EP4288077A1 - Formulation pour le traitement de l'asthénopie - Google Patents
Formulation pour le traitement de l'asthénopieInfo
- Publication number
- EP4288077A1 EP4288077A1 EP22706675.0A EP22706675A EP4288077A1 EP 4288077 A1 EP4288077 A1 EP 4288077A1 EP 22706675 A EP22706675 A EP 22706675A EP 4288077 A1 EP4288077 A1 EP 4288077A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- weight
- asthenopia
- ophthalmic formulation
- formulation according
- peptide
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 51
- 208000003464 asthenopia Diseases 0.000 title claims abstract description 38
- 238000009472 formulation Methods 0.000 title claims abstract description 36
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 19
- 208000024891 symptom Diseases 0.000 claims description 15
- 125000004122 cyclic group Chemical group 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- AJLNZWYOJAWBCR-OOPVGHQCSA-N (4s)-4-acetamido-5-[[(2s)-1-[[(2s)-1-[[(2s)-5-amino-1-[[(2s)-1-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-4-car Chemical compound OC(=O)CC[C@H](NC(C)=O)C(=C)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(N)=O AJLNZWYOJAWBCR-OOPVGHQCSA-N 0.000 claims description 6
- 208000003164 Diplopia Diseases 0.000 claims description 6
- 206010019233 Headaches Diseases 0.000 claims description 6
- 206010034960 Photophobia Diseases 0.000 claims description 6
- 208000003251 Pruritus Diseases 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 231100000869 headache Toxicity 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 230000007803 itching Effects 0.000 claims description 6
- 230000035807 sensation Effects 0.000 claims description 6
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 5
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 5
- 206010013774 Dry eye Diseases 0.000 claims description 5
- 206010015958 Eye pain Diseases 0.000 claims description 5
- 229920002674 hyaluronan Polymers 0.000 claims description 5
- 229960003160 hyaluronic acid Drugs 0.000 claims description 5
- 201000005111 ocular hyperemia Diseases 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- 229940095094 acetyl hexapeptide-8 Drugs 0.000 claims description 4
- 108010006338 acetyl-glutamyl-glutamyl-methionyl-glutaminyl-arginyl-argininamide Proteins 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 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 description 4
- -1 pentapeptide-3 Chemical compound 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 3
- ZHUJMSMQIPIPTF-JMBSJVKXSA-N (2s)-2-[[(2s)-2-[[2-[[(2r)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoic acid Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ZHUJMSMQIPIPTF-JMBSJVKXSA-N 0.000 claims description 2
- QGGBBQJHVCVVKM-XOBYPWAZSA-N (4s)-4-acetamido-5-[[(2s)-1-[[(2s)-1-[[(2s)-5-amino-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-amino-3-carboxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amin Chemical compound OC(=O)CC[C@H](NC(C)=O)C(=C)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(N)=O QGGBBQJHVCVVKM-XOBYPWAZSA-N 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 229940078033 acetyl octapeptide-3 Drugs 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000007979 citrate buffer Substances 0.000 claims description 2
- 239000003607 modifier Substances 0.000 claims description 2
- 239000006174 pH buffer Substances 0.000 claims description 2
- 239000008363 phosphate buffer Substances 0.000 claims description 2
- 229920000058 polyacrylate Polymers 0.000 claims description 2
- 229920001285 xanthan gum Polymers 0.000 claims description 2
- 239000000872 buffer Substances 0.000 claims 1
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 239000000230 xanthan gum Substances 0.000 claims 1
- 229940082509 xanthan gum Drugs 0.000 claims 1
- 235000010493 xanthan gum Nutrition 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 11
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 239000000902 placebo Substances 0.000 description 5
- 229940068196 placebo Drugs 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000593989 Scardinius erythrophthalmus Species 0.000 description 2
- 230000004308 accommodation Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 229920013818 hydroxypropyl guar gum Polymers 0.000 description 2
- 239000002357 osmotic agent Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 244000166124 Eucalyptus globulus Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- 208000004350 Strabismus Diseases 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 208000029444 double vision Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 201000004356 excessive tearing Diseases 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 208000014733 refractive error Diseases 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/03—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
-
- 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
Definitions
- Asthenopia also known as eye strain, describes a series of non-specific symptoms associated with the prolonged use of video terminals, prolonged reading, or working in poorly lit environments.
- Asthenopia is recognized through the onset of non-specific ophthalmic symptoms such as fatigue, pain, burning, and headache or specific symptoms such as photophobia, blurred vision, double vision, itching, tearing, and foreign body sensation.
- Asthenopia can be divided into internal and external asthenopia.
- Prior art document CN 109646518 describes a silk eye patch soaked in a traditional Chinese medicine herb-based preparation, such as eucalyptus, to be applied to the eyelids, thus with the eyes closed (as reported in paragraphs 30 and 31), for about 15-20 minutes.
- the present patent application describes compounds for medical use in the treatment of asthenopia.
- the present patent application describes an ophthalmic formulation comprising the compounds of the invention.
- Ophthalmic formulations having specific compositions represent further aspects of the present invention.
- Figure 1 and figure 2 show the graphs with the results of the clinical assessments carried out using the formulations of the invention with respect to a placebo.
- the present invention describes compounds for medical use in the treatment of asthenopia.
- asthenopia refers to ocular symptoms linked to eye strain.
- Such symptomatology is linked to ocular surface dysfunctions.
- such symptomatology comprises one or more of the following symptoms: headache, photophobia, eye fatigue, eye pain, diplopia, tearing, itching, red eye, dry eye, foreign body sensation.
- the formulations of the present patent application are described for use in treating all the symptoms of asthenopia: headache, photophobia, eye fatigue, eye pain, diplopia, tearing, itching, eye redness, dry eye, and foreign body sensation.
- AA 1 is Arg, Lys or Asn
- AA 2 is Arg or Lys
- AA 3 is Gin, Glu, Asn or Asp
- AA 4 is Met or Leu
- AA 5 is Glu, Asp or Gin
- AA 6 is Glu, Asp, Gin,
- W, X, Y and Z can be any amino acid independently of each other; a, b, c, d can be 0 or 1 independently of each other; R 1 can be H, a polymeric radical of the polyethylene glycol type, a non-cyclic, cyclic aliphatic group, a heterocyclic, a heteroalkylaryl, an aryl group and R 5 -CO- where R 5 can be a non- cyclic, cyclic aliphatic group, a heterocyclic, a heteroalkylaryl, an aryl group;
- R 2 can be an -NR 3 R 4 , -OR 3 , -SR 3 group where R 3 and R 4 can be independently selected from H, a polymeric radical of the polyethylene glycol type, a non-cyclic, cyclic aliphatic group, a heterocyclic, a heteroalkylaryl, an aryl group.
- both R 1 and R 2 are not amino acids.
- the compounds of the present invention are represented by the peptides selected from the group comprising: acetyl hexapeptide-8 (also known as acetyl hexapeptide-3), pentapeptide-3, pentapeptide-18, tripeptide-3, acetyl octapeptide-3.
- acetyl hexapeptide-8 also known as acetyl hexapeptide-3.
- the present invention describes ophthalmic formulations comprising the compounds of the invention.
- such formulations are aqueous.
- the peptides described are comprised, individually or in mixtures, in a concentration of about 0.001-2% (weight/weight).
- such compounds can be comprised in a concentration of about 0.01-2% (weight/weight) or 0.05-2% (weight/weight) or about 0.1-2% (weight/weight) or about 0.5-2% (weight/weight) or about 1-2% (weight/weight).
- formulations described can comprise one or more of the following further components: pH buffers or modifiers, osmotic agents, viscosifying agents, antioxidants, stabilizers.
- the ophthalmic compositions of the invention can have pH values between about 5 and 8.
- Citrate buffer or phosphate buffer can be used as pH buffering agents.
- compositions are characterized by an osmolality of about 150 and 390 mOsm/Kg.
- osmotic agents for example, compounds can be used selected from the group comprising: glycerol, mannitol, sorbitol, trehalose and chlorides of alkaline or alkaline-earth metals.
- the ophthalmic compositions of the invention can contain viscosifying agents in quantities of about 0.001-4% (weight/weight).
- compounds can be used selected from the group comprising: hyaluronic acid and the salts thereof, polyacrylates such as Carbopol, cellulose such as carboxymethylcellulose (CMC) and hydroxypropyl methylcellulose (HPMC), xanthan and hydroxypropyl-guar gum (HP-G), or mixtures thereof.
- polyacrylates such as Carbopol, cellulose such as carboxymethylcellulose (CMC) and hydroxypropyl methylcellulose (HPMC), xanthan and hydroxypropyl-guar gum (HP-G), or mixtures thereof.
