCCC*)=O)=O 0.000 description 1
Classifications
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- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- 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
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Ophthalmology & Optometry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Emergency Medicine (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP18290082.9 | 2018-07-12 | ||
| EP18290082 | 2018-07-12 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2020036665A Division JP7080268B2 (ja) | 2018-07-12 | 2020-03-04 | 一酸化窒素放出プロスタミドを含有する眼科用組成物 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2020011955A JP2020011955A (ja) | 2020-01-23 |
| JP6672512B2 true JP6672512B2 (ja) | 2020-03-25 |
Family
ID=63012964
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2019128085A Active JP6672512B2 (ja) | 2018-07-12 | 2019-07-10 | 一酸化窒素放出プロスタミドを含有する眼科用組成物 |
| JP2020036665A Active JP7080268B2 (ja) | 2018-07-12 | 2020-03-04 | 一酸化窒素放出プロスタミドを含有する眼科用組成物 |
| JP2022084562A Active JP7397910B2 (ja) | 2018-07-12 | 2022-05-24 | 一酸化窒素放出プロスタミドを含有する眼科用組成物 |
| JP2023203763A Pending JP2024023498A (ja) | 2018-07-12 | 2023-12-01 | 一酸化窒素放出プロスタミドを含有する眼科用組成物 |
Family Applications After (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2020036665A Active JP7080268B2 (ja) | 2018-07-12 | 2020-03-04 | 一酸化窒素放出プロスタミドを含有する眼科用組成物 |
| JP2022084562A Active JP7397910B2 (ja) | 2018-07-12 | 2022-05-24 | 一酸化窒素放出プロスタミドを含有する眼科用組成物 |
| JP2023203763A Pending JP2024023498A (ja) | 2018-07-12 | 2023-12-01 | 一酸化窒素放出プロスタミドを含有する眼科用組成物 |
Country Status (28)
| Country | Link |
|---|---|
| US (5) | US10688073B2 (https=) |
| EP (2) | EP3718535B1 (https=) |
| JP (4) | JP6672512B2 (https=) |
| KR (1) | KR102861273B1 (https=) |
| CN (2) | CN111249228B (https=) |
| AR (1) | AR115734A1 (https=) |
| AU (2) | AU2019300203B2 (https=) |
| BR (1) | BR112021000240A2 (https=) |
| CA (1) | CA3105989A1 (https=) |
| CY (1) | CY1123706T1 (https=) |
| DK (1) | DK3593788T3 (https=) |
| ES (2) | ES2847853T3 (https=) |
| HR (2) | HRP20251098T1 (https=) |
| HU (2) | HUE072927T2 (https=) |
| LT (1) | LT3593788T (https=) |
| MA (2) | MA52258B1 (https=) |
| MD (2) | MD3593788T2 (https=) |
| MX (2) | MX2021000411A (https=) |
| MY (1) | MY205816A (https=) |
| PH (1) | PH12020552112A1 (https=) |
| PL (2) | PL3718535T3 (https=) |
| PT (1) | PT3593788T (https=) |
| RS (2) | RS61348B1 (https=) |
| SG (1) | SG11202100064WA (https=) |
| SI (1) | SI3593788T1 (https=) |
| SM (2) | SMT202100034T1 (https=) |
| TW (1) | TWI839364B (https=) |
| WO (1) | WO2020011845A1 (https=) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2019300203B2 (en) * | 2018-07-12 | 2025-01-30 | Nicox S.A. | Ophthalmic compositions containing a nitric oxide releasing prostamide |
| EP4404936A1 (en) * | 2021-09-20 | 2024-07-31 | Nicox SA | Nitric oxide releasing prostamide as neuroprotective agent |
| JP7665073B1 (ja) | 2024-04-05 | 2025-04-18 | ロート製薬株式会社 | 容器に収容してなる眼科用組成物 |
| US20260053768A1 (en) * | 2024-05-07 | 2026-02-26 | Maher Hadaya | Sustained Nitric Oxide Releasing Drug Delivery Systems |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2918891B1 (fr) | 2007-07-20 | 2009-09-25 | Thea Sa Lab | Solution ophtalmique a base de prostaglandines sans conservateur |
| US9629852B2 (en) | 2007-10-16 | 2017-04-25 | Sun Pharma Advanced Research Company Ltd. | Ophthalmic composition comprising a prostaglandin |
| AR076731A1 (es) | 2008-05-09 | 2011-07-06 | Pfizer | Prostamidas donadoras de oxido nitrico, uso de los mismos y composiciones farmaceuticas |
| MX2011002688A (es) | 2008-09-12 | 2011-04-12 | Critical Pharmaceuticals Ltd | Mejoramientos en la absorcion de agentes terapeuticos a traves de las membranas mucosas o la piel. |
| US20130267591A1 (en) * | 2010-05-07 | 2013-10-10 | Sun Pharma Advanced Research Company Limited | Novel ophthalmic compositions |
| FR2961694B1 (fr) * | 2010-06-29 | 2013-01-25 | Thea Lab | Systeme de delivrance polymerique d'une solution non visqueuse a base de prostaglandine sans conservateur |
