JP7404231B2 - 改良された超粒子 - Google Patents
改良された超粒子 Download PDFInfo
- Publication number
- JP7404231B2 JP7404231B2 JP2020516508A JP2020516508A JP7404231B2 JP 7404231 B2 JP7404231 B2 JP 7404231B2 JP 2020516508 A JP2020516508 A JP 2020516508A JP 2020516508 A JP2020516508 A JP 2020516508A JP 7404231 B2 JP7404231 B2 JP 7404231B2
- Authority
- JP
- Japan
- Prior art keywords
- superparticles
- another example
- payload
- superparticle
- neurotrophin
- 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
- 239000002245 particle Substances 0.000 title description 29
- 108010025020 Nerve Growth Factor Proteins 0.000 claims description 124
- 102000007072 Nerve Growth Factors Human genes 0.000 claims description 115
- 239000011148 porous material Substances 0.000 claims description 114
- 239000000203 mixture Substances 0.000 claims description 97
- 239000002105 nanoparticle Substances 0.000 claims description 86
- 235000010443 alginic acid Nutrition 0.000 claims description 73
- 229920000615 alginic acid Polymers 0.000 claims description 73
- 239000003900 neurotrophic factor Substances 0.000 claims description 71
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 claims description 55
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 claims description 55
- 238000011068 loading method Methods 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 46
- 108090000742 Neurotrophin 3 Proteins 0.000 claims description 41
- 102000004230 Neurotrophin 3 Human genes 0.000 claims description 41
- 229940032018 neurotrophin 3 Drugs 0.000 claims description 41
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 39
- 239000003814 drug Substances 0.000 claims description 32
- 230000002902 bimodal effect Effects 0.000 claims description 26
- 239000000783 alginic acid Substances 0.000 claims description 24
- 229960001126 alginic acid Drugs 0.000 claims description 24
- 150000004781 alginic acids Chemical class 0.000 claims description 24
- 230000001225 therapeutic effect Effects 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 206010011878 Deafness Diseases 0.000 claims description 20
- 238000007787 electrohydrodynamic spraying Methods 0.000 claims description 19
- 231100000888 hearing loss Toxicity 0.000 claims description 19
- 230000010370 hearing loss Effects 0.000 claims description 19
- 208000016354 hearing loss disease Diseases 0.000 claims description 19
- 229920001282 polysaccharide Polymers 0.000 claims description 16
- 239000005017 polysaccharide Substances 0.000 claims description 16
- 150000004804 polysaccharides Chemical class 0.000 claims description 16
- 239000000377 silicon dioxide Substances 0.000 claims description 16
- 238000013268 sustained release Methods 0.000 claims description 16
- 239000012730 sustained-release form Substances 0.000 claims description 16
- 238000009472 formulation Methods 0.000 claims description 14
- 239000000017 hydrogel Substances 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 210000002569 neuron Anatomy 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 230000004083 survival effect Effects 0.000 claims description 8
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical class CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 6
- 238000001354 calcination Methods 0.000 claims description 6
- 230000001788 irregular Effects 0.000 claims description 6
- 210000001323 spiral ganglion Anatomy 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 230000002459 sustained effect Effects 0.000 claims description 3
- 229920002527 Glycogen Polymers 0.000 claims description 2
- 229940096919 glycogen Drugs 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000004325 lysozyme Substances 0.000 description 70
- 229960000274 lysozyme Drugs 0.000 description 70
- 239000000243 solution Substances 0.000 description 59
- 102000016943 Muramidase Human genes 0.000 description 53
- 108010014251 Muramidase Proteins 0.000 description 53
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 53
- 235000010335 lysozyme Nutrition 0.000 description 53
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 52
- 229940072056 alginate Drugs 0.000 description 48
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 45
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 41
- 239000011859 microparticle Substances 0.000 description 32
