CA2312975C - Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents - Google Patents
Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents Download PDFInfo
- Publication number
- CA2312975C CA2312975C CA2312975A CA2312975A CA2312975C CA 2312975 C CA2312975 C CA 2312975C CA 2312975 A CA2312975 A CA 2312975A CA 2312975 A CA2312975 A CA 2312975A CA 2312975 C CA2312975 C CA 2312975C
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- Prior art keywords
- compound
- substituted
- group
- alkyls
- mmol
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- 239000000651 prodrug Substances 0.000 title claims abstract description 98
- 229940002612 prodrug Drugs 0.000 title claims abstract description 98
- 125000002887 hydroxy group Chemical group [H]O* 0.000 title claims abstract description 24
- 239000012867 bioactive agent Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 187
- -1 nitro- Chemical class 0.000 claims abstract description 57
- 229920000642 polymer Polymers 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 32
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 30
- 125000005647 linker group Chemical group 0.000 claims abstract description 30
- 125000003118 aryl group Chemical group 0.000 claims abstract description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 24
- 150000001412 amines Chemical class 0.000 claims abstract description 22
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 18
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims abstract description 15
- 125000004404 heteroalkyl group Chemical group 0.000 claims abstract description 14
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 14
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 14
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 11
- 125000004181 carboxyalkyl group Chemical group 0.000 claims abstract description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims abstract description 7
- 230000001588 bifunctional effect Effects 0.000 claims abstract description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 7
- 230000000890 antigenic effect Effects 0.000 claims abstract description 6
- 125000004405 heteroalkoxy group Chemical group 0.000 claims abstract description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 14
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims abstract 11
- 229910052717 sulfur Inorganic materials 0.000 claims abstract 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract 4
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims abstract 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 105
- 239000002202 Polyethylene glycol Substances 0.000 claims description 88
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 15
- 230000003213 activating effect Effects 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 239000003574 free electron Substances 0.000 claims description 9
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 101150020251 NR13 gene Proteins 0.000 claims description 6
- 241001061127 Thione Species 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 230000002441 reversible effect Effects 0.000 claims description 6
- 150000001413 amino acids Chemical group 0.000 claims description 5
- 229920000233 poly(alkylene oxides) Polymers 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000000539 amino acid group Chemical group 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 3
- WEZDRVHTDXTVLT-GJZGRUSLSA-N 2-[[(2s)-2-[[(2s)-2-[(2-aminoacetyl)amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 WEZDRVHTDXTVLT-GJZGRUSLSA-N 0.000 claims description 2
- 108010009504 Gly-Phe-Leu-Gly Proteins 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000006116 polymerization reaction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000001727 in vivo Methods 0.000 abstract description 19
- 238000003379 elimination reaction Methods 0.000 abstract description 8
- 125000000623 heterocyclic group Chemical class 0.000 abstract description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 3
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 129
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 105
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 101
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 87
- 239000000203 mixture Substances 0.000 description 67
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 61
