HRP20211996T1 - Sustav mukoadhezivne disperzijske nanočestice i metoda proizvodnje istog - Google Patents
Sustav mukoadhezivne disperzijske nanočestice i metoda proizvodnje istog Download PDFInfo
- Publication number
- HRP20211996T1 HRP20211996T1 HRP20211996TT HRP20211996T HRP20211996T1 HR P20211996 T1 HRP20211996 T1 HR P20211996T1 HR P20211996T T HRP20211996T T HR P20211996TT HR P20211996 T HRP20211996 T HR P20211996T HR P20211996 T1 HRP20211996 T1 HR P20211996T1
- Authority
- HR
- Croatia
- Prior art keywords
- nanoparticle system
- polysorbate
- nanoparticles
- solid lipid
- mucoadhesive
- Prior art date
Links
- 239000002105 nanoparticle Substances 0.000 title claims 14
- 239000006185 dispersion Substances 0.000 title claims 13
- 230000003232 mucoadhesive effect Effects 0.000 title claims 10
- 238000004519 manufacturing process Methods 0.000 title claims 2
- 239000002047 solid lipid nanoparticle Substances 0.000 claims 11
- 239000000203 mixture Substances 0.000 claims 4
- 239000013543 active substance Substances 0.000 claims 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 3
- 150000002632 lipids Chemical group 0.000 claims 3
- GJJVAFUKOBZPCB-UHFFFAOYSA-N 2-methyl-2-(4,8,12-trimethyltrideca-3,7,11-trienyl)-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-UHFFFAOYSA-N 0.000 claims 2
- 241001677259 Acanthophoenix rubra Species 0.000 claims 2
- 235000019482 Palm oil Nutrition 0.000 claims 2
- 229920001219 Polysorbate 40 Polymers 0.000 claims 2
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 claims 2
- 239000012736 aqueous medium Substances 0.000 claims 2
- 239000007864 aqueous solution Substances 0.000 claims 2
- 239000012141 concentrate Substances 0.000 claims 2
- 239000002540 palm oil Substances 0.000 claims 2
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims 2
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims 2
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims 2
- 229920000136 polysorbate Polymers 0.000 claims 2
- 229950008882 polysorbate Drugs 0.000 claims 2
- 229940101027 polysorbate 40 Drugs 0.000 claims 2
- 239000007787 solid Substances 0.000 claims 2
- 238000003756 stirring Methods 0.000 claims 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims 2
- 229930003802 tocotrienol Natural products 0.000 claims 2
- 239000011731 tocotrienol Substances 0.000 claims 2
- 235000019148 tocotrienols Nutrition 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 2
- 229920001213 Polysorbate 20 Polymers 0.000 claims 1
- 229920001214 Polysorbate 60 Polymers 0.000 claims 1
- 239000007853 buffer solution Substances 0.000 claims 1
- 239000004203 carnauba wax Substances 0.000 claims 1
- 235000013869 carnauba wax Nutrition 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 239000002537 cosmetic Substances 0.000 claims 1
- 229940039227 diagnostic agent Drugs 0.000 claims 1
- 239000000032 diagnostic agent Substances 0.000 claims 1
- 235000015872 dietary supplement Nutrition 0.000 claims 1
- 238000000265 homogenisation Methods 0.000 claims 1
- -1 lipid compound Chemical class 0.000 claims 1
- 229940127554 medical product Drugs 0.000 claims 1
- 239000002609 medium Substances 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims 1
- 229940068977 polysorbate 20 Drugs 0.000 claims 1
- 229940113124 polysorbate 60 Drugs 0.000 claims 1
- 229920000053 polysorbate 80 Polymers 0.000 claims 1
- 229940068968 polysorbate 80 Drugs 0.000 claims 1
- 239000003755 preservative agent Substances 0.000 claims 1
- 239000000047 product Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 235000013311 vegetables Nutrition 0.000 claims 1
- 239000001993 wax Substances 0.000 claims 1
Classifications
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K9/0043—Nose
-
- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (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)
- Otolaryngology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Organic Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Medicines Containing Plant Substances (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Claims (8)
1. Sustav mukoadhezivne disperzijske nanočestice, uključujući vodeni farmaceutski prihvatljiv medij i nanočestice, naznačen time da vodeni medij sadrži 0,01 do 2,00 % mase hidroksipropil metil celuloze, a nanočestice su čvrste lipidne nanočestice (SLN) u obliku disperzije i u količini od 0,10 do 10% mase, disperzija čvrstih lipidnih nanočestica (SLN) sadrži nanočestice promjera od 15 do 100 nm, dok se nanočestice sastoje od 20 do 99 masenog udjela dijelova čvrstog lipida odabranog iz skupine prirodnog biljnog ili sintetskog voska, od 0,01 do 20 masenog udjela d-α-tokoferil polietilen glikol 1000 sukcinata (TPGS), koncentrat crvenog palminog ulja sa sadržajem 30% tokotrienola u količini do 20% od ukupnog lipida i od 0,00001 do 70 masenog udjela ugrađenog u njihovu jezgru aktivne tvari.