- 229940079593 drug Drugs 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 26
- 108090000099 Neurotrophin-4 Proteins 0.000 description 25
- 102000003683 Neurotrophin-4 Human genes 0.000 description 25
- 229940097998 neurotrophin 4 Drugs 0.000 description 25
- 102000034615 Glial cell line-derived neurotrophic factor Human genes 0.000 description 23
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 23
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 21
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 21
- 238000000338 in vitro Methods 0.000 description 18
- 230000008569 process Effects 0.000 description 15
- 210000003027 ear inner Anatomy 0.000 description 14
- 238000010304 firing Methods 0.000 description 14
- 102000003815 Interleukin-11 Human genes 0.000 description 13
- 108090000177 Interleukin-11 Proteins 0.000 description 13
- -1 alginate sodium salt Chemical class 0.000 description 13
- 208000035475 disorder Diseases 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 11
- 239000007943 implant Substances 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 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 10
- 210000000959 ear middle Anatomy 0.000 description 10
- 239000002953 phosphate buffered saline Substances 0.000 description 10
- 230000000946 synaptic effect Effects 0.000 description 10
- 102000015336 Nerve Growth Factor Human genes 0.000 description 9
- 238000011534 incubation Methods 0.000 description 9
- 229940053128 nerve growth factor Drugs 0.000 description 9
- 229920001992 poloxamer 407 Polymers 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 241000702421 Dependoparvovirus Species 0.000 description 8
- 210000003477 cochlea Anatomy 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 239000000499 gel Substances 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 108091033409 CRISPR Proteins 0.000 description 6
- 238000010354 CRISPR gene editing Methods 0.000 description 6
- 206010011891 Deafness neurosensory Diseases 0.000 description 6
- 101710163270 Nuclease Proteins 0.000 description 6
- 229920000954 Polyglycolide Polymers 0.000 description 6
- 208000009966 Sensorineural Hearing Loss Diseases 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000004633 polyglycolic acid Substances 0.000 description 6
- 231100000879 sensorineural hearing loss Toxicity 0.000 description 6
- 208000023573 sensorineural hearing loss disease Diseases 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 210000002768 hair cell Anatomy 0.000 description 5
- 238000002513 implantation Methods 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 102000039446 nucleic acids Human genes 0.000 description 5
- 108020004707 nucleic acids Proteins 0.000 description 5
- 150000007523 nucleic acids Chemical class 0.000 description 5
- 229920000867 polyelectrolyte Polymers 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- 235000010413 sodium alginate Nutrition 0.000 description 5
- 239000000661 sodium alginate Substances 0.000 description 5
- 229940005550 sodium alginate Drugs 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 4
- CJLHTKGWEUGORV-UHFFFAOYSA-N Artemin Chemical compound C1CC2(C)C(O)CCC(=C)C2(O)C2C1C(C)C(=O)O2 CJLHTKGWEUGORV-UHFFFAOYSA-N 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 230000001186 cumulative effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 108091033319 polynucleotide Proteins 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 239000002157 polynucleotide Substances 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- 210000003454 tympanic membrane Anatomy 0.000 description 4
- 230000001720 vestibular Effects 0.000 description 4
- 230000035899 viability Effects 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 102000053602 DNA Human genes 0.000 description 3
- 239000012901 Milli-Q water Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000010954 inorganic particle Substances 0.000 description 3
- 239000002858 neurotransmitter agent Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000002924 silencing RNA Substances 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical group CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 description 2
- 102100026376 Artemin Human genes 0.000 description 2
