CA2261835C - Long-acting drugs and pharmaceutical compositions comprising them - Google Patents
Long-acting drugs and pharmaceutical compositions comprising them Download PDFInfo
- Publication number
- CA2261835C CA2261835C CA002261835A CA2261835A CA2261835C CA 2261835 C CA2261835 C CA 2261835C CA 002261835 A CA002261835 A CA 002261835A CA 2261835 A CA2261835 A CA 2261835A CA 2261835 C CA2261835 C CA 2261835C
- Authority
- CA
- Canada
- Prior art keywords
- insulin
- fmoc
- radical
- drug
- compound according
- 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.)
- Expired - Lifetime
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 12
- 239000003509 long acting drug Substances 0.000 title description 2
- 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 abstract description 353
- 229940125396 insulin Drugs 0.000 claims abstract description 212
- 102000004877 Insulin Human genes 0.000 claims abstract description 130
- 108090001061 Insulin Proteins 0.000 claims abstract description 130
- 229940079593 drug Drugs 0.000 claims abstract description 51
- 239000003814 drug Substances 0.000 claims abstract description 51
- -1 amino, carboxyl Chemical group 0.000 claims abstract description 27
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 125000000524 functional group Chemical group 0.000 claims abstract description 11
- 125000003396 thiol group Chemical class [H]S* 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 3
- VRKCDEWVVXAWCZ-UHFFFAOYSA-N amino(nitro)sulfamic acid Chemical compound [O-][N+](=O)N(N)S(O)(=O)=O VRKCDEWVVXAWCZ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 108010006025 bovine growth hormone Proteins 0.000 claims abstract description 3
- 229910018828 PO3H2 Inorganic materials 0.000 claims abstract 2
- 239000004026 insulin derivative Substances 0.000 claims description 53
- 229940106164 cephalexin Drugs 0.000 claims description 36
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 30
- 206010012601 diabetes mellitus Diseases 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 23
- 238000011282 treatment Methods 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 19
- 229920000024 polymyxin B Polymers 0.000 claims description 19
- 229960005266 polymyxin b Drugs 0.000 claims description 19
- 229960003712 propranolol Drugs 0.000 claims description 19
- 125000003277 amino group Chemical group 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 14
- 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 11
- 238000010254 subcutaneous injection Methods 0.000 claims description 11
- 230000000844 anti-bacterial effect Effects 0.000 claims description 9
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 7
- 239000007929 subcutaneous injection Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000674 adrenergic antagonist Substances 0.000 claims description 5
- 239000003472 antidiabetic agent Substances 0.000 claims description 5
- 229960002292 piperacillin Drugs 0.000 claims description 5
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 241000283690 Bos taurus Species 0.000 claims description 3
- 239000002220 antihypertensive agent Substances 0.000 claims description 3
- 229940127088 antihypertensive drug Drugs 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 239000003443 antiviral agent Substances 0.000 claims description 3
- 230000003115 biocidal effect Effects 0.000 claims description 3
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 3
- 101001011741 Bos taurus Insulin Proteins 0.000 claims description 2
- 108010005991 Pork Regular Insulin Proteins 0.000 claims description 2
- 229940035676 analgesics Drugs 0.000 claims description 2
- 229940127003 anti-diabetic drug Drugs 0.000 claims description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 2
- 239000000043 antiallergic agent Substances 0.000 claims description 2
- 239000000924 antiasthmatic agent Substances 0.000 claims description 2
- IXIBAKNTJSCKJM-BUBXBXGNSA-N bovine insulin 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)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)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(C)C)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 IXIBAKNTJSCKJM-BUBXBXGNSA-N 0.000 claims description 2
- 239000000122 growth hormone Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 claims 2
- 239000000730 antalgic agent Substances 0.000 claims 1
- 230000001088 anti-asthma Effects 0.000 claims 1
- 239000002260 anti-inflammatory agent Substances 0.000 claims 1
- 239000003529 anticholesteremic agent Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 abstract description 28
- 239000000651 prodrug Substances 0.000 abstract description 28
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 abstract description 19
- 229940088710 antibiotic agent Drugs 0.000 abstract description 7
- 239000003242 anti bacterial agent Substances 0.000 abstract description 6
- 230000004962 physiological condition Effects 0.000 abstract description 6
- 108010000521 Human Growth Hormone Proteins 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 50
- 241000700159 Rattus Species 0.000 description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- 238000002360 preparation method Methods 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- 230000036515 potency Effects 0.000 description 32
- 239000000243 solution Substances 0.000 description 27
- 238000000034 method Methods 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 22
- 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 description 21
- 239000008103 glucose Substances 0.000 description 21
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- 229940088597 hormone Drugs 0.000 description 20
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- 108010093965 Polymyxin B Proteins 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000003556 assay Methods 0.000 description 18
- AVGYWQBCYZHHPN-CYJZLJNKSA-N cephalexin monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 AVGYWQBCYZHHPN-CYJZLJNKSA-N 0.000 description 17
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- 238000007920 subcutaneous administration Methods 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
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- 210000004369 blood Anatomy 0.000 description 14
- 150000003254 radicals Chemical group 0.000 description 14
- 230000009471 action Effects 0.000 description 13
- LEMUFSYUPGXXCM-JNEQYSBXSA-N caninsulin Chemical compound [Zn].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](CC3N=CN=C3)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(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)C1C=NC=N1 LEMUFSYUPGXXCM-JNEQYSBXSA-N 0.000 description 12
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- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 11
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 6
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- 210000004185 liver Anatomy 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 229940100066 Long-acting insulin Drugs 0.000 description 5
- 102000007327 Protamines Human genes 0.000 description 5
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- 150000001413 amino acids Chemical class 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 235000021051 daily weight gain Nutrition 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
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- 239000011780 sodium chloride Substances 0.000 description 1
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Classifications
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
- A61K47/51—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 non-active ingredient being a modifying agent
- A61K47/54—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 non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/555—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 non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
- A61K47/51—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 non-active ingredient being a modifying agent
- A61K47/54—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 non-active ingredient being a modifying agent the modifying agent being an organic compound
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- A—HUMAN NECESSITIES
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- A61K47/51—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 non-active ingredient being a modifying agent
- A61K47/54—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 non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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- A—HUMAN NECESSITIES
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Endocrinology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Virology (AREA)
- Heart & Thoracic Surgery (AREA)
- Obesity (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL11902996A IL119029A0 (en) | 1996-08-07 | 1996-08-07 | Long-acting drugs and pharamaceutical compositions comprising them |
| IL119029 | 1996-08-07 | ||
| PCT/IL1997/000265 WO1998005361A2 (en) | 1996-08-07 | 1997-08-05 | Long-acting drugs and pharmaceutical compositions comprising them |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2261835A1 CA2261835A1 (en) | 1998-02-12 |
| CA2261835C true CA2261835C (en) | 2008-07-29 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002261835A Expired - Lifetime CA2261835C (en) | 1996-08-07 | 1997-08-05 | Long-acting drugs and pharmaceutical compositions comprising them |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US6504005B1 (enExample) |
| EP (1) | EP1019089B1 (enExample) |
| JP (1) | JP4416184B2 (enExample) |
| KR (1) | KR20000029806A (enExample) |
| CN (1) | CN1227501A (enExample) |
| AT (1) | ATE308998T1 (enExample) |
| AU (1) | AU725468B2 (enExample) |
| BR (1) | BR9711045A (enExample) |
| CA (1) | CA2261835C (enExample) |
| CZ (1) | CZ36999A3 (enExample) |
| DE (1) | DE69734607T2 (enExample) |
| DK (1) | DK1019089T3 (enExample) |
| ES (1) | ES2252787T3 (enExample) |
| HU (1) | HUP0000809A2 (enExample) |
| IL (3) | IL119029A0 (enExample) |
| NO (1) | NO990518L (enExample) |
| NZ (1) | NZ333845A (enExample) |
| WO (1) | WO1998005361A2 (enExample) |
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| IL139400A0 (en) * | 2000-11-01 | 2001-11-25 | Yeda Res & Dev | Long-acting cytokine derivatives and pharmaceutical compositions comprising them |
| EP1390061A2 (en) * | 2000-12-13 | 2004-02-25 | Eli Lilly And Company | Chronic treatment regimen using glucagon-like insulinotropic peptides |
| NZ531460A (en) | 2001-10-19 | 2005-05-27 | Idexx Lab Inc | Controlled release - over at least 4-15 days - of injectable compositions comprising a lipophilic counterion such a saturated or unsaturated C10-C18 fatty acid |
| US6946137B2 (en) * | 2001-10-19 | 2005-09-20 | Idexx Laboratories, Inc. | Methods for the controlled delivery of pharmacologically active compounds |
| US20030171285A1 (en) * | 2001-11-20 | 2003-09-11 | Finn Rory F. | Chemically-modified human growth hormone conjugates |
| BE1015608A6 (fr) * | 2003-07-15 | 2005-06-07 | Messadek Jallal | Traitement des arterites. |
| JP4033382B2 (ja) * | 2002-04-08 | 2008-01-16 | 久光製薬株式会社 | インスリン投与装置 |
| SG153699A1 (en) * | 2003-01-16 | 2009-07-29 | Caprotec Bioanalytics Gmbh | Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions |
| CA2843439A1 (en) | 2003-04-08 | 2004-10-21 | Yeda Research And Development Co. Ltd | Reversible pegylated drugs |
| WO2004091601A1 (fr) * | 2003-04-17 | 2004-10-28 | Jallal Messadek | Formulations orales flottantes pour la liberation controlee de la betaine |
| KR101159559B1 (ko) | 2003-08-05 | 2012-06-26 | 노보 노르디스크 에이/에스 | 신규의 인슐린 유도체 |
| BE1016128A6 (fr) * | 2004-07-22 | 2006-03-07 | Messadek Jallal | Combinaisons therapeutiques |
| US7282487B2 (en) * | 2004-10-28 | 2007-10-16 | Idexx Laboratories | Method for treating bacterial infections in horses or pigs with tilmicosin |
| WO2006050581A2 (en) * | 2004-11-10 | 2006-05-18 | Jallal Messadek | Betaine as agent against arthropod - or mosquito -borne diseases |
| BRPI0610249A2 (pt) * | 2005-04-27 | 2010-06-08 | Jallal Messadek | associação ou combinação farmacêutica, composição farmacêutica, processo de co-cristalização e o uso de insulina ou análogo de insulina |
| US20090074882A1 (en) | 2005-12-28 | 2009-03-19 | Novo Nordisk A/S | Insulin compositions and method of making a composition |
| WO2008152106A1 (en) * | 2007-06-13 | 2008-12-18 | Novo Nordisk A/S | Pharmaceutical formulation comprising an insulin derivative |
| WO2009065193A1 (en) * | 2007-11-21 | 2009-05-28 | Jallal Messadek | Treatment of aspirin resistance with betaine and/or betaine enriched molasses |
| MX2010009850A (es) | 2008-03-18 | 2010-09-30 | Novo Nordisk As | Analogos de insulina acilados y etabilizados contra proteasas. |
| EP2306986B1 (en) | 2008-06-26 | 2018-03-21 | Prolynx Llc | Prodrugs and drug-macromolecule conjugates having controlled drug release rates |
| EP2344200A2 (en) * | 2008-09-19 | 2011-07-20 | Nektar Therapeutics | Modified therapeutics peptides, methods of their preparation and use |
| AU2009292643B2 (en) | 2008-09-19 | 2016-02-18 | Nektar Therapeutics | Polymer conjugates of therapeutic peptides |
| PL2431741T3 (pl) | 2008-10-21 | 2014-01-31 | Baxalta Inc | Sposoby określania ilości aktywnych składników w prolekach, będących koniugatami PEG-białko, za pomocą reagentów uwalniających PEG (depegylacja in vitro) |
| CA2738615A1 (en) * | 2008-10-30 | 2010-05-06 | Novo Nordisk A/S | Treating diabetes melitus using insulin injections with less than daily injection frequency |
| JP2012519666A (ja) | 2009-03-05 | 2012-08-30 | アセンディス ファーマ エーエス | インターフェロンアルファ担体プロドラッグ |
| WO2011013128A2 (en) | 2009-07-31 | 2011-02-03 | Yeda Research And Development Co. Ltd. | Vectors for delivery of neurotherapeutics to the central nervous system |
| JP5977229B2 (ja) * | 2010-05-05 | 2016-08-24 | プロリンクス リミテッド ライアビリティ カンパニー | 巨大分子共役体からの徐放 |
| JP6049625B2 (ja) | 2010-10-27 | 2016-12-21 | ノヴォ ノルディスク アー／エス | 様々な注射間隔を用いて施されるインスリン注射を使用する、真性糖尿病の治療 |
| EP2490378B1 (en) | 2011-02-18 | 2014-07-09 | NTT DoCoMo, Inc. | Apparatus and method for determining a control unit using feasibility requests and feasibility responses |
| EP2714070B1 (en) | 2011-06-02 | 2024-03-20 | OPKO Biologics Ltd. | Long-acting glp-1/glucagon receptor agonists |
| US10166295B2 (en) | 2011-06-02 | 2019-01-01 | Opko Biologics Ltd. | Pegylated OXM variants |
| KR20150002777A (ko) | 2012-04-11 | 2015-01-07 | 노보 노르디스크 에이/에스 | 인슐린 제제 |
| KR102092025B1 (ko) | 2012-06-04 | 2020-03-24 | 옵코 바이오로직스 리미티드 | 페길화된 옥신토모둘린 변이체 |
| US20150111820A1 (en) | 2012-07-09 | 2015-04-23 | Novo Nordisk A/S | Novel use of insulin derivatives |
| WO2014177623A1 (en) | 2013-04-30 | 2014-11-06 | Novo Nordisk A/S | Novel administration regime |
| MA49116A (fr) | 2016-12-16 | 2020-03-25 | Novo Nordisk As | Compositions pharmaceutiques contenant de l'insuline |
| US10335464B1 (en) | 2018-06-26 | 2019-07-02 | Novo Nordisk A/S | Device for titrating basal insulin |
| US12441776B2 (en) | 2018-11-30 | 2025-10-14 | Eirgen Pharma Ltd. | Oxyntomodulin peptide analog formulations |
| US20200254065A1 (en) | 2019-02-11 | 2020-08-13 | Opko Biologics Ltd. | Long-acting glp-2 analogs |
| CN114096269B (zh) | 2019-07-12 | 2024-06-11 | 诺和诺德股份有限公司 | 高浓度胰岛素制剂 |
| JP7784993B2 (ja) | 2019-09-30 | 2025-12-12 | 奥金生命科学（宜興）有限公司 | タンパク質－巨大分子コンジュゲート及びその使用方法 |
| CN113773398B (zh) * | 2020-06-10 | 2023-05-23 | 宁波鲲鹏生物科技有限公司 | 一种德谷胰岛素衍生物及其应用 |
| CN117551008B (zh) * | 2023-11-10 | 2025-10-17 | 沈阳药科大学 | 一种去铁胺偶联物及其制备方法和应用 |
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| HU906340D0 (en) * | 1986-10-13 | 1991-04-29 | Sandoz Ag | Synthesis in solid phase for producing peptonic alcohols |
| GB8717446D0 (en) | 1987-07-23 | 1987-08-26 | Merck Sharp & Dohme | Chemical compounds |
| US6313094B1 (en) * | 1990-12-11 | 2001-11-06 | Japan Energy Corporation | β-amino-α-hydroxycarboxylic acid derivatives and HIV protease inhibitors |
| JPH0687887A (ja) * | 1992-08-19 | 1994-03-29 | Upjohn Co:The | ペプチドのエナミン誘導体およびそれをプロドラッグとして含有するペプチド製剤 |
| WO1995000546A1 (en) | 1993-06-25 | 1995-01-05 | Kyowa Hakko Kogyo Co., Ltd. | Endothelin-antagonizing peptide |
| US5880131A (en) * | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
| DE4437604A1 (de) * | 1994-10-21 | 1996-04-25 | Basf Ag | Konjugate aus einem Poly- oder Oligopeptid und einer niedermolekularen lipophilen Verbindung |
| JPH10511340A (ja) | 1995-02-09 | 1998-11-04 | ブリガム アンド ウィメンズ ホスピタル | ゲル生成ポリペプチド誘導体 |
| AU5377296A (en) * | 1995-03-30 | 1996-10-16 | Southpac Trust International, Inc. | Self-erecting container which is collapsible to be substanti ally flat |
| US5688992A (en) | 1995-03-31 | 1997-11-18 | The United States Of America As Represented By The Department Of Health And Human Services | O-malonyltryrosyl compounds, O-malonyltryrosyl compound-containing peptides, and use thereof |
| US5846934A (en) * | 1996-02-20 | 1998-12-08 | American Cyanamid Company | Pure somatostatin antagonist and methods of use thereof |
| US6057297A (en) * | 1996-08-06 | 2000-05-02 | Polifarma S.P.A. | Inhibitor compounds of zinc-dependent metalloproteinases associated with pathological conditions, and therapeutic use thereof |
-
1996
- 1996-08-07 IL IL11902996A patent/IL119029A0/xx unknown
-
1997
- 1997-08-05 EP EP97933828A patent/EP1019089B1/en not_active Expired - Lifetime
- 1997-08-05 AU AU37060/97A patent/AU725468B2/en not_active Ceased
- 1997-08-05 AT AT97933828T patent/ATE308998T1/de active
- 1997-08-05 DE DE69734607T patent/DE69734607T2/de not_active Expired - Lifetime
- 1997-08-05 CA CA002261835A patent/CA2261835C/en not_active Expired - Lifetime
- 1997-08-05 WO PCT/IL1997/000265 patent/WO1998005361A2/en not_active Ceased
- 1997-08-05 ES ES97933828T patent/ES2252787T3/es not_active Expired - Lifetime
- 1997-08-05 IL IL12827497A patent/IL128274A0/xx active IP Right Grant
- 1997-08-05 KR KR1019997000941A patent/KR20000029806A/ko not_active Withdrawn
- 1997-08-05 DK DK97933828T patent/DK1019089T3/da active
- 1997-08-05 BR BR9711045A patent/BR9711045A/pt not_active IP Right Cessation
- 1997-08-05 CN CN97197122A patent/CN1227501A/zh active Pending
- 1997-08-05 NZ NZ333845A patent/NZ333845A/xx unknown
- 1997-08-05 JP JP50777098A patent/JP4416184B2/ja not_active Expired - Lifetime
- 1997-08-05 CZ CZ99369A patent/CZ36999A3/cs unknown
- 1997-08-05 HU HU0000809A patent/HUP0000809A2/hu unknown
- 1997-08-05 US US09/242,026 patent/US6504005B1/en not_active Expired - Lifetime
-
1999
- 1999-01-28 IL IL128274A patent/IL128274A/en not_active IP Right Cessation
- 1999-02-04 NO NO990518A patent/NO990518L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000515542A (ja) | 2000-11-21 |
| ES2252787T3 (es) | 2006-05-16 |
| JP4416184B2 (ja) | 2010-02-17 |
| AU3706097A (en) | 1998-02-25 |
| EP1019089B1 (en) | 2005-11-09 |
| EP1019089A2 (en) | 2000-07-19 |
| CA2261835A1 (en) | 1998-02-12 |
| HUP0000809A2 (hu) | 2000-11-28 |
| BR9711045A (pt) | 1999-08-17 |
| NZ333845A (en) | 2000-09-29 |
| NO990518D0 (no) | 1999-02-04 |
| IL128274A (en) | 2006-08-01 |
| US6504005B1 (en) | 2003-01-07 |
| ATE308998T1 (de) | 2005-11-15 |
| AU725468B2 (en) | 2000-10-12 |
| WO1998005361A2 (en) | 1998-02-12 |
| IL119029A0 (en) | 1996-11-14 |
| NO990518L (no) | 1999-04-06 |
| IL128274A0 (en) | 1999-11-30 |
| DK1019089T3 (da) | 2006-03-13 |
| CN1227501A (zh) | 1999-09-01 |
| DE69734607D1 (de) | 2005-12-15 |
| DE69734607T2 (de) | 2006-08-03 |
| KR20000029806A (ko) | 2000-05-25 |
| CZ36999A3 (cs) | 1999-07-14 |
| WO1998005361A3 (en) | 1998-06-18 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20170807 |