JPWO2019136386A5 - - Google Patents
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- JPWO2019136386A5 JPWO2019136386A5 JP2020537138A JP2020537138A JPWO2019136386A5 JP WO2019136386 A5 JPWO2019136386 A5 JP WO2019136386A5 JP 2020537138 A JP2020537138 A JP 2020537138A JP 2020537138 A JP2020537138 A JP 2020537138A JP WO2019136386 A5 JPWO2019136386 A5 JP WO2019136386A5
- Authority
- JP
- Japan
- Prior art keywords
- glycero
- biotin
- insulin
- nanoparticles
- phosphate
- 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
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- 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 claims description 96
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 74
- 239000002105 nanoparticle Substances 0.000 claims description 72
- 102000004877 Insulin Human genes 0.000 claims description 52
- 108090001061 Insulin Proteins 0.000 claims description 52
- 150000002632 lipids Chemical class 0.000 claims description 50
- 229940125396 insulin Drugs 0.000 claims description 48
- 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 claims description 44
- 239000011616 biotin Substances 0.000 claims description 33
- 235000020958 biotin Nutrition 0.000 claims description 33
- 229960002685 biotin Drugs 0.000 claims description 33
- 239000012528 membrane Substances 0.000 claims description 32
- 102000005962 receptors Human genes 0.000 claims description 32
- 108020003175 receptors Proteins 0.000 claims description 32
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 26
- 210000003494 hepatocyte Anatomy 0.000 claims description 25
- 229910019142 PO4 Inorganic materials 0.000 claims description 22
- 235000012000 cholesterol Nutrition 0.000 claims description 22
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 22
- 239000010452 phosphate Substances 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 18
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 claims description 14
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims description 14
- UXDBPOWEWOXJCE-DIPNUNPCSA-N 1,2-dihexadecyl-sn-glycero-3-phosphoethanolamine Chemical compound CCCCCCCCCCCCCCCCOC[C@H](COP(O)(=O)OCCN)OCCCCCCCCCCCCCCCC UXDBPOWEWOXJCE-DIPNUNPCSA-N 0.000 claims description 12
- YFWHNAWEOZTIPI-DIPNUNPCSA-N 1,2-dioctadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCCCC YFWHNAWEOZTIPI-DIPNUNPCSA-N 0.000 claims description 12
- IQGPMZRCLCCXAG-RUZDIDTESA-N 2-stearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@H](CO)COP([O-])(=O)OCC[N+](C)(C)C IQGPMZRCLCCXAG-RUZDIDTESA-N 0.000 claims description 12
- NFRFUGBXJTXTMZ-QYKZUBHNSA-L disodium;[(2r)-2,3-di(hexadecanoyloxy)propyl] phosphate Chemical compound [Na+].[Na+].CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])([O-])=O)OC(=O)CCCCCCCCCCCCCCC NFRFUGBXJTXTMZ-QYKZUBHNSA-L 0.000 claims description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- -1 sulfo-NHS-biotin Chemical compound 0.000 claims description 12
- 206010012601 diabetes mellitus Diseases 0.000 claims description 10
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-methyl-PhOH Natural products CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 6
- 102000001554 Hemoglobins Human genes 0.000 claims description 6
- 108010054147 Hemoglobins Proteins 0.000 claims description 6
- 239000008103 glucose Substances 0.000 claims description 6
- 239000003381 stabilizer Substances 0.000 claims description 6
- ALIFRMFPRBTNNH-WFXMLNOXSA-N 12-[5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]dodecanoic acid Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCCCCCCCC(=O)O)SC[C@@H]21 ALIFRMFPRBTNNH-WFXMLNOXSA-N 0.000 claims description 4
- 239000011665 D-biotin Substances 0.000 claims description 4
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 4
- 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 4
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 claims description 4
- 230000003451 hyperinsulinaemic effect Effects 0.000 claims description 4
- 201000008980 hyperinsulinism Diseases 0.000 claims description 4
- 230000000642 iatrogenic effect Effects 0.000 claims description 4
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 4
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 108010057186 Insulin Glargine Proteins 0.000 claims description 3
- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 229960002869 insulin glargine Drugs 0.000 claims description 3
- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 claims description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
- BPNHGUOHVHHZMG-WQYNNSOESA-N (3as,4s,6ar)-4-(4-aminobutyl)-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-2-one;hydrochloride Chemical compound Cl.N1C(=O)N[C@@H]2[C@H](CCCCN)SC[C@@H]21 BPNHGUOHVHHZMG-WQYNNSOESA-N 0.000 claims description 2
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 2
- BIABMEZBCHDPBV-BEBVUIBBSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-BEBVUIBBSA-N 0.000 claims description 2
- HKAVADYDPYUPRD-UHFFFAOYSA-N 1h-pyrazine-2-thione Chemical compound SC1=CN=CC=N1 HKAVADYDPYUPRD-UHFFFAOYSA-N 0.000 claims description 2
- GVJXGCIPWAVXJP-UHFFFAOYSA-N 2,5-dioxo-1-oxoniopyrrolidine-3-sulfonate Chemical compound ON1C(=O)CC(S(O)(=O)=O)C1=O GVJXGCIPWAVXJP-UHFFFAOYSA-N 0.000 claims description 2