- 101710205806 Artemin Proteins 0.000 description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 2
- 206010011903 Deafness traumatic Diseases 0.000 description 2
- 102000004038 Glia Maturation Factor Human genes 0.000 description 2
- 108090000495 Glia Maturation Factor Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000027601 Inner ear disease Diseases 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102000004058 Leukemia inhibitory factor Human genes 0.000 description 2
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 102000007339 Nerve Growth Factor Receptors Human genes 0.000 description 2
- 108010032605 Nerve Growth Factor Receptors Proteins 0.000 description 2
- 102100021584 Neurturin Human genes 0.000 description 2
- 108010015406 Neurturin Proteins 0.000 description 2
- 208000002946 Noise-Induced Hearing Loss Diseases 0.000 description 2
- 102100036660 Persephin Human genes 0.000 description 2
- 206010036626 Presbyacusis Diseases 0.000 description 2
- 108091005682 Receptor kinases Proteins 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 241000711975 Vesicular stomatitis virus Species 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 229940126575 aminoglycoside Drugs 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000000611 antibody drug conjugate Substances 0.000 description 2
- 229940049595 antibody-drug conjugate Drugs 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229910052788 barium Inorganic materials 0.000 description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 2
- 102000023732 binding proteins Human genes 0.000 description 2
- 108091008324 binding proteins Proteins 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 208000024055 brain glioblastoma Diseases 0.000 description 2
- 201000011609 brain glioblastoma multiforme Diseases 0.000 description 2
- 235000010410 calcium alginate Nutrition 0.000 description 2
- 239000000648 calcium alginate Substances 0.000 description 2
- 229960002681 calcium alginate Drugs 0.000 description 2
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=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](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000395 magnesium oxide Substances 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000002923 metal particle Substances 0.000 description 2
- 108091070501 miRNA Proteins 0.000 description 2
- 239000002679 microRNA Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 230000000508 neurotrophic effect Effects 0.000 description 2
- 239000011146 organic particle Substances 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 108010070453 persephin Proteins 0.000 description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 2
- 239000004584 polyacrylic acid Substances 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 239000004632 polycaprolactone Substances 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 235000010408 potassium alginate Nutrition 0.000 description 2
- 239000000737 potassium alginate Substances 0.000 description 2
- MZYRDLHIWXQJCQ-YZOKENDUSA-L potassium alginate Chemical compound [K+].[K+].O1[C@@H](C([O-])=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@@H](O)[C@H]1O MZYRDLHIWXQJCQ-YZOKENDUSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 208000009800 presbycusis Diseases 0.000 description 2
- 239000011164 primary particle Substances 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 210000004116 schwann cell Anatomy 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 230000007480 spreading Effects 0.000 description 2
- 238000003892 spreading Methods 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 229910052712 strontium Inorganic materials 0.000 description 2
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 210000000225 synapse Anatomy 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- QQJLHRRUATVHED-UHFFFAOYSA-N tramazoline Chemical compound N1CCN=C1NC1=CC=CC2=C1CCCC2 QQJLHRRUATVHED-UHFFFAOYSA-N 0.000 description 2
- 229960001262 tramazoline Drugs 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 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 description 1
- AFENDNXGAFYKQO-VKHMYHEASA-N (S)-2-hydroxybutyric acid Chemical compound CC[C@H](O)C(O)=O AFENDNXGAFYKQO-VKHMYHEASA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102000038778 CNTF family Human genes 0.000 description 1