2. Sustav mukoadhezivne disperzijske nanočestice prema zahtjevu 1, naznačen time što hidroksipropil metil celuloza sustava mukoadhezivne disperzijske nanočestice ima viskozitet od 2500 do 5500 cps (mPa.s), poželjno više od 3000 do manje od 5000 cps. poželjnije od 3200 do 4800 cps (mPa.s).
3. Sustav mukoadhezivne disperzijske nanočestice prema zahtjevima 1 i 2, naznačen time, da je čvrsti lipid u sastavu čvrstih lipidnih nanočestica (SLN) karnauba vosak.
4. Sustav mukoadhezivne disperzijske nanočestice prema zahtjevima od 1 do 3, naznačen time, da vodeni medij nadalje sadrži pufersku otopinu, izotonične soli i konzervanse.
5. Sustav mukoadhezivne disperzijske nanočestice prema zahtjevima od 1 do 4, naznačen time, da čvrste lipidne nanočestice (SLN) nadalje sadrže od 0,01 do 10 masenog udjela polisorbata, odabranog između polisorbata 20, polisorbata 40, polisorbata 60 ili polisorbata 80.
6. Sustav mukoadhezivne disperzijske nanočestice prema zahtjevu 5, naznačen time, da je polisorbat, polisorbat 40.
7. Sustav mukoadhezivne disperzijske nanočestice prema zahtjevima od 1 do 6, naznačen time, da je aktivna tvar ugrađena u jezgru čvrste lipidne nanočestice (SLN) odabrana između farmaceutski aktivnih spojeva, te od tvari koje se koriste kao dijagnostički agensi, biološki proizvodi, dodatci prehrani te u kozmetici, medicinskim proizvodima.
8. Metoda za proizvodnju sustava mukoadhezivne disperzijske nanočestice prema zahtjevima od 1 do 7, naznačena time, da se hidroksipropil metil celuloza otopi u vodi da nastane vodena otopina, nakon čega se dobivena vodena otopina dodaje u ohlađenu postupno uz miješanje do 20°C +/-2°C disperziju čvrstih lipidnih nanočestica, koja se dobiva miješanjem lipidnog spoja, d-α-tocopheryl polietilen glikol 1000 sukcinata (TPGS), koncentrata crvenog palminog ulja sa sadržajem 30% tokotrienola i aktivne tvari, dobivena smjesa se zagrije na 90°C +/-2°C da se otopi, miješa se do homogenizacije nakon čega se u smjesu dobivenu uz miješanje dodaje voda zagrijana do 90°C +/-2° C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2018/001073 WO2020053609A1 (en) | 2018-09-11 | 2018-09-11 | Mucoadhesive dispersion nanoparticle system and method for production the same |
| EP18786389.9A EP3820439B1 (en) | 2018-09-11 | 2018-09-11 | Mucoadhesive dispersion nanoparticle system and method for production the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20211996T1 true HRP20211996T1 (hr) | 2022-04-01 |
Family
ID=63857975
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20211996TT HRP20211996T1 (hr) | 2018-09-11 | 2018-09-11 | Sustav mukoadhezivne disperzijske nanočestice i metoda proizvodnje istog |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US20210353553A1 (hr) |
| EP (1) | EP3820439B1 (hr) |
| JP (1) | JP7164700B2 (hr) |
| BR (1) | BR112021001674A2 (hr) |
| CA (1) | CA3110773C (hr) |
| DK (1) | DK3820439T3 (hr) |
| ES (1) | ES2901469T3 (hr) |
| HR (1) | HRP20211996T1 (hr) |
| HU (1) | HUE056959T2 (hr) |
| IL (1) | IL280371B (hr) |
| LT (1) | LT3820439T (hr) |
| MX (1) | MX2021001397A (hr) |
| PL (1) | PL3820439T3 (hr) |
| SI (1) | SI3820439T1 (hr) |
| WO (1) | WO2020053609A1 (hr) |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4603131A (en) | 1982-04-26 | 1986-07-29 | Bernstein Joel E | Method and composition for treating and preventing irritation of the mucous membranes of the nose |
| US5976573A (en) | 1996-07-03 | 1999-11-02 | Rorer Pharmaceutical Products Inc. | Aqueous-based pharmaceutical composition |
| IL136591A (en) | 1998-01-30 | 2005-08-31 | Novartis Consumer Health Sa | Nasal pharmaceutical solutions |