- 238000003786 synthesis reaction Methods 0.000 description 61
- 230000015572 biosynthetic process Effects 0.000 description 59
- 239000000243 solution Substances 0.000 description 52
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 47
- 239000000047 product Substances 0.000 description 40
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 39
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 38
- 239000002904 solvent Substances 0.000 description 36
- 238000004821 distillation Methods 0.000 description 33
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 30
- 235000018102 proteins Nutrition 0.000 description 27
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- 230000007062 hydrolysis Effects 0.000 description 21
- 238000006460 hydrolysis reaction Methods 0.000 description 21
- 238000002425 crystallisation Methods 0.000 description 20
- 230000008025 crystallization Effects 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 229910001868 water Inorganic materials 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 18
- 102000004190 Enzymes Human genes 0.000 description 17
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- 229940088598 enzyme Drugs 0.000 description 17
- CZGCEKJOLUNIFY-UHFFFAOYSA-N 4-Chloronitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1 CZGCEKJOLUNIFY-UHFFFAOYSA-N 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 229960000975 daunorubicin Drugs 0.000 description 16
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 15
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 15
- BVJSUAQZOZWCKN-UHFFFAOYSA-N p-hydroxybenzyl alcohol Chemical compound OCC1=CC=C(O)C=C1 BVJSUAQZOZWCKN-UHFFFAOYSA-N 0.000 description 15
- 206010028980 Neoplasm Diseases 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 14
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 13
- 238000003556 assay Methods 0.000 description 13
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 13
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- 239000000543 intermediate Substances 0.000 description 12
- 229920001427 mPEG Polymers 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- 102000004196 processed proteins & peptides Human genes 0.000 description 9
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
- 229940123237 Taxane Drugs 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 8
- 229960003272 asparaginase Drugs 0.000 description 8
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 8
- 230000021615 conjugation Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- AXKGIPZJYUNAIW-UHFFFAOYSA-N (4-aminophenyl)methanol Chemical compound NC1=CC=C(CO)C=C1 AXKGIPZJYUNAIW-UHFFFAOYSA-N 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 229940127093 camptothecin Drugs 0.000 description 6
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 6
- 102000015790 Asparaginase Human genes 0.000 description 5
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- 229930012538 Paclitaxel Natural products 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 5
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Classifications
-
- 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
- A61K47/51—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
- A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Polyethers (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US99243597A | 1997-12-17 | 1997-12-17 | |
| US08/992,435 | 1997-12-17 | ||
| US09/183,557 | 1998-10-30 | ||
| US09/183,557 US6180095B1 (en) | 1997-12-17 | 1998-10-30 | Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents |
| PCT/US1998/026565 WO1999030727A1 (en) | 1997-12-17 | 1998-12-14 | Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2312975A1 CA2312975A1 (en) | 1999-06-24 |
| CA2312975C true CA2312975C (en) | 2012-08-21 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2312975A Expired - Fee Related CA2312975C (en) | 1997-12-17 | 1998-12-14 | Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US6720306B2 (enExample) |
| EP (1) | EP1037649B1 (enExample) |
| JP (1) | JP4465109B2 (enExample) |
| AU (1) | AU1825299A (enExample) |
| CA (1) | CA2312975C (enExample) |
| WO (1) | WO1999030727A1 (enExample) |
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| KR100361933B1 (ko) | 1993-09-08 | 2003-02-14 | 라 졸라 파마슈티칼 컴파니 | 화학적으로정의된비중합성결합가플랫폼분자및그것의콘주게이트 |
| US6624142B2 (en) * | 1997-12-30 | 2003-09-23 | Enzon, Inc. | Trimethyl lock based tetrapartate prodrugs |
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| US7060708B2 (en) * | 1999-03-10 | 2006-06-13 | New River Pharmaceuticals Inc. | Active agent delivery systems and methods for protecting and administering active agents |
| US6541508B2 (en) | 1999-09-13 | 2003-04-01 | Nobex Corporation | Taxane prodrugs |
| US6380405B1 (en) * | 1999-09-13 | 2002-04-30 | Nobex Corporation | Taxane prodrugs |
| US6713454B1 (en) * | 1999-09-13 | 2004-03-30 | Nobex Corporation | Prodrugs of etoposide and etoposide analogs |
| US6413507B1 (en) | 1999-12-23 | 2002-07-02 | Shearwater Corporation | Hydrolytically degradable carbamate derivatives of poly (ethylene glycol) |
| AU2001268228A1 (en) | 2000-06-08 | 2001-12-17 | La Jolla Pharmaceutical Company | Multivalent platform molecules comprising high molecular weight polyethylene oxide |
| MXPA03000587A (es) * | 2000-07-21 | 2004-04-05 | Gilead Sciences Inc | Profarmacos de analogos de nucleotido de fosfonato y metodos para seleccionar y elaborar los mismos. |
| US7163918B2 (en) | 2000-08-22 | 2007-01-16 | New River Pharmaceuticals Inc. | Iodothyronine compositions |
| US20020099013A1 (en) * | 2000-11-14 | 2002-07-25 | Thomas Piccariello | Active agent delivery systems and methods for protecting and administering active agents |
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| US8394813B2 (en) | 2000-11-14 | 2013-03-12 | Shire Llc | Active agent delivery systems and methods for protecting and administering active agents |
| AU2002239405A1 (en) * | 2000-12-01 | 2002-06-11 | Enzon, Inc. | Tetrapartate prodrugs |
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| US20060014697A1 (en) | 2001-08-22 | 2006-01-19 | Travis Mickle | Pharmaceutical compositions for prevention of overdose or abuse |
| US7169752B2 (en) * | 2003-09-30 | 2007-01-30 | New River Pharmaceuticals Inc. | Compounds and compositions for prevention of overdose of oxycodone |
| US20070066537A1 (en) * | 2002-02-22 | 2007-03-22 | New River Pharmaceuticals Inc. | Compounds and compositions for prevention of overdose of oxycodone |
| US7375082B2 (en) * | 2002-02-22 | 2008-05-20 | Shire Llc | Abuse-resistant hydrocodone compounds |
| JP4663233B2 (ja) * | 2001-11-09 | 2011-04-06 | エンゾン，インコーポレーテッド | ベンジル脱離系を利用する高分子チオール結合プロドラッグ |
| DK1450822T3 (da) * | 2001-11-09 | 2010-04-19 | Enzon Inc | Polyalkylenoxidkonjugater af thiolholdige medicinske præparater |
| WO2003051113A1 (en) | 2001-12-14 | 2003-06-26 | The University Of Wyoming | Methods and compositions for controlled release of drugs |
| CN1176137C (zh) * | 2002-01-15 | 2004-11-17 | 泛亚生物技术有限公司 | 多臂树杈型功能化聚乙二醇制备方法及它在药物中的应用 |
| SK3102004A3 (sk) * | 2002-01-18 | 2005-01-03 | Biogen Idec MA Inc. | Polyalkylénglykol s časťou na konjugáciu biologicky aktívnej zlúčeniny |
| EP1496278A4 (en) * | 2002-02-12 | 2005-09-14 | Nsk Ltd | PULLEY BEARING FOR AUXILIARY MOTOR ELEMENTS |
| US7659253B2 (en) | 2002-02-22 | 2010-02-09 | Shire Llc | Abuse-resistant amphetamine prodrugs |
| IL163667A0 (en) * | 2002-02-22 | 2005-12-18 | New River Pharmaceuticals Inc | Novel sustained release pharmaceutical compounds to preventabuse of controlled substances |
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| WO2003072735A2 (en) * | 2002-02-22 | 2003-09-04 | New River Pharmaceuticals Inc. | Use of peptide-drug conjugation to reduce inter-subject variability of drug serum levels |
| US7700561B2 (en) * | 2002-02-22 | 2010-04-20 | Shire Llc | Abuse-resistant amphetamine prodrugs |
| SE0201863D0 (en) * | 2002-06-18 | 2002-06-18 | Cepep Ab | Cell penetrating peptides |
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| RU2375384C2 (ru) * | 2004-09-22 | 2009-12-10 | Ниппон Каяку Кабусики Кайся | Новый блок-сополимер, мицеллярный препарат и противораковое средство, включающее мицеллярный препарат в качестве активного ингредиента |
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| EP1037649A4 (en) | 2004-11-17 |
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| CA2312975A1 (en) | 1999-06-24 |
| US20010031873A1 (en) | 2001-10-18 |
| AU1825299A (en) | 1999-07-05 |
| EP1037649B1 (en) | 2009-09-30 |
| EP1037649A1 (en) | 2000-09-27 |
| JP4465109B2 (ja) | 2010-05-19 |
| WO1999030727A1 (en) | 1999-06-24 |
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