- 108091064557 CNTF family Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241001631457 Cannula Species 0.000 description 1
- 102100035345 Cerebral dopamine neurotrophic factor Human genes 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 230000007067 DNA methylation Effects 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000160765 Erebia ligea Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010073324 Glutaminase Proteins 0.000 description 1
- 102000009127 Glutaminase Human genes 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 229940122597 Histone acetyltransferase inhibitor Drugs 0.000 description 1
- 101000737775 Homo sapiens Cerebral dopamine neurotrophic factor Proteins 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- 206010048865 Hypoacusis Diseases 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 102000007547 Laminin Human genes 0.000 description 1
- 108010085895 Laminin Proteins 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000016397 Methyltransferase Human genes 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 102000048238 Neuregulin-1 Human genes 0.000 description 1
- 108090000556 Neuregulin-1 Proteins 0.000 description 1
- 101800000675 Neuregulin-2 Proteins 0.000 description 1
- 101800000673 Neuregulin-3 Proteins 0.000 description 1
- 101800002641 Neuregulin-4 Proteins 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 102100022668 Pro-neuregulin-2, membrane-bound isoform Human genes 0.000 description 1
- 102100022659 Pro-neuregulin-3, membrane-bound isoform Human genes 0.000 description 1
- 102100022658 Pro-neuregulin-4, membrane-bound isoform Human genes 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- 108010092464 Urate Oxidase Proteins 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- MCMNRKCIXSYSNV-UHFFFAOYSA-N ZrO2 Inorganic materials O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000003349 alamar blue assay Methods 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229920001586 anionic polysaccharide Polymers 0.000 description 1
- 150000004836 anionic polysaccharides Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 1
- 229910001626 barium chloride Inorganic materials 0.000 description 1
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 1
- 239000010428 baryte Substances 0.000 description 1
- 229910052601 baryte Inorganic materials 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 229960000106 biosimilars Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 229910000420 cerium oxide Inorganic materials 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 238000000942 confocal micrograph Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- OOTFVKOQINZBBF-UHFFFAOYSA-N cystamine Chemical compound CCSSCCN OOTFVKOQINZBBF-UHFFFAOYSA-N 0.000 description 1
- 229940099500 cystamine Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 210000000883 ear external Anatomy 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 108060002566 ephrin Proteins 0.000 description 1
- 102000012803 ephrin Human genes 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 230000005251 gamma ray Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052595 hematite Inorganic materials 0.000 description 1
- 239000011019 hematite Substances 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000007925 in vitro drug release testing Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000011256 inorganic filler Substances 0.000 description 1
- 229910003475 inorganic filler Inorganic materials 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052809 inorganic oxide Inorganic materials 0.000 description 1
- 229940100601 interleukin-6 Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- LIKBJVNGSGBSGK-UHFFFAOYSA-N iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Fe+3].[Fe+3] LIKBJVNGSGBSGK-UHFFFAOYSA-N 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000002171 loop diuretic Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 229940088644 n,n-dimethylacrylamide Drugs 0.000 description 1
- YLGYACDQVQQZSW-UHFFFAOYSA-N n,n-dimethylprop-2-enamide Chemical compound CN(C)C(=O)C=C YLGYACDQVQQZSW-UHFFFAOYSA-N 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 231100000763 ototoxin Toxicity 0.000 description 1
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 1