| US6319513B1 (en) | 1998-08-24 | 2001-11-20 | The Procter & Gamble Company | Oral liquid mucoadhesive compounds |
| GB2423711B (en) | 2005-10-24 | 2007-02-14 | Fortune Apex Dev Ltd | Method for preparing a pharmaceutical composition with enhanced mucoadhesion |
| ES2284398B2 (es) | 2006-04-27 | 2008-12-16 | Universidad Complutense De Madrid | Formulacion de vesiculas liposomales en soluciones acuosas con caracteristicas de pelicula lagrimal. |
| WO2008105852A2 (en) | 2006-10-26 | 2008-09-04 | Creighton University | Mucoadhesive nanoparticles for cancer treatment |
| EP2123261A1 (en) | 2008-05-20 | 2009-11-25 | Stallergenes S.A. | Mucoadhesive particulate formulation for inducing antigen-specific immune tolerance |
| US9321782B2 (en) | 2010-08-04 | 2016-04-26 | Meril Life Sciences Pvt. Ltd. | Process for preparation of novel 42-O-(heteroalkoxyalkyl) rapamicin compounds with anti-proliferative properties |
| KR20140031227A (ko) | 2011-03-24 | 2014-03-12 | 레오 파마 에이/에스 | 지질 나노입자들 및 코르티코스테로이드 또는 비타민 ｄ 유도체를 포함하는 조성물 |
| US20140005379A1 (en) | 2012-06-20 | 2014-01-02 | Frank GU | Nanoparticle delivery system and components thereof |
| BR112015030341A2 (pt) | 2013-06-20 | 2017-07-25 | Glenmark Pharmaceuticals Sa | formulações de nanoparticulado e processo para prepará-las, composição farmacêutica e uso de composto ou seu sal farmaceuticamente aceitável e estabilizante de superfície |
| CN103784421B (zh) * | 2014-02-27 | 2016-04-27 | 哈尔滨医科大学 | 载姜黄素和胡椒碱的固体脂质纳米粒及其制备方法 |
| CA2952622A1 (en) * | 2014-06-16 | 2015-12-23 | Loewi LLC | Methods of anesthetizing nerve tissue in the trigeminal nerve pathway and medical uses thereof |
| JP2016034918A (ja) | 2014-08-01 | 2016-03-17 | 静岡県公立大学法人 | 難水溶性抗酸化物質送達用組成物 |
| JP2018533579A (ja) | 2015-10-30 | 2018-11-15 | ザ・ジョンズ・ホプキンス・ユニバーシティー | 高分子量かつ密な被覆を有する粘液浸透粒子 |
| WO2017097783A1 (en) | 2015-12-08 | 2017-06-15 | Glaxosmithkline Biologicals S.A. | Novel adjuvant formulations |
-
2018
- 2018-09-11 WO PCT/IB2018/001073 patent/WO2020053609A1/en unknown
- 2018-09-11 BR BR112021001674-0A patent/BR112021001674A2/pt unknown
- 2018-09-11 JP JP2021501025A patent/JP7164700B2/ja active Active
- 2018-09-11 ES ES18786389T patent/ES2901469T3/es active Active
- 2018-09-11 SI SI201830522T patent/SI3820439T1/sl unknown
- 2018-09-11 US US17/274,197 patent/US20210353553A1/en active Pending
- 2018-09-11 CA CA3110773A patent/CA3110773C/en active Active
- 2018-09-11 HR HRP20211996TT patent/HRP20211996T1/hr unknown
- 2018-09-11 MX MX2021001397A patent/MX2021001397A/es unknown
- 2018-09-11 DK DK18786389.9T patent/DK3820439T3/da active
- 2018-09-11 HU HUE18786389A patent/HUE056959T2/hu unknown
- 2018-09-11 PL PL18786389T patent/PL3820439T3/pl unknown
- 2018-09-11 EP EP18786389.9A patent/EP3820439B1/en active Active
- 2018-09-11 LT LTEPPCT/IB2018/001073T patent/LT3820439T/lt unknown
-
2021
- 2021-01-24 IL IL280371A patent/IL280371B/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| JP2022511223A (ja) | 2022-01-31 |
| LT3820439T (lt) | 2022-01-10 |
| JP7164700B2 (ja) | 2022-11-01 |
| EP3820439A1 (en) | 2021-05-19 |
| SI3820439T1 (sl) | 2022-02-28 |
| IL280371B (en) | 2021-05-31 |
| EP3820439B1 (en) | 2021-09-29 |
| WO2020053609A1 (en) | 2020-03-19 |
| HUE056959T2 (hu) | 2022-04-28 |
| CA3110773C (en) | 2023-02-28 |
| IL280371A (en) | 2021-03-01 |
| DK3820439T3 (da) | 2021-12-20 |
| MX2021001397A (es) | 2021-04-12 |
| PL3820439T3 (pl) | 2022-04-04 |
| ES2901469T3 (es) | 2022-03-22 |
| US20210353553A1 (en) | 2021-11-18 |
| CA3110773A1 (en) | 2020-03-19 |
| BR112021001674A2 (pt) | 2021-05-04 |
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