- YZKOXCJYWZCAFW-UHFFFAOYSA-N 2,6-ditert-butyl-4-methylphenol;phenylmethanol Chemical class OCC1=CC=CC=C1.CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 YZKOXCJYWZCAFW-UHFFFAOYSA-N 0.000 claims description 2
- XWJBVGZSIAZDKJ-FXQIFTODSA-N 2-[3-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]propyl]propanedioic acid Chemical compound N1C(=O)N[C@@H]2[C@H](CCCC(C(=O)O)C(O)=O)SC[C@@H]21 XWJBVGZSIAZDKJ-FXQIFTODSA-N 0.000 claims description 2
- KCSKCIQYNAOBNQ-KBUMHGCDSA-N 5-[(3as,4s,5r,6ar)-2,5-dioxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoic acid Chemical compound N1C(=O)N[C@H]2C[S@@](=O)[C@@H](CCCCC(=O)O)[C@H]21 KCSKCIQYNAOBNQ-KBUMHGCDSA-N 0.000 claims description 2
- CCSGGWGTGOLEHK-OBJOEFQTSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-(5-aminopentyl)pentanamide Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCN)SC[C@@H]21 CCSGGWGTGOLEHK-OBJOEFQTSA-N 0.000 claims description 2
- IJJWOSAXNHWBPR-HUBLWGQQSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-(6-hydrazinyl-6-oxohexyl)pentanamide Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCC(=O)NN)SC[C@@H]21 IJJWOSAXNHWBPR-HUBLWGQQSA-N 0.000 claims description 2
- NDKQUODALAUTFL-KWBADKCTSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-[2-[(2-iodoacetyl)amino]ethyl]pentanamide Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCNC(=O)CI)SC[C@@H]21 NDKQUODALAUTFL-KWBADKCTSA-N 0.000 claims description 2
- BRLRJZRHRJEWJY-VCOUNFBDSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-[3-[3-(4-azido-2-nitroanilino)propyl-methylamino]propyl]pentanamide Chemical compound C([C@H]1[C@H]2NC(=O)N[C@H]2CS1)CCCC(=O)NCCCN(C)CCCNC1=CC=C(N=[N+]=[N-])C=C1[N+]([O-])=O BRLRJZRHRJEWJY-VCOUNFBDSA-N 0.000 claims description 2
- DNXDWMHPTVQBIP-ZQIUZPCESA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-[6-[(2-iodoacetyl)amino]hexyl]pentanamide Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCCNC(=O)CI)SC[C@@H]21 DNXDWMHPTVQBIP-ZQIUZPCESA-N 0.000 claims description 2
- QLPHBNRMJLFRGO-YDHSSHFGSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-[6-[3-(pyridin-2-yldisulfanyl)propanoylamino]hexyl]pentanamide Chemical compound C([C@H]1[C@H]2NC(=O)N[C@H]2CS1)CCCC(=O)NCCCCCCNC(=O)CCSSC1=CC=CC=N1 QLPHBNRMJLFRGO-YDHSSHFGSA-N 0.000 claims description 2
- YNIUDHSTAXEOHP-UFLZEWODSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoic acid;ethane-1,2-diamine Chemical compound NCCN.N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YNIUDHSTAXEOHP-UFLZEWODSA-N 0.000 claims description 2
- CIVGYTYIDWRBQU-UFLZEWODSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoic acid;pyrrole-2,5-dione Chemical compound O=C1NC(=O)C=C1.N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 CIVGYTYIDWRBQU-UFLZEWODSA-N 0.000 claims description 2
- CMUGHZFPFWNUQT-HUBLWGQQSA-N 6-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoylamino]-hexanoic acid Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCC(=O)O)SC[C@@H]21 CMUGHZFPFWNUQT-HUBLWGQQSA-N 0.000 claims description 2
- LOIYZIMLLRKKNS-FIKGOQFSSA-N Biotin-xx hydrazide Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCC(=O)NCCCCCC(=O)NN)SC[C@@H]21 LOIYZIMLLRKKNS-FIKGOQFSSA-N 0.000 claims description 2
- 235000000638 D-biotin Nutrition 0.000 claims description 2
- 108010033040 Histones Proteins 0.000 claims description 2
- 102000013266 Human Regular Insulin Human genes 0.000 claims description 2
- 108010090613 Human Regular Insulin Proteins 0.000 claims description 2
- 208000013016 Hypoglycemia Diseases 0.000 claims description 2
- 108010073961 Insulin Aspart Proteins 0.000 claims description 2
- 108010065920 Insulin Lispro Proteins 0.000 claims description 2
- 108010039918 Polylysine Proteins 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 241000051616 Ulmus minor Species 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 125000000539 amino acid group Chemical group 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
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| US9872890B2 (en) * | 2003-03-19 | 2018-01-23 | Paul C. Davidson | Determining insulin dosing schedules and carbohydrate-to-insulin ratios in diabetic patients |
| CN101237854B (zh) | 2005-05-23 | 2013-03-27 | Sdg公司 | 将胰岛素输送到哺乳动物的脂构建体 |
| US20110135725A1 (en) * | 2005-05-23 | 2011-06-09 | Sdg, Inc. | Lipid Construct for Delivery of Insulin to a Mammal |
| US8962015B2 (en) * | 2007-09-28 | 2015-02-24 | Sdg, Inc. | Orally bioavailable lipid-based constructs |
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| WO2010080976A1 (en) * | 2009-01-09 | 2010-07-15 | Sdg, Inc. (An Ohio Corporation) | Insulin therapies for the treatment of diabetes, diabetes related ailments, and/or diseases or conditions other than diabetes or diabetes related ailments |
| AU2011265294B2 (en) * | 2010-06-10 | 2015-01-22 | Aquestive Therapeutics, Inc. | Nanoparticle film delivery systems |
| KR20140026396A (ko) * | 2011-03-08 | 2014-03-05 | 어섹스 팔마큐티칼스 인코포레이티드 | 생물학적 막을 가로질러 활성물질의 전달을 위한 표적화된 나노담체 시스템 |
| US20170000899A1 (en) * | 2013-11-26 | 2017-01-05 | The Brigham And Women's Hospital, Inc. | Receptor-targeted nanoparticles for enhanced transcytosis mediated drug delivery |
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