- RVTZCBVAJQQJTK-UHFFFAOYSA-N oxygen(2-);zirconium(4+) Chemical compound [O-2].[O-2].[Zr+4] RVTZCBVAJQQJTK-UHFFFAOYSA-N 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 210000004049 perilymph Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003213 poly(N-isopropyl acrylamide) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003902 salicylic acid esters Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000002275 spiral lamina Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000000733 zeta-potential measurement Methods 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Images
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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
-
- 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
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2073—IL-11
-
- 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
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- 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
- A61K9/0046—Ear
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
-
- 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
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/5192—Processes
-
- 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
-
- 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
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/5115—Inorganic compounds
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Inorganic Chemistry (AREA)
- Neurosurgery (AREA)
- Optics & Photonics (AREA)
- Nanotechnology (AREA)
- Physics & Mathematics (AREA)
- Psychology (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Ceramic Engineering (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
特に別段の定義がなされない限り、本明細書において使用される全ての技術用語及び科学用語は、(例えば、生理学、臨床研究、分子生物学、高表面積分子、エレクトロスプレー、生化学)の分野の当業者によって一般に理解されるものと同一の意味を持つものと解釈される。
本開示によれば、超粒子は様々なペイロードを含むことができる。上記「ペイロード」は、障害の治療に有用な任意の薬剤であってよい。薬剤の例としては、ポリヌクレオチド、抗体、モノクローナル抗体、抗体フラグメント、抗体薬物コンジュゲート、タンパク質、生物学的に活性なタンパク質、融合タンパク質、組換えタンパク質、ペプチド、ポリペプチド、合成ポリペプチド、ワクチン、治療用血清、ウイルス、ポリヌクレオチド、幹細胞などの細胞、またはそれらの一部などの生物学的産物、ならびに小分子が挙げられる。
本開示の文脈において、用語「超粒子」(「SP」)は、細孔のネットワークを備える凝集粒子を指すために用いられる。上記細孔のネットワークにより、ペイロードを担持するための大きな細孔容積及び表面積を有する超粒子が提供される。大きな細孔容積及び表面積は、それらによって超粒子に担持することができるペイロードの量を高めることが可能になることから有利である。一例において、本開示に係る超粒子は凝集ナノ粒子である。
超粒子は、対象への投与に適した医薬組成物として製剤化されてもよい。例示的な医薬組成物は超粒子を単独で、または薬学的に許容される担体、希釈剤、もしくは賦形剤との組み合わせで提供してもよい。これらの組成物において、超粒子は、治療有効量のペイロードを対象に送達するのに十分な量で提供される。特定の投与経路に応じて、例えばRemington’s Pharmaceutical Sciences (Mack Publishing Co. N.J. USA, 1991)に記載されるように、当技術分野で公知の様々な許容される担体を使用することができる。
本開示は、本明細書において規定される超粒子を投与することを含む、疾患または障害の治療方法を包含する。したがって、一例において、本開示に係る超粒子を含む組成物は、対象の疾患または障害を治療するのに有効な量で上記対象に投与される。一例において、上記疾患または障害は難聴である。本開示の文脈において、用語「難聴」は、音を検出または処理する対象の能力の低下を指すために用いられる。したがって、難聴への言及は、部分的な聴覚低下または完全な聴覚喪失を含む。
本開示に係る超粒子は、キットまたはパック中で提供されてもよい。例えば、本明細書に開示の組成物は、内耳障害を治療するための書面による指示と共に、適宜の容器中に包装されていてもよい。一例において、組成物は、点耳器または充填済み注射器などの単回投与容器中で提供されてもよい。
本開示は、高レベルのペイロードを担持可能な超粒子の製造方法を包含する。一例において、上記超粒子は、ナノ粒子とアルギン酸またはその多糖誘導体とを含む組成物から製造することができる。ナノ粒子の様々な例を上記に示している。一例において、上記ナノ粒子は二峰性細孔構造を有する。ナノ粒子は様々な方法を用いて製造することができる。かかる方法の1つがCui et al. 2015, ACS Nano, 9, 1571-1580に記載される。
メソポーラスシリカナノ粒子(MS-NP)を、Cui et al. 2015, ACS Nano, 9, 1571-1580に記載の方法に基づく方法を用いて製造した。l.lgの臭化セチルトリメチルアンモニウム(CTAB)を撹拌しながら50mlのMilli-Q水に完全に溶解した。続いて4.3gのポリアクリル酸溶液(PAA、Mw=250kDa、35wt%水溶液)を、25℃で20分間激しく撹拌しながら添加し、透明な溶液が得られるまで撹拌を続けた。次いでこの溶液に、激しく撹拌しながら3.5mlの水酸化アンモニウム溶液(28~30%)を添加したところ、乳白色の懸濁液が得られた。20分間撹拌した後、4.46mlのオルトケイ酸テトラエチル(TEOS)を添加した。この溶液を更に15分間撹拌した後、この混合物をテフロン(登録商標)で密封したオートクレーブに移し、90℃で48時間静置した。
メソポーラスシリカ(MS)ナノ粒子をWang et al. (2010) Chem Mater. 22, 3829-3831に従って調製した。MSナノ粒子をMilli-Q水中に粒子濃度5wt%で分散させ、短時間超音波処理して安定なコロイド懸濁液を形成した。次いで、上記MSナノ粒子分散液の0.5~2.0μLのアリコートを、パラフィンフィルムで事前に被覆した平坦な表面に塗布した。これらの液滴を空気流下で乾燥し、毛管力作用によってMSナノ粒子をメソポーラスシリカ超粒子(毛管力MS-SP)へと組織化することを推進した。上記毛管力MS-SPの径は、液滴で塗布したナノ粒子分散液の容積によって制御した。
80mgのMS-NP粉末を2mlのアルギン酸ナトリウム塩溶液(30mg・mL-1の水溶液)に添加した。このMS-NPがアルギン酸ナトリウム塩溶液中に均一に分布するまで、得られた溶液を1時間超音波処理した。
MS-SP(LMS-SPalg)を実施例3に記載の方法を用いて製造した。650℃で30時間焼成することによってアルギン酸ナトリウム塩を除去した。このステップにより、全ての有機成分が除去され、メソポーラスシリカ(MS-SP)ならびに微量の塩化カルシウム及び塩化ナトリウムのみが残留した。次いでMS-SPにペイロードを担持した。これらの粒子に関しては、プロセスAによって製造した粒子と比較して、薬物担持性能の顕著な向上、すなわち、粒子当り約7.8μgのタンパク質、が観測された。
リゾチーム
滅菌したSPを100μLのFITCリゾチーム溶液(0.2mg・mL-1 Milli-Q水溶液)と共にインキュベートすることにより、イン・ビトロ放出検討用にFITCリゾチーム担持SPを調製した。リゾチームはニューロトロフィンBDNFを模倣するのに適したモデルタンパク質であり、これは、リゾチームが類似の物理化学的特性を共有すること(リゾチーム:Mw=14.3±0.5KDa、RH=18.9±0.25Å、及びpI=11;BDNF:Mw=13KDa、RH=24.0±3.2Å、及びpI=10)、ならびにBDNFは高価である一方でリゾチームは安価で容易に入手できることによる。
次いで、MS-SPにフルオレセイン標識リゾチーム(FITCリゾチーム)を担持した。図2に示すように、pH値が4から10に上昇すると、MS-SPは約-7.6mV~-33.9mVの範囲の負のゼータ電位を示した。したがって、正に荷電したリゾチーム及びBDNFは静電的な駆動力を利用してMS-SPに担持することができる。共焦点顕微鏡画像(図3のa、b)はMS-SPの表面上に担持されたFITCリゾチームを示した。但し、MS-SPの径は非常に大きい(数百マイクロメートルの径)ために、標準的なレーザー走査型共焦点顕微鏡はSPの内部構造の撮像には適さない。しかし、手術用メスでこのMS-SPを破断したところ内部を撮像することができ、MS-SPの多孔性内部構造中にもFITCリゾチームが観察されることが判った(図3のc)。
次いで、FITCリゾチームを用い、3日間のインキュベーション時間で、異なる担持時の濃度における、種々の種類のSPの担持容量を検討した(図4)。概括的には、FITCリゾチームの濃度が増加すると、薬物担持量が増加した。結果は、アルギン酸塩を含有するNMS-SPalg、SMS-SPalg、及びLMS-SPalgは、アルギン酸塩を除去したNMS-SP、SMS-SP、及びLMS-SP(同等の担持時の濃度)よりも担持容量が高いことを示す。このことは、中性のpH値付近における、正に荷電したFITCリゾチームと負に荷電したアルギン酸塩との間の高い静電的相互作用に起因する可能性がある。更に、低いFITCリゾチームの担持時の濃度(<0.4mg・mL-1)においては、LMS-SPalgの薬物担持容量は非多孔性MS-SPalg及びSMS-SPalgと同様であったが、担持時の濃度がより高かった場合(>0.4mg・mL-1)には、NMS-SPalg及びSMS-SPalgと比較して、より多くのFITCリゾチームをLMS-SPalgに担持することができた。アルギン酸塩を除去したMS-SPに関しても同様の傾向が観測された。すなわち、LMS-SPには、NMS-SP及びSMS-SPよりも多くのFITCリゾチームを担持することができた。これらの結果は、大きな多孔性構造(LMS-SP及びLMS-SPalgにおける)が薬物担持量を向上させるための重要な因子であり、それはおそらく、更なる表面を与え、延いては、粒子の外表面と粒子内部の領域(SP構造内の)とが薬物によって完全に飽和された場合に、更なる担持容量を与えることによる可能性が高いことを示している。更に、上記担持容量はMS-SPの径にも依存し、より大きなMS-SP(1000μm)の担持容量はより小さなMS-SP(200μm)よりも大きかった(図5)。
MS-SPを100μlのエタノール(80 vol/vol%)4時間に浸漬して滅菌し、その後100μlのMilli-Q水で6回すすいだ。次いで、MS-SPを0.1Mリン酸緩衝生理食塩水(PBS)中で1回洗浄した。MS-SPを15μlのBDNF(Geneway, BDNF Human Protein,カタログ番号 10-663-45078)溶液(BDNFの1mg/ml)が入ったエッペンドルフ・チューブに入れ、時々手で振とうしながら室温で3日間インキュベートすることによって、該MS-SPに担持した。驚くべきことに、約10μgのBDNFの担持を達成した。
MS-SPを生体適合性の薬物担体として適用することができるかを検討するために、MS-SPのイン・ビトロ細胞毒性の検討を実施した。ヒト脳神経膠芽腫細胞(U87MG細胞株)をMS-SPと共にインキュベートし、細胞生存率をAlamar Blueアッセイによって評価した。図6に示すように、MS-SPの数をウェル当り10まで増加した場合においても(ウェル当り1×104細胞)、MS-SPは非毒性であった。同様の粒子システムの典型的なイン・ビボ治療計画において、内耳当り1~8のSPの投与が提案されている。
担持容量の結果に基づいて、10のLMS-SP及び10のMS-SPalgをPBS(pH7.4)中、37℃でインキュベートすることにより、FITCリゾチームの放出の検討(担持時間3日間、担持時の濃度0.2mg・mL-1)を実施した。
生物学的環境において分解することが可能である多孔性シリカ粒子(例えばケイ酸へと分解され、ケイ酸は尿を介して排泄することができる)は、多様な生物医学的用途にとって関心の対象である。分解率を調べるために、MS-SPを150日間インキュベートした(PBS、pH7.4、37℃)(図14)。上記MS-SPの径が約55%減少することが観測され、上記MS-SPの形状/モルホロジーも大幅に変化した。上記MS-SPの表面上のシリカ一次粒子は、モルホロジー及び径の両方が変化した。
イン・ビボ検討を実施して、耳に移植した超粒子中で送達したニューロトロフィンの薬物ペイロード及びクリアランスを、移植の4時間後、3日後、及び7日後に測定した。この目的は、経時的に蝸牛中に残存するニューロトロフィンの量を測定することであった。
Clark GM, et al. (1984) Ann Otol Rhinol Laryngol 93:204-207
Clark GM, et al. (1991) Ear and Hearing Suppl. 12:15S-24S
Cui et al. (2015) ACS Nano 9:1571-1580
Jaworek (2007) Powder Technology 176(1), 18-35
Langer R (1990) Science. 249, 1527-1533
Remington’s Pharmaceutical Sciences (Mack Publishing Co. N.J. USA, 1991)
Tan et al. (2012) Adv. Mater. 24: 3362-3366
Wang et al. (2009) J. Mater. Chem. 19: 6451-6464
Wang et al. (2010) Chem Mater. 22: 3829-3831
Yang and Pierstorff (2012) JALA. 17, 50-58
Claims (23)
- 超粒子を含む組成物であって、前記超粒子がメソポーラスシリカナノ粒子及び少なくとも1つのペイロードを含み、前記ペイロードが少なくとも1.5μgの神経栄養因子であり、前記超粒子がナノ粒子溶液のエレクトロスプレーによって製造される、前記組成物。
- 前記超粒子が少なくとも5μgのペイロードを含む、請求項1に記載の組成物。
- 前記超粒子が1.5μg~10μgのペイロードを含む、請求項1に記載の組成物。
- 前記超粒子が、径が少なくとも50~100nmである細孔を備える、請求項1~3のいずれか1項に記載の組成物。
- 前記超粒子が不規則な細孔構造を有する、または、二峰性細孔構造を有するナノ粒子から構成される、請求項1~4のいずれか1項に記載の組成物。
- 前記神経栄養因子の等電点が8~10である、請求項1~5のいずれか一項に記載の組成物。
- 前記神経栄養因子がBDNFである、請求項1~6のいずれか1項に記載の組成物。
- 前記神経栄養因子がニューロトロフィン-3である、請求項1~6のいずれか1項に記載の組成物。
- 前記超粒子が、少なくとも2種、少なくとも3種、少なくとも4種、または少なくとも5種の異なるペイロードを含む、請求項1~8のいずれか1項に記載の組成物。
- 異なるペイロードを含む少なくとも2種類の超粒子を含む、請求項1~9のいずれか1項に記載の組成物。
- 徐放性製剤として提供される、請求項1~10のいずれか1項に記載の組成物。
- グリコーゲンヒドロゲルを含む、請求項11に記載の組成物。
- 前記超粒子が、メソポーラスシリカナノ粒子を含む組成物をジカチオン水溶液中にエレクトロスプレーすることによって製造される、請求項1から12のいずれか一項に記載の組成物。
- 前記超粒子が、ナノ粒子及びアルギン酸またはその多糖誘導体を含む組成物をジカチオン水溶液中にエレクトロスプレーすることによって製造される、請求項1から13のいずれか一項に記載の組成物。
- 難聴を治療するための薬剤の製造における、請求項1~14のいずれか1項に記載の組成物の使用であって、前記神経栄養因子がニューロトロフィンである、使用。
- 前記ニューロトロフィンがBDNFである、請求項15に記載の使用。
- 前記ニューロトロフィンがニューロトロフィン-3である、請求項15又は16に記載の使用。
- 前記薬剤が、対象の耳におけるらせん神経節ニューロンの生存を促進する、請求項15から17のいずれか一項に記載の使用。
- 対象における治療用ペイロードの持続的送達が望ましい疾病の治療のための薬剤の製造における、請求項1~14のいずれか1項に記載の組成物の使用。
- メソポーラスシリカナノ粒子及びアルギン酸を含む組成物を、ジカチオン水溶液中にエレクトロスプレーすることを含み、製造された超粒子に少なくとも1.5μgの神経栄養因子を担持することを更に含む、請求項1から14のいずれか一項に記載の超粒子の製造方法。
- アルギン酸がアルギン酸ナトリウム塩[Na(C6H8O6)n]である、請求項20に記載の方法。
- 超粒子を焼成に供してアルギン酸を除去することを更に含む、請求項20又は21に記載の方法。
- 焼成が約650℃で、または、約6~約30時間行われる、請求項22に記載の方法。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2017903829A AU2017903829A0 (en) | 2017-09-20 | Method of treatment | |
AU2017903828A AU2017903828A0 (en) | 2017-09-20 | Improved supraparticles | |
AU2017903829 | 2017-09-20 | ||
AU2017903828 | 2017-09-20 | ||
AU2018902513A AU2018902513A0 (en) | 2018-07-11 | Improved supraparticles | |
AU2018902513 | 2018-07-11 | ||
PCT/AU2018/051029 WO2019056062A1 (en) | 2017-09-20 | 2018-09-20 | SUPERPARTICLES IMPROVED |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2020535130A JP2020535130A (ja) | 2020-12-03 |
JP2020535130A5 JP2020535130A5 (ja) | 2021-11-11 |
JP7404231B2 true JP7404231B2 (ja) | 2023-12-25 |
Family
ID=65810122
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020516514A Pending JP2020535131A (ja) | 2017-09-20 | 2018-09-20 | 処置の方法 |
JP2020516508A Active JP7404231B2 (ja) | 2017-09-20 | 2018-09-20 | 改良された超粒子 |
JP2023131227A Pending JP2023154035A (ja) | 2017-09-20 | 2023-08-10 | 処置の方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020516514A Pending JP2020535131A (ja) | 2017-09-20 | 2018-09-20 | 処置の方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023131227A Pending JP2023154035A (ja) | 2017-09-20 | 2023-08-10 | 処置の方法 |
Country Status (7)
Country | Link |
---|---|
US (4) | US20200253865A1 (ja) |
EP (2) | EP3684342B1 (ja) |
JP (3) | JP2020535131A (ja) |
CN (2) | CN111278428A (ja) |
AU (2) | AU2018337076A1 (ja) |
ES (1) | ES2962580T3 (ja) |
WO (2) | WO2019056061A1 (ja) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2018337076A1 (en) | 2017-09-20 | 2020-04-09 | The Bionics Institute Of Australia | Method of treatment |
CN112368011A (zh) * | 2018-04-11 | 2021-02-12 | 俄亥俄州创新基金会 | 缓释微粒用于眼用药物递送的方法和组合物 |
CN114040753A (zh) * | 2019-03-19 | 2022-02-11 | 澳大利亚仿生研究所 | 超粒子制剂 |
CN110063968B (zh) * | 2019-04-18 | 2021-09-03 | 朗姿赛尔生物科技(广州)有限公司 | 一种特异性干细胞修复病变胰岛的方法 |
WO2022269540A1 (en) * | 2021-06-24 | 2022-12-29 | Cochlear Limited | Methods and pharmaceutical formulations for modulating the properties of the blood labyrinth barrier |
GB202213060D0 (en) * | 2022-09-07 | 2022-10-19 | Rinri Therapeutics Ltd | Surgical method for treatment of auditory disease or condition |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4468498A (en) | 1980-06-12 | 1984-08-28 | Rohm And Haas Company | Sequential heteropolymer dispersion and a particulate materal obtainable therefrom, useful in coating compositions as a thickening and/or opacifying agent |
US5521253A (en) | 1990-10-12 | 1996-05-28 | The Dow Chemical Company | Hollow polymer latex particles |
US5157084A (en) | 1990-10-12 | 1992-10-20 | The Dow Chemical Company | Process of making hollow polymer latex particles |
SE9903958D0 (sv) | 1999-11-02 | 1999-11-02 | Boerje Sellergren | Porous materials for selective binding or transport of molecular guests |
CA2583054A1 (en) | 2004-10-05 | 2006-04-13 | The University Of Melbourne | Porous polyelectrolyte materials |
WO2009079688A1 (en) | 2007-12-21 | 2009-07-02 | The University Of Melbourne | Porous silica shell-mediated assembly of macromolecular capsules |
CN102380102A (zh) * | 2011-11-02 | 2012-03-21 | 东华大学 | 一种环境响应性介孔硅纳米粒子的制备方法 |
KR102030369B1 (ko) * | 2012-03-28 | 2019-10-10 | 보레알리스 아게 | 다중모드 고분자 |
CN104582782B (zh) * | 2012-08-20 | 2018-11-27 | 奥雷制药有限公司 | 用于制备药物递送制剂的方法 |
WO2015051364A1 (en) * | 2013-10-05 | 2015-04-09 | Omnova Solutions Inc | Supraparticles including hollow polymeric particles |
US9534213B2 (en) | 2014-03-04 | 2017-01-03 | The Regents Of The University Of Michigan | Spontaneously formed terminal supraparticles having nanoparticles for protein stabilization |
CN104003404B (zh) * | 2014-05-19 | 2016-03-16 | 国家纳米科学中心 | 一种多孔二氧化硅纳米粒子的制备方法及其用途 |
AU2018337076A1 (en) | 2017-09-20 | 2020-04-09 | The Bionics Institute Of Australia | Method of treatment |
-
2018
- 2018-09-20 AU AU2018337076A patent/AU2018337076A1/en active Pending
- 2018-09-20 JP JP2020516514A patent/JP2020535131A/ja active Pending
- 2018-09-20 EP EP18857932.0A patent/EP3684342B1/en active Active
- 2018-09-20 ES ES18858164T patent/ES2962580T3/es active Active
- 2018-09-20 WO PCT/AU2018/051028 patent/WO2019056061A1/en unknown
- 2018-09-20 EP EP18858164.9A patent/EP3684343B1/en active Active
- 2018-09-20 JP JP2020516508A patent/JP7404231B2/ja active Active
- 2018-09-20 US US16/648,858 patent/US20200253865A1/en not_active Abandoned
- 2018-09-20 AU AU2018337668A patent/AU2018337668A1/en active Pending
- 2018-09-20 WO PCT/AU2018/051029 patent/WO2019056062A1/en unknown
- 2018-09-20 CN CN201880069810.9A patent/CN111278428A/zh active Pending
- 2018-09-20 CN CN201880068028.5A patent/CN111225663A/zh active Pending
-
2019
- 2019-07-01 US US16/459,263 patent/US11369661B2/en active Active
-
2022
- 2022-05-25 US US17/824,654 patent/US20220362337A1/en active Pending
- 2022-12-21 US US18/086,412 patent/US20230135903A1/en active Pending
-
2023
- 2023-08-10 JP JP2023131227A patent/JP2023154035A/ja active Pending
Non-Patent Citations (1)
Title |
---|
Biomacromolecules, (2014), 15, [11], p.4146-4151 |
Also Published As
Publication number | Publication date |
---|---|
EP3684342A1 (en) | 2020-07-29 |
EP3684342B1 (en) | 2024-04-24 |
WO2019056062A1 (en) | 2019-03-28 |
EP3684342A4 (en) | 2021-05-26 |
JP2020535131A (ja) | 2020-12-03 |
US11369661B2 (en) | 2022-06-28 |
US20200253865A1 (en) | 2020-08-13 |
EP3684343A4 (en) | 2021-07-14 |
JP2020535130A (ja) | 2020-12-03 |
WO2019056061A1 (en) | 2019-03-28 |
EP3684343B1 (en) | 2023-09-13 |
CN111278428A (zh) | 2020-06-12 |
US20220362337A1 (en) | 2022-11-17 |
EP3684342C0 (en) | 2024-04-24 |
CN111225663A (zh) | 2020-06-02 |
EP3684343C0 (en) | 2023-09-13 |
AU2018337076A1 (en) | 2020-04-09 |
US20230135903A1 (en) | 2023-05-04 |
JP2023154035A (ja) | 2023-10-18 |
AU2018337668A1 (en) | 2020-04-09 |
ES2962580T3 (es) | 2024-03-19 |
EP3684343A1 (en) | 2020-07-29 |
US20200000879A1 (en) | 2020-01-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7404231B2 (ja) | 改良された超粒子 | |
Schmidt et al. | Long-term delivery of brain-derived neurotrophic factor (BDNF) from nanoporous silica nanoparticles improves the survival of spiral ganglion neurons in vitro | |
US7846466B2 (en) | Biodegradable scaffolds and uses thereof | |
JP2017536969A (ja) | 組織増大への適用、生物医学的適用および美容的適用のためのガラス組成物 | |
US20160296635A1 (en) | Affinity Hydrogels for Controlled Protein Release | |
Ma et al. | Gel-mediated electrospray assembly of silica supraparticles for sustained drug delivery | |
US11213490B2 (en) | Encapsulation-free controlled protein release system | |
Lee et al. | Collagen gel combined with mesoporous nanoparticles loading nerve growth factor as a feasible therapeutic three-dimensional depot for neural tissue engineering | |
JP2024028827A (ja) | 標的化送達のための磁性ナノ粒子 | |
Tamariz et al. | Delivery of chemotropic proteins and improvement of dopaminergic neuron outgrowth through a thixotropic hybrid nano-gel | |
Ma et al. | Engineering biocoatings to prolong drug release from supraparticles | |
Guo et al. | Enhanced drug release from a pH-responsive nanocarrier can augment colon cancer treatment by blocking PD-L1 checkpoint and consuming tumor glucose | |
Wu et al. | Targeted delivery of mitomycin C-loaded and LDL-conjugated mesoporous silica nanoparticles for inhibiting the proliferation of pterygium subconjunctival fibroblasts | |
Negron et al. | Non-adhesive and highly stable biodegradable nanoparticles that provide widespread and safe transgene expression in orthotopic brain tumors | |
US20220168228A1 (en) | Supraparticle Formulations | |
Ghaffari et al. | Drug delivery nanosystems for musculoskeletal regeneration | |
Karagoz et al. | PRODUCING AFLIBERCEPT LOADED POLY (LACTIC co GLYCOLIC ACID)[PLGA] NANOPARTICLES AS A NEW OCULAR DRUG DELIVERY SYSTEM AND ITS CHALLENGES | |
Hosseinpour et al. | Nanobiomaterials in Craniofacial Bone Regeneration | |
Khwaza et al. | Ruwizhi Ngonidzashe, Opeoluwa O. Oyedeji and Blessing A. Aderibigbe Department of Chemistry, University of Fort Hare, Alice Campus, Eastern Cape, South Africa | |
Sable et al. | Applications of Electrospraying in Tissue Repair and Regeneration |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210921 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210921 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20221003 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230104 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230410 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230710 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230809 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20230810 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20231113 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20231213 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7404231 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |