JP2023525533A - 安定性が向上したドネペジル含有経皮吸収製剤 - Google Patents
安定性が向上したドネペジル含有経皮吸収製剤 Download PDFInfo
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- JP2023525533A JP2023525533A JP2022568614A JP2022568614A JP2023525533A JP 2023525533 A JP2023525533 A JP 2023525533A JP 2022568614 A JP2022568614 A JP 2022568614A JP 2022568614 A JP2022568614 A JP 2022568614A JP 2023525533 A JP2023525533 A JP 2023525533A
- Authority
- JP
- Japan
- Prior art keywords
- donepezil
- monothioglycerol
- stabilizer
- catechin
- comparative example
- 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.)
- Granted
Links
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 title claims abstract description 188
- 229960003530 donepezil Drugs 0.000 title claims abstract description 89
- 239000000203 mixture Substances 0.000 title claims abstract description 60
- 238000009472 formulation Methods 0.000 title claims description 22
- 239000003381 stabilizer Substances 0.000 claims abstract description 161
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims abstract description 141
- 238000002360 preparation method Methods 0.000 claims abstract description 109
- 238000010521 absorption reaction Methods 0.000 claims abstract description 78
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 45
- 239000003814 drug Substances 0.000 claims abstract description 34
- 229940079593 drug Drugs 0.000 claims abstract description 33
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 claims abstract description 32
- 238000004519 manufacturing process Methods 0.000 claims abstract description 17
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims abstract description 16
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims abstract description 16
- 235000007219 (+)-catechin Nutrition 0.000 claims abstract description 15
- PFTAWBLQPZVEMU-DZGCQCFKSA-N (+)-catechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-DZGCQCFKSA-N 0.000 claims abstract description 15
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229940030275 epigallocatechin gallate Drugs 0.000 claims abstract description 14
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 13
- 239000011668 ascorbic acid Substances 0.000 claims abstract description 13
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 13
- 229930013915 (+)-catechin Natural products 0.000 claims abstract description 9
- 206010012289 Dementia Diseases 0.000 claims abstract description 6
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical group [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 claims description 51
- 229940116357 potassium thiocyanate Drugs 0.000 claims description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 20
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-isoascorbic acid Chemical compound OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 claims description 19
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- 239000002585 base Substances 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
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- 239000004480 active ingredient Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- XMOCLSLCDHWDHP-IUODEOHRSA-N epi-Gallocatechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@H]2O)=CC(O)=C(O)C(O)=C1 XMOCLSLCDHWDHP-IUODEOHRSA-N 0.000 claims 2
- XMOCLSLCDHWDHP-UHFFFAOYSA-N L-Epigallocatechin Natural products OC1CC2=C(O)C=C(O)C=C2OC1C1=CC(O)=C(O)C(O)=C1 XMOCLSLCDHWDHP-UHFFFAOYSA-N 0.000 claims 1
- DZYNKLUGCOSVKS-UHFFFAOYSA-N epigallocatechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3cc(O)c(O)c(O)c3 DZYNKLUGCOSVKS-UHFFFAOYSA-N 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
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- 230000007774 longterm Effects 0.000 abstract description 56
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- 239000012948 isocyanate Substances 0.000 abstract 1
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- 230000000052 comparative effect Effects 0.000 description 176
- 239000000126 substance Substances 0.000 description 89
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- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 description 26
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 description 26
- 235000005493 rutin Nutrition 0.000 description 26
- IKGXIBQEEMLURG-BKUODXTLSA-N rutin Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@@H]1OC[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-BKUODXTLSA-N 0.000 description 26
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 description 26
- 229960004555 rutoside Drugs 0.000 description 26
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 20
- 238000004458 analytical method Methods 0.000 description 20
- -1 donepezil pyridine analog Chemical class 0.000 description 17
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- XRPRYHONRUINMG-UHFFFAOYSA-N 2-[(1-benzyl-1-oxidopiperidin-1-ium-4-yl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CC[N+]1([O-])CC1=CC=CC=C1 XRPRYHONRUINMG-UHFFFAOYSA-N 0.000 description 12
- PGBZORAISITZTF-UHFFFAOYSA-N Donepezil metabolite M4 Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC1CCNCC1 PGBZORAISITZTF-UHFFFAOYSA-N 0.000 description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 11
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 10
- 230000033228 biological regulation Effects 0.000 description 10
- 238000011156 evaluation Methods 0.000 description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 229910052751 metal Inorganic materials 0.000 description 9
- 239000002184 metal Substances 0.000 description 9
- YHMYGUUIMTVXNW-UHFFFAOYSA-N 1,3-dihydrobenzimidazole-2-thione Chemical compound C1=CC=C2NC(S)=NC2=C1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- 235000010388 propyl gallate Nutrition 0.000 description 8
- 239000000473 propyl gallate Substances 0.000 description 8
- 229940075579 propyl gallate Drugs 0.000 description 8
- 229920000346 polystyrene-polyisoprene block-polystyrene Polymers 0.000 description 7
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 7
- 235000019345 sodium thiosulphate Nutrition 0.000 description 7
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- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
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- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- AIMUHNZKNFEZSN-UHFFFAOYSA-M sodium;decane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCS([O-])(=O)=O AIMUHNZKNFEZSN-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000011115 styrene butadiene Substances 0.000 description 1
- 229920003048 styrene butadiene rubber Polymers 0.000 description 1
- 229920000468 styrene butadiene styrene block copolymer Polymers 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003784 tall oil Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 229910052716 thallium Inorganic materials 0.000 description 1
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 1
- 229920002725 thermoplastic elastomer Polymers 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-L thiosulfate(2-) Chemical compound [O-]S([S-])(=O)=O DHCDFWKWKRSZHF-UHFFFAOYSA-L 0.000 description 1
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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Abstract
Description
*赤色:不適合
類縁物質分析法第2法の場合は、それぞれの経皮吸収製剤を酢酸エチルに60分間攪拌して溶かした後、0.1N塩酸:メタノールが25:75で混合された溶液を添加して60分間攪拌し、その後、5分間遠心分離した上澄み液を検液として、米国薬局方「ドネペジル錠剤」項の類縁物質分析法第2法に従って下記表10の基準に評価した。標準液は、ドネペジル塩酸塩標準品を、酢酸エチル:メタノール:0.1N塩酸=100:675:225(体積比)で混合した溶媒を用いて、10μg/mLとなるように製造して使用した。
移動相A:リン酸1mLを精製水1Lに添加した後、トリエチルアミンを用いてpHを6.5に調整した。得られた溶液を濾過した後、超音波洗浄機で気泡を除去して移動相として使用した。
*赤色:不適合
*赤色:不適合
*赤色:不適合
*赤色:不適合
*赤色:不適合
Claims (13)
- 支持層、薬物含有層及び剥離層で構成された認知症治療用ドネペジル経皮吸収製剤であって、
前記薬物含有層には、有効成分としてドネペジル又はその薬学的に許容される塩、粘着基剤、及び安定化剤の組み合わせとして(i)チオシアン酸塩と、茶カテキン、(+)-カテキン、没食子酸エピガロカテキン、アスコルビン酸およびイソアスコルビン酸の中から選択される安定化剤との混合物、又は(ii)モノチオグリセロールと、茶カテキン、(+)-カテキン、および没食子酸エピガロカテキンからなる群から選択される安定化剤との混合物を含む、経皮吸収製剤。 - 前記ドネペジルが、遊離塩基(free base)形態であることを特徴とする、請求項1に記載の経皮吸収製剤。
- 前記安定化剤の組み合わせが、チオシアン酸塩と、茶カテキン、(+)-カテキン、没食子酸エピガロカテキン、アスコルビン酸およびイソアスコルビン酸からなる群から選択される安定化剤との混合物であることを特徴とする、請求項1に記載の経皮吸収製剤。
- 前記チオシアン酸塩が、チオシアン酸カリウムであることを特徴とする、請求項1又は3に記載の経皮吸収製剤。
- 前記安定化剤の組み合わせが、モノチオグリセロールをさらに含むことを特徴とする、請求項3に記載の経皮吸収製剤。
- 前記安定化剤の組み合わせが、モノチオグリセロールと、茶カテキン、(+)-カテキンおよび没食子酸エピガロカテキンからなる群から選択される安定化剤との混合物であることを特徴とする、請求項1に記載の経皮吸収製剤。
- 支持層、薬物含有層及び剥離層で構成されたドネペジル経皮吸収製剤の製造方法であって、
i)有機溶媒に、ドネペジル又はその薬学的に許容される塩、粘着基剤、及び安定化剤の組み合わせとしてチオシアン酸塩と、茶カテキン、(+)-カテキン、没食子酸エピガロカテキン、アスコルビン酸、およびイソアスコルビン酸からなる群から選択される安定化剤との混合物、又はモノチオグリセロールと、茶カテキン、(+)-カテキンおよび没食子酸エピガロカテキンからなる群から選択される安定化剤との混合物を含む多様な成分を溶解させるステップと、
ii))前記ステップで製造された溶液を剥離層に塗布して乾燥させ、薬物含有層を形成するステップと、
iii)前記薬物含有層を前記支持層とラミネートするステップと、を含む、ドネペジル経皮吸収製剤の製造方法。 - 前記有機溶媒が、酢酸エチル、トルエン、ヘキサン、2-プロパノール、メタノール、エタノール、塩化メチレン及びテトラヒドロフランの中から選択されることを特徴とする、請求項7に記載のドネペジル経皮吸収製剤の製造方法。
- 前記ドネペジルが、遊離塩基(free base)形態であることを特徴とする、請求項7に記載のドネペジル経皮吸収製剤の製造方法。
- 前記安定化剤の組み合わせが、チオシアン酸塩と、茶カテキン、(+)-カテキン、没食子酸エピガロカテキン、アスコルビン酸およびイソアスコルビン酸からなる群から選択される安定化剤との混合物であることを特徴とする、請求項7に記載のドネペジル経皮吸収製剤の製造方法。
- 前記チオシアン酸塩が、チオシアン酸カリウムであることを特徴とする、請求項7又は10に記載の経皮吸収製剤の製造方法。
- 前記安定化剤の組み合わせが、モノチオグリセロールをさらに含むことを特徴とする、請求項10に記載のドネペジル経皮吸収製剤の製造方法。
- 前記安定化剤の組み合わせが、モノチオグリセロールと、茶カテキン、(+)-カテキ、および没食子酸エピガロカテキンからなる群から選択される安定化剤との混合物であることを特徴とする、請求項7に記載のドネペジル経皮吸収製剤の製造方法。
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WO2021230647A1 (en) | 2021-11-18 |
MA58444B1 (fr) | 2023-09-27 |
AU2021270155A1 (en) | 2022-11-24 |
MA58444A1 (fr) | 2023-03-31 |
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BR112022023127A2 (pt) | 2022-12-20 |
EP4149442A1 (en) | 2023-03-22 |
CL2022002984A1 (es) | 2023-05-12 |
CA3181045A1 (en) | 2021-11-18 |
KR102218593B1 (ko) | 2021-02-22 |
AU2021270155B2 (en) | 2023-11-09 |
PE20240490A1 (es) | 2024-03-15 |
JP7419565B2 (ja) | 2024-01-22 |
CN115666536A (zh) | 2023-01-31 |
MX2022013702A (es) | 2022-12-07 |
EP4149442A4 (en) | 2024-05-29 |
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