- hyaluronic acid or a salt thereof can be comprised in a concentration of about 0.10 or 0.15% (weight/weight) and up to 0.3% (weight/weight).
- the formulations of the invention can include antioxidants and stabilizers at low concentrations.
- taurine can be used as an antioxidant.
- the peptides of the invention have a concentration of about 0.005 or about 1.0 (weight/weight).
- the peptides of the invention have a concentration of about 0.005, 0.01, 0.02, 0.5, 1 or 2%
- the ocular symptoms were: headache, photophobia, eye pain, diplopia, tired eyes; the signs of ocular surface distress were: excessive tearing, itching, red eye, dry eye, foreign body sensation.
- the frequency of symptoms and signs for the enrolled patients is shown in Table 1 below.
- the 160 patients were divided into 4 groups of 40, named according to the ophthalmic composition in use: E1, E7, E13 and Placebo (PBS, phosphate buffered saline). All 160 patients enrolled were given a box of 90 single-dose vials containing the compositions in question (E1, E7, E13 and Placebo). The administration was three drops three times a day for thirty days for each eye. During the thirty days of treatment, the patients continued their normal private and professional routine and no concomitant topical or systemic treatment was performed other than the administration of the compositions E1, E7, E13 and Placebo. At the end of the trial, the signs and symptoms were assessed and these were the percentages in the three groups.
- Table 2 below shows the percentage of the signs and symptoms in the patients who administered the compositions E1, E7, E13.
- the formulations E1, E7 and E13 i.e., those containing the peptides of the invention, surprisingly reduced the signs and symptoms related to eye strain.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Ophthalmology & Optometry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
La présente demande de brevet concerne des formulations pour application ophtalmique utilisées dans le traitement de l'asthénopie.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP21155214.6A EP4039263A1 (fr) | 2021-02-04 | 2021-02-04 | Formulation pour le traitement de l'asthénopie |
| PCT/IB2022/050980 WO2022167987A1 (fr) | 2021-02-04 | 2022-02-04 | Formulation pour le traitement de l'asthénopie |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP4288077A1 true EP4288077A1 (fr) | 2023-12-13 |
Family
ID=74870561
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP21155214.6A Withdrawn EP4039263A1 (fr) | 2021-02-04 | 2021-02-04 | Formulation pour le traitement de l'asthénopie |
| EP22706675.0A Pending EP4288077A1 (fr) | 2021-02-04 | 2022-02-04 | Formulation pour le traitement de l'asthénopie |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP21155214.6A Withdrawn EP4039263A1 (fr) | 2021-02-04 | 2021-02-04 | Formulation pour le traitement de l'asthénopie |
Country Status (2)
| Country | Link |
|---|---|
| EP (2) | EP4039263A1 (fr) |
| WO (1) | WO2022167987A1 (fr) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2009261285B2 (en) * | 2008-06-19 | 2012-12-13 | Fuso Pharmaceutical Industries, Ltd | Peptide derivative and composition for promoting tear secretion comprising the same |
| WO2013143026A1 (fr) * | 2012-03-31 | 2013-10-03 | Abmart (Shanghai) Co., Ltd | Bibliothèques de peptides et d'anticorps et leurs utilisations |
| JP2020511633A (ja) * | 2017-02-22 | 2020-04-16 | ヘルステル・インコーポレイテッドＨｅａｌｔｈｔｅｌｌ Ｉｎｃ． | 感染のスクリーニング方法 |
| CN109646518A (zh) * | 2019-02-20 | 2019-04-19 | 张家界茶坤缘杜仲生物科技开发有限公司 | 杜仲眼贴及其制备方法 |
-
2021
- 2021-02-04 EP EP21155214.6A patent/EP4039263A1/fr not_active Withdrawn
-
2022
- 2022-02-04 WO PCT/IB2022/050980 patent/WO2022167987A1/fr not_active Ceased
- 2022-02-04 EP EP22706675.0A patent/EP4288077A1/fr active Pending
Non-Patent Citations (1)
| Title |
|---|
| DATABASE GNPD [online] MINTEL; 8 November 2019 (2019-11-08), ANONYMOUS: "Argireline Solution 10%", XP055842074, retrieved from https://www.gnpd.com/sinatra/recordpage/7017479/ Database accession no. 7017479 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2022167987A1 (fr) | 2022-08-11 |
| EP4039263A1 (fr) | 2022-08-10 |
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