| BR112013034051A2 (pt) * | 2011-06-29 | 2019-09-24 | Allergan Inc | formulações de macrogol 15 hidroxiestearato |
| CA2841644A1 (en) | 2011-08-02 | 2013-02-07 | Cipla Limited | Pharmaceutical composition comprising ebastine and fluticasone |
| CN105012231A (zh) * | 2014-04-30 | 2015-11-04 | 四川科伦药物研究院有限公司 | 一种包含PGF2α衍生物的稳定性良好的眼用制剂及其制备方法 |
| CN105380901B (zh) * | 2015-11-18 | 2018-07-17 | 侯宇华 | 一种他氟前列素滴眼剂及其制备方法 |
| AU2019300203B2 (en) * | 2018-07-12 | 2025-01-30 | Nicox S.A. | Ophthalmic compositions containing a nitric oxide releasing prostamide |
-
2019
- 2019-07-10 AU AU2019300203A patent/AU2019300203B2/en active Active
- 2019-07-10 MD MDE20200084T patent/MD3593788T2/ro unknown
- 2019-07-10 EP EP20172140.4A patent/EP3718535B1/en active Active
- 2019-07-10 CA CA3105989A patent/CA3105989A1/en active Pending
- 2019-07-10 MA MA52258A patent/MA52258B1/fr unknown
- 2019-07-10 DK DK19185400.9T patent/DK3593788T3/da active
- 2019-07-10 KR KR1020217004141A patent/KR102861273B1/ko active Active
- 2019-07-10 ES ES19185400T patent/ES2847853T3/es active Active
- 2019-07-10 MD MDE20210162T patent/MD3718535T2/ro unknown
- 2019-07-10 MX MX2021000411A patent/MX2021000411A/es unknown
- 2019-07-10 SM SM20210034T patent/SMT202100034T1/it unknown
- 2019-07-10 PL PL20172140.4T patent/PL3718535T3/pl unknown
- 2019-07-10 EP EP19185400.9A patent/EP3593788B1/en active Active
- 2019-07-10 US US16/508,028 patent/US10688073B2/en active Active
- 2019-07-10 CN CN202010145208.8A patent/CN111249228B/zh active Active
- 2019-07-10 PL PL19185400T patent/PL3593788T3/pl unknown
- 2019-07-10 SI SI201930023T patent/SI3593788T1/sl unknown
- 2019-07-10 WO PCT/EP2019/068511 patent/WO2020011845A1/en not_active Ceased
- 2019-07-10 MY MYPI2021000130A patent/MY205816A/en unknown
- 2019-07-10 TW TW108124327A patent/TWI839364B/zh active
- 2019-07-10 CN CN201910622356.1A patent/CN110237031B/zh active Active
- 2019-07-10 HU HUE20172140A patent/HUE072927T2/hu unknown
- 2019-07-10 HU HUE19185400A patent/HUE052747T2/hu unknown
- 2019-07-10 JP JP2019128085A patent/JP6672512B2/ja active Active
- 2019-07-10 PT PT191854009T patent/PT3593788T/pt unknown
- 2019-07-10 HR HRP20251098TT patent/HRP20251098T1/hr unknown
- 2019-07-10 SM SM20250425T patent/SMT202500425T1/it unknown
- 2019-07-10 SG SG11202100064WA patent/SG11202100064WA/en unknown
- 2019-07-10 RS RS20210008A patent/RS61348B1/sr unknown
- 2019-07-10 MA MA48919A patent/MA48919B1/fr unknown
- 2019-07-10 RS RS20250698A patent/RS67054B1/sr unknown
- 2019-07-10 LT LTEP19185400.9T patent/LT3593788T/lt unknown
- 2019-07-10 BR BR112021000240-5A patent/BR112021000240A2/pt unknown
- 2019-07-10 ES ES20172140T patent/ES3036636T3/es active Active
- 2019-07-10 AR ARP190101947A patent/AR115734A1/es unknown
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2020
- 2020-03-04 JP JP2020036665A patent/JP7080268B2/ja active Active
- 2020-03-11 US US16/815,923 patent/US11020368B2/en active Active
- 2020-12-07 PH PH12020552112A patent/PH12020552112A1/en unknown
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2021
- 2021-01-05 CY CY20211100004T patent/CY1123706T1/el unknown
- 2021-01-11 MX MX2023007091A patent/MX2023007091A/es unknown
- 2021-01-11 US US17/146,057 patent/US12186295B2/en active Active
- 2021-01-26 HR HRP20210138TT patent/HRP20210138T1/hr unknown
- 2021-03-29 US US17/216,195 patent/US12178793B2/en active Active
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2022
- 2022-05-24 JP JP2022084562A patent/JP7397910B2/ja active Active
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2023
- 2023-12-01 JP JP2023203763A patent/JP2024023498A/ja active Pending
-
2024
- 2024-11-15 US US18/949,815 patent/US20250073196A1/en active Pending
-
2025
- 2025-04-29 AU AU2025203019A patent/AU2025203019A1/en active Pending
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| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |