US20040162308A1 - Use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids - Google Patents
Use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids Download PDFInfo
- Publication number
- US20040162308A1 US20040162308A1 US10/779,129 US77912904A US2004162308A1 US 20040162308 A1 US20040162308 A1 US 20040162308A1 US 77912904 A US77912904 A US 77912904A US 2004162308 A1 US2004162308 A1 US 2004162308A1
- Authority
- US
- United States
- Prior art keywords
- administration
- methylnaltrexone
- opioid
- opioids
- amount
- 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.)
- Abandoned
Links
- JVLBPIPGETUEET-WIXLDOGYSA-O (3r,4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one Chemical compound C([N@+]1(C)[C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)C1CC1 JVLBPIPGETUEET-WIXLDOGYSA-O 0.000 title claims abstract description 56
- 229960002921 methylnaltrexone Drugs 0.000 title claims abstract description 56
- 229940005483 opioid analgesics Drugs 0.000 title claims abstract description 23
- 206010010774 Constipation Diseases 0.000 title claims abstract description 16
- 238000011282 treatment Methods 0.000 title description 14
- 150000001875 compounds Chemical class 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 35
- 238000001990 intravenous administration Methods 0.000 claims abstract description 15
- HLMSIZPQBSYUNL-IPOQPSJVSA-N Noroxymorphone Chemical group O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4 HLMSIZPQBSYUNL-IPOQPSJVSA-N 0.000 claims abstract description 14
- 238000007918 intramuscular administration Methods 0.000 claims abstract description 9
- 230000007160 gastrointestinal dysfunction Effects 0.000 claims abstract description 6
- 230000000694 effects Effects 0.000 description 23
- 208000003251 Pruritus Diseases 0.000 description 22
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 21
- 239000002702 enteric coating Substances 0.000 description 19
- 238000009505 enteric coating Methods 0.000 description 19
- 239000003814 drug Substances 0.000 description 13
- 206010046555 Urinary retention Diseases 0.000 description 12
- 230000037396 body weight Effects 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- -1 amine derivative of naltrexone Chemical class 0.000 description 11
- 230000035611 feeding Effects 0.000 description 11
- 206010013954 Dysphoria Diseases 0.000 description 10
- 210000003169 central nervous system Anatomy 0.000 description 10
- 229960005181 morphine Drugs 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 8
- 229920001577 copolymer Polymers 0.000 description 7
- 229960004715 morphine sulfate Drugs 0.000 description 7
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 7
- 229940068196 placebo Drugs 0.000 description 7
- 239000000902 placebo Substances 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 6
- 102000003840 Opioid Receptors Human genes 0.000 description 5
- 108090000137 Opioid Receptors Proteins 0.000 description 5
- 230000008499 blood brain barrier function Effects 0.000 description 5
- 210000001218 blood-brain barrier Anatomy 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 230000002496 gastric effect Effects 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 230000030136 gastric emptying Effects 0.000 description 4
- 229960001340 histamine Drugs 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 4
- 229960003086 naltrexone Drugs 0.000 description 4
- 239000003401 opiate antagonist Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010021518 Impaired gastric emptying Diseases 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 229940125715 antihistaminic agent Drugs 0.000 description 3
- 239000000739 antihistaminic agent Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 230000010243 gut motility Effects 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 3
- 229960004127 naloxone Drugs 0.000 description 3
- 239000003887 narcotic antagonist Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 2
- 229940126701 oral medication Drugs 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 0 *[N+]1(C)CCC23C4=C5C=CC(O)=C4OC2C(=O)CCC3(O)C1C5 Chemical compound *[N+]1(C)CCC23C4=C5C=CC(O)=C4OC2C(=O)CCC3(O)C1C5 0.000 description 1
- RPZANUYHRMRTTE-UHFFFAOYSA-N 2,3,4-trimethoxy-6-(methoxymethyl)-5-[3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[3,4,5-tris(2-hydroxybutoxy)-6-[4,5,6-tris(2-hydroxybutoxy)-2-(2-hydroxybutoxymethyl)oxan-3-yl]oxyoxan-2-yl]methoxy]butan-2-ol Chemical compound COC1C(OC)C(OC)C(COC)OC1OC1C(OC)C(OC)C(OC)OC1COC.CCC(O)COC1C(OCC(O)CC)C(OCC(O)CC)C(COCC(O)CC)OC1OC1C(OCC(O)CC)C(OCC(O)CC)C(OCC(O)CC)OC1COCC(O)CC RPZANUYHRMRTTE-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- YUXIBTJKHLUKBD-UHFFFAOYSA-N Dibutyl succinate Chemical compound CCCCOC(=O)CCC(=O)OCCCC YUXIBTJKHLUKBD-UHFFFAOYSA-N 0.000 description 1
- DKMROQRQHGEIOW-UHFFFAOYSA-N Diethyl succinate Chemical compound CCOC(=O)CCC(=O)OCC DKMROQRQHGEIOW-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229920003139 Eudragit® L 100 Polymers 0.000 description 1
- 229920003141 Eudragit® S 100 Polymers 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229920006243 acrylic copolymer Polymers 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000011374 additional therapy Methods 0.000 description 1
- 229920013820 alkyl cellulose Polymers 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 229940127243 cholinergic drug Drugs 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- PCYQQSKDZQTOQG-NXEZZACHSA-N dibutyl (2r,3r)-2,3-dihydroxybutanedioate Chemical compound CCCCOC(=O)[C@H](O)[C@@H](O)C(=O)OCCCC PCYQQSKDZQTOQG-NXEZZACHSA-N 0.000 description 1
- JBSLOWBPDRZSMB-FPLPWBNLSA-N dibutyl (z)-but-2-enedioate Chemical compound CCCCOC(=O)\C=C/C(=O)OCCCC JBSLOWBPDRZSMB-FPLPWBNLSA-N 0.000 description 1
- 229960002097 dibutylsuccinate Drugs 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 238000009429 electrical wiring Methods 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 210000004229 gastric stump Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229920013819 hydroxyethyl ethylcellulose Polymers 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940090044 injection Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229940068938 morphine injection Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 229940051877 other opioids in atc Drugs 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 235000020004 porter Nutrition 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
Definitions
- the present invention is directed at the treatment of certain side effects associated with the use of opioids as analgesics.
- the present invention is directed at treating opioid-induced dysphoria, opioid-induced pruritus, opioid-induced urinary retention, inhibition of gastric emptying, and decreased gut motility.
- Opioids are effective analgesics, however, their use is associated with a number of undesirable side effects.
- One of these side effects is pruritus, or itching.
- Pruritus is a common side effect associated with the use of opioids and may be very severe. Pruritus can occur when the opioid is administered intramuscularly, intravenously, transdermally, transmucosally or intrathecally.
- opioid induced pruritus results from the release of histamine in response to the administration of opioids.
- Opioids are thought to stimulate histamine release by binding to opioid receptors on the central nervous system. This, in turn, causes peripheral nerves and histamine containing cells to release histamine.
- urinary retention Another undesirable side effect of opioids is urinary retention, or the patient's inability to spontaneously empty his or her bladder.
- This urinary retention is a common side effect that can occur when opioids or related compounds are administered intramuscularly, intravenously, transmucosally, transdermally, or intrathecally. It is not clear why opioids cause urinary retention, but it is thought to be related to the central anticholinergic stimulation that opioids induce. Based on this theory, a number of cholinergic-type drugs have been used to treat urinary retention. However, due to the side effects of cholinergic drugs, catheterization of the bladder with a tube to drain urine remains the mainstay of treatment.
- Another opioid-induced side effect is dysphoria, a feeling of unpleasantness or discomfort. Many subjects, especially those without pain, report unpleasant psychomimetic responses to the administration of an opioid alone. These responses have been previously attributed to activation of centrally located opioid receptors.
- This opioid-induced dysphoria is commonly treated by the addition of other drugs, such as benzodiazepines, to decrease the dysphoria or to blunt the recall of the dysphoria. These drugs, however are associated with increased levels of sedation and may enhance respiratory depression caused by the opioid.
- opioid antagonists which cross the blood-brain-barrier, or which are administered directly into the central nervous system.
- Opioid antagonists such as naltrexone and naloxone have been administered intramuscularly or orally to treat opioid induced pruritus.
- Naltrexone and naloxone are highly lipid soluble and rapidly diffuse across biological membranes, including the blood-brain-barrier.
- naltrexone, naloxone and other opioid antagonists also reduce the analgesic effect of the opioid being used.
- oral medications are particularly desirable both for the treatment of opioid-induced side effects (such as urinary retention, pruritus, and some forms of constipation) and for the treatment of nonopioid-induced side effects (such as other forms of constipation and delayed gastric emptying from enteric feeding).
- opioid-induced side effects such as urinary retention, pruritus, and some forms of constipation
- nonopioid-induced side effects such as other forms of constipation and delayed gastric emptying from enteric feeding.
- the present invention is directed at methods for preventing and treating endogenous opioid induced gastrointestinal dysfunction.
- the method for preventing endogenous opioid-induced dysfunction comprises administering methylnaltrexone or other quaternary derivatives of noroxymorphone to a patient, wherein the route of administration is selected from the group consisting of parenteral, intramuscular, intravenous and oral administration, in a standard or enterically coated preparation in an effective amount, more preferably in an amount between 0.03 and 1.0 mg/kg.
- the present invention is directed at methods for preventing and treating opioid-induced dysphoria, opioid-induced pruritus, opioid-induced urinary retention, opioid- or nonopioid-induced inhibition of gastric emptying by enteric feeding, and opioid- or nonopioid-induced constipation.
- opioid-induced dysphoria opioid-induced pruritus
- opioid-induced urinary retention opioid- or nonopioid-induced inhibition of gastric emptying by enteric feeding
- opioid- or nonopioid-induced constipation When used as a treatment for these opioid- and nonopioid-induced side effects, orally administered, particularly if enteric coated, methylnaltrexone (MNTX) or other quaternary derivatives of noroxymorphone (QDMN) provides prolonged relief of the side effects.
- MNTX methylnaltrexone
- QDMN quaternary derivatives of noroxymorphone
- enteric coating surprisingly allows for equal or better efficacy despite lower plasma levels.
- Idiopathic constipation i.e., that due to causes other than exogenous administration of opioids, may be mediated by opioid sensitive mechanisms.
- Endogenous opioid receptors have been identified in the gut, and these receptors may modulate gut motility.
- R is allyl or a related radical such as chlorallyl, cyclopropyl-methyl or propargyl
- X is the anion of an acid, especially a chloride, bromide,. iodide or methylsulfate anion.
- the presently preferred quaternary derivative of noroxymorphone is methylnaltrexone.
- Methylnaltrexone is a quaternary amine derivative of naltrexone.
- Methylnaltrexone has been found to have only 2 to 4% of the opiate antagonistic activity of naltrexone in vivo due to its inability to pass the blood-brain-barrier and bind to the opiate receptors in the central nervous system.
- Opioids are typically administered at a morphine equivalent dosage of: 0.005 to 0.15 mg/kg body weight for intrathecal administration; 0.05 to 1.0 mg/kg body weight for intravenous administration; 0.05 to 1.0 mg/kg body weight for intramuscular administration; 0.05 to 1.0 mg/kg body weight/hour for transmucosal or transdermal administration.
- morphine equivalent dosage is meant representative doses of other opioids which equal one milligram of morphine, for example 10 mg meperidine, 1 mg methadone, and 80 .mu.g fentanyl.
- methylnaltrexone is administered at a dosage of: 0.03 to 1.0 mg/kg body weight for intravenous administration; 0.03 to 1.0 mg/kg body weight for intramuscular administration; 0.03 to 1.0 mg/kg body weight for transmucosal administration and 1.0 to 40.0 mg/kg body weight for oral administration.
- enteric coated methylnaltrexone is administered at a dosage of 1.0 to 80.0 mg/kg body weight for oral administration.
- the administration of the methylnaltrexone is preferably commenced prior to administration of the opioid to prevent opioid-induced dysphoria, pruritus, urinary retention, inhibition of gastric emptying with enteric feeding, or constipation. It is desirable to commence administration of methylnaltrexone about 5 minutes for parenteral MNTX administration and 20 minutes for enteral MNTX administration prior to administration of opioids in order to prevent these opioid-induced side effects. It is also preferable to administer the methylnaltrexone prior to the onset of nonopioid-induced gastric dysfunction symptoms, inhibition of gastric emptying with enteric feeding or constipation, in order to prevent these symptoms from manifesting. While the prevention of symptoms is preferred, methylnaltrexone administration may also be commenced after the administration of the opioid or after the onset of opioid induced symptoms as a treatment for those symptoms.
- Methylnaltrexone is rapidly absorbed after oral administration from the stomach and bowel. Initial plasma levels of the drug are seen within 5-10 minutes of the administration of non-enteric coated compound. Addition of an enteric coating which prevents gastric absorption is associated with lower plasma levels of the methylnaltrexone. Surprisingly, the addition of an enteric coating (i.e., a coating which will prevent degradation or release in the stomach, but will release drug in the small and large bowel) appears to enhance the efficacy of methylnaltrexone in the prevention of decreases in gut motility by intravenously administered opioids (morphine).
- an enteric coating i.e., a coating which will prevent degradation or release in the stomach, but will release drug in the small and large bowel
- methylnaltrexone is formulated with saline or other physiologically acceptable carriers; for intramuscular administration, the methylnaltrexone is formulated with saline or other pharmacologically acceptable carriers; for transmucosal administration the methylnaltrexone is formulated with a sugar and cellulose mix or other pharmacologically acceptable carriers known in the art; and for oral administration, the methylnaltrexone is formulated with pharmacologically acceptable binders to make a tablet or capsule with or without an enteric coating. Methods for such formulations are well known to those skilled in the art.
- the MNTX is enterically coated and administered orally.
- the enteric coating may be made of any suitable composition. Suitable enteric coatings are described, for example, in U.S. Pat. Nos. 4,311,833 to Namikoshi, et al.; 4,377,568 to Chopra; 4,385,078 to Onda, et al.; 4,457,907 to Porter; 4,462,839 to McGinley, et al.; 4,518,433 to McGinley, et al.; 4,556,552 to Porter, et al.; 4,606,909 to Bechgaard et al.; 4,615,885 to Nakagame, et al.; 4,670,287 to Tsuji; 5,536,507 TO Abramowitz, et al.; 5,567,423 to Ying, et al.; 5,591,433 to Michael, et al.; 5,597,564 to Ying, et al.; 5,609,871 to
- enteric coating compositions include alkyl and hydroxyalkyl celluloses and their aliphatic esters, e.g., methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethylethylcellulose, hydroxyprophymethylcellulose, hydroxybutylmethylcellulose, hydroxypropylcellulose phthalate, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succyere; carboxyalkylcelluloses and their salts, e.g., carboxymethylethylcellulose; cellulose acetate phthalate; cellulose acetate trimellitate, polycarboxymethylene and its salts and derivatives; polyvinylalcohol and its esters: polyvinyl acetate phthalate; polycarboxymethylene copolymer with sodium formaldehyde carboxylate; acrylic polymers and copolymers, e.g., methacrylic
- enteric coatings include polyvinylacetate esters, e.g., polyvinyl acetate phthalate; alkyleneglycolether esters of copolymers such as partial ethylene glycol monomethylether ester of ethylacrylate-maleic anhydride copolymer or diethyleneglycol monomethylether ester of methylacrylate-maleic anhydride copolymer, N-butylacrylatemaleic anhydride copolymer, isobutylacrylate-maleic anhydride copolymer or ethylacrylate-maleic anhydride copolymer; and polypeptides resistant to degradation in the gastric environment, e.g., polyarginine and polylysine.
- the presently preferred enteric coating comprises cellulose acetate phthalate.
- the enteric coating material may be mixed with various excipients including plasticizers such as triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl subacute, dibutyl tartrate, dibutyl maleate, dibutyl succinate and diethyl succinate and inert fillers such as chalk or pigments.
- plasticizers such as triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl subacute, dibutyl tartrate, dibutyl maleate, dibutyl succinate and diethyl succinate and inert fillers such as chalk or pigments.
- composition and thickness of the enteric coating may be selected to dissolve immediately upon coated with the digestive juice of the intestine.
- the composition and thickness of the anterior coating may be selected to be a time-release coating which dissolves over a selected period of time, as is well known in the art.
- the amount of enteric coating depends on the particular enteric coating composition used and is preferably sufficient to substantially prevent the absorption of MNTX in the stomach.
- Hydroxyalkyl celluloses and their aliphatic esters, carboxyalkyl celluloses and their salts, polycarboxymethylene and its salts and derivatives, polyvinyl alcohol and its esters, polycarboxymethylene copolymer with sodium formaldehyde carboxylates, polyvinylpyrrolidone, and polyethylene glycol and its esters can be applied as enteric coatings by first dissolving the compound in a minimum amount of water. Alcohol is then added to the point of incipient cloudiness. The mixture can then be applied by conventional techniques.
- cellulose acetate phthalate may be accomplished by simply dissolving the cellulose acetate phthalate in a minimum amount of alcohol and then applying by conventional techniques.
- Hydrogenated vegetable oils may be applied by first dissolving the oil in a minimal amount of a non-polymer solvent, such as methylene chloride, chloroform or carbon tetrachloride, then adding alcohol to the point of incipient cloudiness and then applying by conventional techniques.
- the MNTX is coated with Eudragit L100 or S100, a methacrylic acid copolymer enteric coating, at a 50% coating level to provide stability at gastric pH and dissolution at gut pH per a US Pharmacopeia (USP) standard for enteric coatings.
- USP US Pharmacopeia
- transdermal administration is preferably via a patch applied to the skin with a membrane of sufficient permeability to allow diffusion of MNTX at a fixed rate in the range of 1.0 to 10.0 mg/hr.
- the rate of administration may be varied by varying the size of the membrane contact area and/or applying an electrical wiring potential to a drug reservoir.
- the patch preferably holds 25 mg to 1 gram of available drug in the reservoir plus additional drug as needed for the mechanics of the system.
- methylnaltrexone is used as an example of a particularly effective QDNM. It is apparent that other QDNM's may be used as desired.
- Morphine (0.05) mg/kg intravenous) was administered to three volunteers after the oral administration of placebo, methylnaltrexone (6.4 mg/kg) in a gelatin capsule (which dissolves readily in the stomach), or methylnaltrexone after enteric coating (12.8 mg/kg of substance to yield a mass of 6.4 mg/kg methylnaltrexone incorporated) which has decreased release and absorption in the stomach.
- Oral-cecal transit time was measured using the lactulose-hydrogen breath test. Plasma levels of methylnaltrexone were measured and after the enteric coated preparation were lower.
- the residual was 150 cc or 58% of the previous bolus feed, after the 3rd dose (12 hours) the residual was 75 cc or 30% of the previous feed, after the 5th dose (20 hours) the residual was 22 cc or 13% of the previous feed and after the 6th and final dose (24 hours) the residual was 8 cc or 5.5% of previous feed.
- the follow-up residual sampling after the final drug-tube feed interval had increased to 50 cc or 38% or previous feed.
- the second patient had greater than 200 cc residual or 100% of previous feedings on two consecutive samplings, that is 8 hrs and 4 hrs before drug administration. After initiation of Methylnaltrexone, 0.45 mg/kg, administered intravenously every 4 hours, the first residual (4 hrs) was 0 cc, the second residual (8 hrs)was 24 cc or 15% of previous bolus feed.
- Methylnaltrexone 0.45 mg/kg intravenously or a placebo.
- Those treated with Methylnaltrexone have resolution of their symptoms, while those administered placebo go on to require additional therapy (usually urinary catheterization).
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)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A method of for preventing or treating gastrointestinal dysfunction and constipation caused by endogenous opioids in a patient who has been chronically taking opioids. The method comprises administering methylnaltrexone or another quaternary derivative of noroxymorphone most preferably by parenteral, intramuscular, intravenous or oral route.
Description
- This application is a continuation of application Ser. No. 10/278,630, filed Oct. 23, 2002; which is a divisional of application Ser. No. 09/862,169, filed May 21, 2001 (herein incorporated by reference) now U.S. Pat. No. 6,608,075; which is a continuation of application Ser. No. 09/120,703, filed Jul. 22, 1998 (herein incorporated by reference) now U.S. Pat. No. 6,274,591; which is a continuation-in-part of application Ser. No. 08/962,742, filed Nov. 3, 1997, now U.S. Pat. No. 5,972,954 the disclosures of which are herein incorporated by reference. This application also claims priority of provisional application Ser. No. 60/168,480, filed Dec. 1, 1999, also herein incorporated by reference.
- The present invention is directed at the treatment of certain side effects associated with the use of opioids as analgesics. In particular the present invention is directed at treating opioid-induced dysphoria, opioid-induced pruritus, opioid-induced urinary retention, inhibition of gastric emptying, and decreased gut motility.
- Opioids are effective analgesics, however, their use is associated with a number of undesirable side effects. One of these side effects is pruritus, or itching. Pruritus is a common side effect associated with the use of opioids and may be very severe. Pruritus can occur when the opioid is administered intramuscularly, intravenously, transdermally, transmucosally or intrathecally.
- It is believed that the opioid induced pruritus results from the release of histamine in response to the administration of opioids. Opioids are thought to stimulate histamine release by binding to opioid receptors on the central nervous system. This, in turn, causes peripheral nerves and histamine containing cells to release histamine.
- Based on this theory a number of treatments have been used to alleviate opioid induced pruritus. The first is the use of antihistamines. However, antihistamines have a variable effect on opioid induced pruritus. Additionally, the use of antihistamines, when effective, only treats the symptom after it has occurred, rather than preventing its occurrence.
- Another undesirable side effect of opioids is urinary retention, or the patient's inability to spontaneously empty his or her bladder. This urinary retention is a common side effect that can occur when opioids or related compounds are administered intramuscularly, intravenously, transmucosally, transdermally, or intrathecally. It is not clear why opioids cause urinary retention, but it is thought to be related to the central anticholinergic stimulation that opioids induce. Based on this theory, a number of cholinergic-type drugs have been used to treat urinary retention. However, due to the side effects of cholinergic drugs, catheterization of the bladder with a tube to drain urine remains the mainstay of treatment.
- Another opioid-induced side effect is dysphoria, a feeling of unpleasantness or discomfort. Many subjects, especially those without pain, report unpleasant psychomimetic responses to the administration of an opioid alone. These responses have been previously attributed to activation of centrally located opioid receptors. This opioid-induced dysphoria is commonly treated by the addition of other drugs, such as benzodiazepines, to decrease the dysphoria or to blunt the recall of the dysphoria. These drugs, however are associated with increased levels of sedation and may enhance respiratory depression caused by the opioid.
- One treatment for side effects such as pruritis, urinary retention and dysphoria is the use of opioid antagonists which cross the blood-brain-barrier, or which are administered directly into the central nervous system. Opioid antagonists such as naltrexone and naloxone have been administered intramuscularly or orally to treat opioid induced pruritus. Naltrexone and naloxone are highly lipid soluble and rapidly diffuse across biological membranes, including the blood-brain-barrier. However, naltrexone, naloxone and other opioid antagonists also reduce the analgesic effect of the opioid being used.
- Many quaternary amine opioid antagonist derivatives, such as methylnaltrexone, do not reduce the analgesic effect of the opioids. These quaternary amine opioid antagonist derivatives, which have a relatively higher polarity and reduced lipid solubility when compared to the tertiary forms of the drugs, were specifically developed to not traverse the blood-brain-barrier or to traverse it at a greatly reduced rate. Since these quaternary opioid antagonist derivatives do not cross the blood-brain-barrier, peripheral administration of these antagonists would not be expected to be effective in the treatment of an opioid induced side effect caused by the opioid within the central nervous system. In fact, experiments show that to be effective in blocking the opioid receptors in the central nervous system, these antagonists must be injected directly into the central nervous system. However, injection of drugs directly into the central nervous system is undesirable since it increases the possibility of introducing bacterial or viral contamination to the central nervous system.
- It is desirable in the treatment of many conditions to have oral medications with prolonged effects. Such oral medications are particularly desirable both for the treatment of opioid-induced side effects (such as urinary retention, pruritus, and some forms of constipation) and for the treatment of nonopioid-induced side effects (such as other forms of constipation and delayed gastric emptying from enteric feeding).
- It is further desirable to develop a method for the prevention of opioid induced dysphoria, opioid induced pruritus, urinary retention, opioid- or nonopioid-induced delayed gastric emptying from enteric feeding, and constipation, which does not counteract the analgesic effects of the opioid, or risk increased levels of pain.
- The present invention is directed at methods for preventing and treating endogenous opioid induced gastrointestinal dysfunction.
- The method for preventing endogenous opioid-induced dysfunction, including gastric dysfunction and constipation, comprises administering methylnaltrexone or other quaternary derivatives of noroxymorphone to a patient, wherein the route of administration is selected from the group consisting of parenteral, intramuscular, intravenous and oral administration, in a standard or enterically coated preparation in an effective amount, more preferably in an amount between 0.03 and 1.0 mg/kg.
- The present invention is directed at methods for preventing and treating opioid-induced dysphoria, opioid-induced pruritus, opioid-induced urinary retention, opioid- or nonopioid-induced inhibition of gastric emptying by enteric feeding, and opioid- or nonopioid-induced constipation. When used as a treatment for these opioid- and nonopioid-induced side effects, orally administered, particularly if enteric coated, methylnaltrexone (MNTX) or other quaternary derivatives of noroxymorphone (QDMN) provides prolonged relief of the side effects. Furthermore, for treatment or prevention of delayed gastric emptying from enteric feeding and constipation, whether caused by extrinsic or endogenous opioids, enteric coating surprisingly allows for equal or better efficacy despite lower plasma levels. Idiopathic constipation, i.e., that due to causes other than exogenous administration of opioids, may be mediated by opioid sensitive mechanisms. Endogenous opioid receptors have been identified in the gut, and these receptors may modulate gut motility. Thus, administration of an opioid antagonist with peripheral action, such a methylnaltrexone or other quaternary derivatives of noroxymorphone, would block the effects of endogenous opioids.
-
- wherein R is allyl or a related radical such as chlorallyl, cyclopropyl-methyl or propargyl, and X is the anion of an acid, especially a chloride, bromide,. iodide or methylsulfate anion.
- The presently preferred quaternary derivative of noroxymorphone is methylnaltrexone. Methylnaltrexone is a quaternary amine derivative of naltrexone. Methylnaltrexone has been found to have only 2 to 4% of the opiate antagonistic activity of naltrexone in vivo due to its inability to pass the blood-brain-barrier and bind to the opiate receptors in the central nervous system.
- Opioids are typically administered at a morphine equivalent dosage of: 0.005 to 0.15 mg/kg body weight for intrathecal administration; 0.05 to 1.0 mg/kg body weight for intravenous administration; 0.05 to 1.0 mg/kg body weight for intramuscular administration; 0.05 to 1.0 mg/kg body weight/hour for transmucosal or transdermal administration. By “morphine equivalent dosage” is meant representative doses of other opioids which equal one milligram of morphine, for example 10 mg meperidine, 1 mg methadone, and 80 .mu.g fentanyl.
- In accordance with the present invention, methylnaltrexone is administered at a dosage of: 0.03 to 1.0 mg/kg body weight for intravenous administration; 0.03 to 1.0 mg/kg body weight for intramuscular administration; 0.03 to 1.0 mg/kg body weight for transmucosal administration and 1.0 to 40.0 mg/kg body weight for oral administration. In accordance with the present invention, enteric coated methylnaltrexone, is administered at a dosage of 1.0 to 80.0 mg/kg body weight for oral administration.
- The administration of the methylnaltrexone is preferably commenced prior to administration of the opioid to prevent opioid-induced dysphoria, pruritus, urinary retention, inhibition of gastric emptying with enteric feeding, or constipation. It is desirable to commence administration of methylnaltrexone about 5 minutes for parenteral MNTX administration and 20 minutes for enteral MNTX administration prior to administration of opioids in order to prevent these opioid-induced side effects. It is also preferable to administer the methylnaltrexone prior to the onset of nonopioid-induced gastric dysfunction symptoms, inhibition of gastric emptying with enteric feeding or constipation, in order to prevent these symptoms from manifesting. While the prevention of symptoms is preferred, methylnaltrexone administration may also be commenced after the administration of the opioid or after the onset of opioid induced symptoms as a treatment for those symptoms.
- Methylnaltrexone is rapidly absorbed after oral administration from the stomach and bowel. Initial plasma levels of the drug are seen within 5-10 minutes of the administration of non-enteric coated compound. Addition of an enteric coating which prevents gastric absorption is associated with lower plasma levels of the methylnaltrexone. Surprisingly, the addition of an enteric coating (i.e., a coating which will prevent degradation or release in the stomach, but will release drug in the small and large bowel) appears to enhance the efficacy of methylnaltrexone in the prevention of decreases in gut motility by intravenously administered opioids (morphine).
- For intravenous administration, methylnaltrexone is formulated with saline or other physiologically acceptable carriers; for intramuscular administration, the methylnaltrexone is formulated with saline or other pharmacologically acceptable carriers; for transmucosal administration the methylnaltrexone is formulated with a sugar and cellulose mix or other pharmacologically acceptable carriers known in the art; and for oral administration, the methylnaltrexone is formulated with pharmacologically acceptable binders to make a tablet or capsule with or without an enteric coating. Methods for such formulations are well known to those skilled in the art.
- In a preferred embodiment for the prevention and/or treatment of constipation, the MNTX is enterically coated and administered orally.
- The enteric coating may be made of any suitable composition. Suitable enteric coatings are described, for example, in U.S. Pat. Nos. 4,311,833 to Namikoshi, et al.; 4,377,568 to Chopra; 4,385,078 to Onda, et al.; 4,457,907 to Porter; 4,462,839 to McGinley, et al.; 4,518,433 to McGinley, et al.; 4,556,552 to Porter, et al.; 4,606,909 to Bechgaard et al.; 4,615,885 to Nakagame, et al.; 4,670,287 to Tsuji; 5,536,507 TO Abramowitz, et al.; 5,567,423 to Ying, et al.; 5,591,433 to Michael, et al.; 5,597,564 to Ying, et al.; 5,609,871 to Michael, et al.; 5,614,222 to Kaplan; 5,626,875 to Rodes, et al.; and 5,629,001 to Michael, et al., all of which are incorporated herein by reference.
- Preferred enteric coating compositions include alkyl and hydroxyalkyl celluloses and their aliphatic esters, e.g., methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethylethylcellulose, hydroxyprophymethylcellulose, hydroxybutylmethylcellulose, hydroxypropylcellulose phthalate, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succincate; carboxyalkylcelluloses and their salts, e.g., carboxymethylethylcellulose; cellulose acetate phthalate; cellulose acetate trimellitate, polycarboxymethylene and its salts and derivatives; polyvinylalcohol and its esters: polyvinyl acetate phthalate; polycarboxymethylene copolymer with sodium formaldehyde carboxylate; acrylic polymers and copolymers, e.g., methacrylic acidmethyl methacrylic acid copolymer and methacrylic acid-methyl acrylate copolymer; edible oils such as peanut oil, palm oil, olive oil and hydrogenated vegetable oils; polyvinylpyrrolidone; polyethyleneglycol and its esters: natural products such as shellac, and zein.
- Other preferred enteric coatings include polyvinylacetate esters, e.g., polyvinyl acetate phthalate; alkyleneglycolether esters of copolymers such as partial ethylene glycol monomethylether ester of ethylacrylate-maleic anhydride copolymer or diethyleneglycol monomethylether ester of methylacrylate-maleic anhydride copolymer, N-butylacrylatemaleic anhydride copolymer, isobutylacrylate-maleic anhydride copolymer or ethylacrylate-maleic anhydride copolymer; and polypeptides resistant to degradation in the gastric environment, e.g., polyarginine and polylysine.
- Mixtures of two or more of the above compounds may be used as desired. The presently preferred enteric coating comprises cellulose acetate phthalate.
- The enteric coating material may be mixed with various excipients including plasticizers such as triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl subacute, dibutyl tartrate, dibutyl maleate, dibutyl succinate and diethyl succinate and inert fillers such as chalk or pigments.
- The composition and thickness of the enteric coating may be selected to dissolve immediately upon coated with the digestive juice of the intestine. Alternatively, the composition and thickness of the anterior coating may be selected to be a time-release coating which dissolves over a selected period of time, as is well known in the art.
- The amount of enteric coating depends on the particular enteric coating composition used and is preferably sufficient to substantially prevent the absorption of MNTX in the stomach.
- Hydroxyalkyl celluloses and their aliphatic esters, carboxyalkyl celluloses and their salts, polycarboxymethylene and its salts and derivatives, polyvinyl alcohol and its esters, polycarboxymethylene copolymer with sodium formaldehyde carboxylates, polyvinylpyrrolidone, and polyethylene glycol and its esters can be applied as enteric coatings by first dissolving the compound in a minimum amount of water. Alcohol is then added to the point of incipient cloudiness. The mixture can then be applied by conventional techniques.
- Application of cellulose acetate phthalate may be accomplished by simply dissolving the cellulose acetate phthalate in a minimum amount of alcohol and then applying by conventional techniques. Hydrogenated vegetable oils may be applied by first dissolving the oil in a minimal amount of a non-polymer solvent, such as methylene chloride, chloroform or carbon tetrachloride, then adding alcohol to the point of incipient cloudiness and then applying by conventional techniques.
- In a particularly preferred embodiment, the MNTX is coated with Eudragit L100 or S100, a methacrylic acid copolymer enteric coating, at a 50% coating level to provide stability at gastric pH and dissolution at gut pH per a US Pharmacopeia (USP) standard for enteric coatings.
- Any art-known transdermal application may be used, but transdermal administration is preferably via a patch applied to the skin with a membrane of sufficient permeability to allow diffusion of MNTX at a fixed rate in the range of 1.0 to 10.0 mg/hr. The rate of administration may be varied by varying the size of the membrane contact area and/or applying an electrical wiring potential to a drug reservoir. The patch preferably holds 25 mg to 1 gram of available drug in the reservoir plus additional drug as needed for the mechanics of the system.
- In the above description, methylnaltrexone is used as an example of a particularly effective QDNM. It is apparent that other QDNM's may be used as desired.
- The following Examples are intended to illustrate aspects of the invention and are not to be construed as limitations upon it. The methylnaltrexone used in the following Examples was manufactured by Mallinckrodt Pharmaceuticals, St. Louis, Mo. The Enteric Coating was manufactured by Coating Place, Inc., Verona, Wis.
- Ten patients were treated with morphine sulfate administered directly to the central nervous system or intravenously. The morphine sulfate was administered at 0.1 mg/kg body weight. The patients in the study had been treated for pain resulting from surgery. All the patients exhibited pruritus as a side effect of the morphine sulfate administration. Subsequent to the onset of the pruritus, methylnaltrexone, at a dosage of 0.3 mg/kg of body weight was administered intravenously as a saline solution containing methylnaltrexone in a concentration of 5 mg/ml to each of the patients. Eighty percent of the 10 patients exhibited relief from the pruritus sixty minutes after receiving methylnaltrexone.
- In a control group, 8 patients were treated with morphine sulfate administered directly to the central nervous system or intravenously. The morphine sulfate was administered at 0.1 mg/kg body weight. The patients in the study had been treated for pain resulting from surgery. All the patients exhibited pruritus as a side effect of the morphine sulfate administration. A placebo, saline at a volume equivalent to the volume administered to patients receiving active drug, was administered intravenously to each of the patients. Only 50% of the patients exhibited relief from the pruritus within sixty minutes.
- The study indicates that methylnaltrexone was effective in treating pruritus induced by morphine sulfate.
- Efficacy of Enteric Coating of Methylnaltrexone
- Morphine (0.05) mg/kg intravenous) was administered to three volunteers after the oral administration of placebo, methylnaltrexone (6.4 mg/kg) in a gelatin capsule (which dissolves readily in the stomach), or methylnaltrexone after enteric coating (12.8 mg/kg of substance to yield a mass of 6.4 mg/kg methylnaltrexone incorporated) which has decreased release and absorption in the stomach. Oral-cecal transit time was measured using the lactulose-hydrogen breath test. Plasma levels of methylnaltrexone were measured and after the enteric coated preparation were lower. In each subject morphine alone increased the oral-cecal transit time by 20-70 minutes, methylnaltrexone blocked this effect, and enteric coated methylnaltrexone blocked the effect to a similar or greater extent than the uncoated methylnaltrexone.
- Enhancement of Enteric Feeding
- Two patients receiving morphine (375 mg/day and 18 mg/day) and receiving enteric tube feedings of 200 ml every four (4) hours were studied. The first patient had residual stomach contents of 50 cc to 100 cc, or 22.0-58.8% of administered feedings measured every 4 hours during a 24 hour control period. Prior to drug administration the residual volume had increased to 260 cc or >100% of previous feeding volume. Methylnaltrexone, 0.45 mg/kg, was administered intravenously every 4 hours for 24 hours, after the control period. After the first dose (4 hours) of MNTX, the residual was 150 cc or 58% of the previous bolus feed, after the 3rd dose (12 hours) the residual was 75 cc or 30% of the previous feed, after the 5th dose (20 hours) the residual was 22 cc or 13% of the previous feed and after the 6th and final dose (24 hours) the residual was 8 cc or 5.5% of previous feed. The follow-up residual sampling after the final drug-tube feed interval had increased to 50 cc or 38% or previous feed.
- The second patient had greater than 200 cc residual or 100% of previous feedings on two consecutive samplings, that is 8 hrs and 4 hrs before drug administration. After initiation of Methylnaltrexone, 0.45 mg/kg, administered intravenously every 4 hours, the first residual (4 hrs) was 0 cc, the second residual (8 hrs)was 24 cc or 15% of previous bolus feed.
- Treatment of Urinary Retention
- Subjects receiving morphine at a variety of doses (via patient controlled analgesia—PCA) who experience urinary retention are administered Methylnaltrexone 0.45 mg/kg intravenously or a placebo. Those treated with Methylnaltrexone have resolution of their symptoms, while those administered placebo go on to require additional therapy (usually urinary catheterization).
- In a double-blind randomized placebo-controlled study, we evaluated the efficacy of oral methylnaltrexone to decrease subjective effects after administering morphine to 10 normal human volunteers. After intravenous morphine injection (0.05 mg/kg), significant increases in subjective ratings were obtained on “nauseous”, “skin itch”, “stimulated”, and “flushing”. Compared to baseline, significant increases were obtained on “nauseous”, “skin itch”, “stimulated”, and “flushing” ratings after placebo and morphine administration (P<0.05, P<0.05, P<0.01 and P<0.01, respectively). Oral methylnaltrexone (19.2 mg/kg) significantly decreased these four ratings (P<0.05, P<0.05, P<0.01 and P<0.01, respectively) compared to placebo and morphine and resulted in no change when compared to baseline. Plasma methylnaltrexone concentrations were also measured and correlation between pharmacological effects of the compound and its plasma levels was shown. Our results indicate that methylnaltrexone decreases dysphoria and some other undesirable subjective effects associated with opioid medications.
- The preceding description and Examples are intended to be illustrative. Those skilled in the art to which the invention pertains will appreciate that alterations and changes in the described protocols may be practiced without departing from the meaning, spirit, and scope of this invention. Therefore, the foregoing description should be read consistent with and as support to the following claims, which are to have their fullest and fair scope.
Claims (28)
1. A method for treating a patient with a gastrointestinal dysfunction caused by endogenous opioids, comprising administering to the patient an amount of a quaternary derivative of noroxymorphone effective to treat the gastrointestinal dysfunction.
2. The method of claim 1 , wherein the administration is parenteral.
3. The method of claim 1 , wherein the administration is intravenous.
4. The method of claim 1 , wherein the administration is intravenous and the amount is between 0.03 and 1.0 mg/kg.
5. The method of claim 1 , wherein the administration is intramuscular and the amount is between 0.03 and 1.0 mg/kg.
6. The method of claim 1 , wherein the administration is oral.
7. The method of claims 1-6, wherein the quaternary derivative or noroxymorphone is methylnaltrexone.
8. A method for preventing in a patient a gastrointestinal dysfunction caused by endogenous opioids, comprising administering to the patient an amount of a quaternary derivative of noroxymorphone effective to treat the gastrointestinal dysfunction.
9. The method of claim 8 , wherein-the administration is parenteral.
10. The method of claim 8 , wherein the administration is intravenous.
11. The method of claim 8 , wherein the administration is intravenous and the amount is between 0.03 and 1.0 mg/kg.
12. The method of claim 1 , wherein the administration is intramuscular and the amount is between 0.03 and 1.0 mg/kg.
13. The method of claim 1 , wherein the administration is oral.
14. The method of claims 8-13, wherein the quaternary derivative or noroxymorphone is methylnaltrexone.
15. A method for treating a patient with constipation caused by endogenous opioids, comprising administering to the patient an amount of a quaternary derivative of noroxymorphone effective to treat the constipation.
16. The method of claim 15 , wherein the administration is parenteral.
17. The method of claim 15 , wherein the administration is intravenous.
18. The method of claim 15 , wherein the administration is intravenous. and the amount is between 0.03 and 1.0 mg/kg.
19. The method of claim 15 , wherein the administration is intramuscular and the amount is between 0.03 and 1.0 mg/kg.
20. The method of claim 15 , wherein the administration is oral.
21. The method of claims 15-20, wherein the quaternary derivative or noroxymorphone is methylnaltrexone.
22. A method for preventing in a patient constipation caused by endogenous opioids, comprising administering to the patient an amount of a quaternary derivative of noroxymorphone effective to treat the constipation.
23. The method of claim 22 , wherein the administration is parenteral.
24. The method of claim 22 , wherein the administration is intravenous.
25. The method of claim 22 , wherein the administration is intravenous and the amount is between 0.03 and 1.0 mg/kg.
26. The method of claim 22 , wherein the administration is intramuscular and the amount is between 0.03 and 1.0 mg/kg.
27. The method of claim 22 , wherein the administration is oral.
28. The method of claims 22-28, wherein the quaternary derivative or noroxymorphone is methylnaltrexone.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/779,129 US20040162308A1 (en) | 1997-11-03 | 2004-02-12 | Use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids |
US12/333,912 US20090312359A1 (en) | 1997-11-03 | 2008-12-12 | Use of methylnaltrexone and related compounds for treatment of gastrointestinal dysfunction induced by endogenous opioids |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/962,742 US5972954A (en) | 1997-11-03 | 1997-11-03 | Use of methylnaltrexone and related compounds |
US09/120,703 US6274591B1 (en) | 1997-11-03 | 1998-07-22 | Use of methylnaltrexone and related compounds |
US09/862,169 US6608075B2 (en) | 1997-11-03 | 2001-05-21 | Use of methylnaltrexone and related compounds |
US10/278,630 US20030065003A1 (en) | 1997-11-03 | 2002-10-23 | Use of methylnaltrexone and related compounds |
US10/779,129 US20040162308A1 (en) | 1997-11-03 | 2004-02-12 | Use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/278,630 Continuation US20030065003A1 (en) | 1997-11-03 | 2002-10-23 | Use of methylnaltrexone and related compounds |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/333,912 Continuation US20090312359A1 (en) | 1997-11-03 | 2008-12-12 | Use of methylnaltrexone and related compounds for treatment of gastrointestinal dysfunction induced by endogenous opioids |
Publications (1)
Publication Number | Publication Date |
---|---|
US20040162308A1 true US20040162308A1 (en) | 2004-08-19 |
Family
ID=26818669
Family Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/120,703 Expired - Lifetime US6274591B1 (en) | 1997-11-03 | 1998-07-22 | Use of methylnaltrexone and related compounds |
US09/862,169 Expired - Lifetime US6608075B2 (en) | 1997-11-03 | 2001-05-21 | Use of methylnaltrexone and related compounds |
US10/278,630 Abandoned US20030065003A1 (en) | 1997-11-03 | 2002-10-23 | Use of methylnaltrexone and related compounds |
US10/779,129 Abandoned US20040162308A1 (en) | 1997-11-03 | 2004-02-12 | Use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids |
US10/962,729 Abandoned US20050048117A1 (en) | 1997-11-03 | 2004-10-12 | Use of methylnaltrexone and related compounds |
US12/333,912 Abandoned US20090312359A1 (en) | 1997-11-03 | 2008-12-12 | Use of methylnaltrexone and related compounds for treatment of gastrointestinal dysfunction induced by endogenous opioids |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/120,703 Expired - Lifetime US6274591B1 (en) | 1997-11-03 | 1998-07-22 | Use of methylnaltrexone and related compounds |
US09/862,169 Expired - Lifetime US6608075B2 (en) | 1997-11-03 | 2001-05-21 | Use of methylnaltrexone and related compounds |
US10/278,630 Abandoned US20030065003A1 (en) | 1997-11-03 | 2002-10-23 | Use of methylnaltrexone and related compounds |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/962,729 Abandoned US20050048117A1 (en) | 1997-11-03 | 2004-10-12 | Use of methylnaltrexone and related compounds |
US12/333,912 Abandoned US20090312359A1 (en) | 1997-11-03 | 2008-12-12 | Use of methylnaltrexone and related compounds for treatment of gastrointestinal dysfunction induced by endogenous opioids |
Country Status (5)
Country | Link |
---|---|
US (6) | US6274591B1 (en) |
EP (1) | EP1047426B1 (en) |
AU (1) | AU758416B2 (en) |
CA (1) | CA2312234C (en) |
WO (1) | WO1999022737A1 (en) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030065003A1 (en) * | 1997-11-03 | 2003-04-03 | The University Of Chicago | Use of methylnaltrexone and related compounds |
US20040162306A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnal trexone and related compounds to treat constipation in chronic opioid users |
US20040259899A1 (en) * | 2003-04-08 | 2004-12-23 | Sanghvi Suketu P. | Combination therapy for constipation |
US20040266806A1 (en) * | 2003-04-08 | 2004-12-30 | Sanghvi Suketu P. | Pharmaceutical formulation |
US20050004155A1 (en) * | 2003-04-08 | 2005-01-06 | Boyd Thomas A. | Use of methylnaltrexone to treat irritable bowel syndrome |
US20060205753A1 (en) * | 2005-01-20 | 2006-09-14 | Israel Robert J | Use of methylnaltrexone and related compounds to treat post-operative gastrointestinal dysfunction |
US20070265293A1 (en) * | 2005-05-25 | 2007-11-15 | Boyd Thomas A | (S)-N-methylnaltrexone |
US20090111844A1 (en) * | 2007-10-18 | 2009-04-30 | Aiko Biotechnology | Combination analgesic employing opioid and neutral antagonist |
US7674904B2 (en) | 2005-05-25 | 2010-03-09 | Progenics Pharmaceuticals, Inc. | Synthesis of R-N-methylnaltrexone |
US8247425B2 (en) | 2008-09-30 | 2012-08-21 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
US8338446B2 (en) | 2007-03-29 | 2012-12-25 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US8471022B2 (en) | 2008-02-06 | 2013-06-25 | Progenics Pharmaceuticals, Inc. | Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone |
US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US8546418B2 (en) | 2007-03-29 | 2013-10-01 | Progenics Pharmaceuticals, Inc. | Peripheral opioid receptor antagonists and uses thereof |
US8685995B2 (en) | 2008-03-21 | 2014-04-01 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
US8748448B2 (en) | 2007-10-18 | 2014-06-10 | Aiko Biotechnology | Combination analgesic employing opioid agonist and neutral antagonist |
US9102680B2 (en) | 2007-03-29 | 2015-08-11 | Wyeth Llc | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
US9662390B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US10307417B2 (en) | 2010-03-11 | 2019-06-04 | Wyeth, Llc | Oral formulations and lipophilic salts of methylnaltrexone |
Families Citing this family (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6559158B1 (en) * | 1997-11-03 | 2003-05-06 | Ur Labs, Inc. | Use of methylnaltrexone and related compounds to treat chronic opioid use side affects |
PT1041987E (en) | 1997-12-22 | 2006-07-31 | Euro Celtique Sa | PHARMACEUTICAL FORM OF ORAL DOSAGE, UNDERSTANDING A COMBINATION OF AN AGRONIST OF OPIOIDE AND NALTREXONE |
US6375957B1 (en) | 1997-12-22 | 2002-04-23 | Euro-Celtique, S.A. | Opioid agonist/opioid antagonist/acetaminophen combinations |
WO2001013909A2 (en) * | 1999-08-25 | 2001-03-01 | Cooper Barrett R | Compositions and methods for treating opiate intolerance |
US6451806B2 (en) | 1999-09-29 | 2002-09-17 | Adolor Corporation | Methods and compositions involving opioids and antagonists thereof |
ATE275402T1 (en) * | 1999-11-01 | 2004-09-15 | John Rhodes | MEDICINAL PRODUCTS FOR THE TREATMENT OF INTESTINAL CONSTITUTION AND irritable colon |
DE60042282D1 (en) * | 1999-11-29 | 2009-07-09 | Adolor Corp | NEW METHODS AND METHODS FOR TREATING AND AVOIDING ILEUS |
US6469030B2 (en) | 1999-11-29 | 2002-10-22 | Adolor Corporation | Methods for the treatment and prevention of ileus |
RS50407B (en) | 2000-02-08 | 2009-12-31 | Euro-Celtique S.A., | Tamper-resistant oral opiod agonist formulations |
DE10059415A1 (en) * | 2000-11-30 | 2002-06-06 | Gruenenthal Gmbh | Use of weak opioids and mixed opioid agonists / antagonists for the treatment of urinary incontinence |
EP1387673B1 (en) | 2001-05-11 | 2010-12-29 | Endo Pharmaceuticals Inc. | Abuse-resistant controlled-release opioid dosage form |
CA2449175A1 (en) | 2001-06-05 | 2002-12-12 | University Of Chicago | Use of methylnaltrexone to treat immune suppression |
DK1416842T3 (en) | 2001-07-18 | 2009-03-16 | Euro Celtique Sa | Pharmaceutical combinations of oxycodone and naloxone |
PL367427A1 (en) | 2001-08-06 | 2005-02-21 | Euro-Celtique S.A. | Opioid agonist formulations with releasable and sequestered antagonist |
CA2475305A1 (en) * | 2002-02-04 | 2004-02-19 | Jonathan Moss | Use of methylnaltrexone in treating gastrointestinal dysfunction in equines |
DE60325567D1 (en) | 2002-04-05 | 2009-02-12 | Euro Celtique Sa | MATRIX FOR THE MODIFIED RELEASE OF ACTIVE SUBSTANCES |
WO2005007135A1 (en) * | 2002-08-15 | 2005-01-27 | Euro-Celtique S.A. | Pharmaceutical compositions |
TWI347201B (en) | 2003-04-21 | 2011-08-21 | Euro Celtique Sa | Pharmaceutical products,uses thereof and methods for preparing the same |
EP1660048A4 (en) * | 2003-08-12 | 2009-07-08 | Endo Pharmaceuticals Inc | Method for deterring abuse of opioids by combination with non-release formulation of emetic |
ES2344350T3 (en) * | 2003-09-25 | 2010-08-25 | Euro-Celtique S.A. | PHARMACEUTICAL COMBINATIONS OF HIDROCODONA AND NALTREXONA. |
JPWO2006064780A1 (en) * | 2004-12-14 | 2008-06-12 | 塩野義製薬株式会社 | Constipation treatment |
EP1702558A1 (en) | 2005-02-28 | 2006-09-20 | Euro-Celtique S.A. | Method and device for the assessment of bowel function |
US20080194611A1 (en) * | 2005-06-03 | 2008-08-14 | Alverdy John C | Modulation of Cell Barrier Dysfunction |
US20070185145A1 (en) * | 2006-02-03 | 2007-08-09 | Royds Robert B | Pharmaceutical composition containing a central opioid agonist, a central opioid antagonist, and a peripheral opioid antagonist, and method for making the same |
US20080027579A1 (en) * | 2006-07-31 | 2008-01-31 | Van Der Hoop Roland Gerritsen | Dosage limiting medication dispensing method and apparatus |
TW200815451A (en) * | 2006-08-04 | 2008-04-01 | Wyeth Corp | 6-carboxy-normorphinan derivatives, synthesis and uses thereof |
TW200817048A (en) * | 2006-09-08 | 2008-04-16 | Wyeth Corp | Dry powder compound formulations and uses thereof |
US8383649B2 (en) * | 2007-07-11 | 2013-02-26 | Mallinckrodt Llc | Crystalline forms of naltrexone methobromide |
EP2306829B1 (en) | 2008-07-01 | 2017-01-04 | University of Chicago | Particles containing a peripheral opioid receptor antagonist |
CN102387802B (en) | 2009-03-10 | 2016-05-04 | 欧洲凯尔特公司 | The release of pharmaceutical compositions immediately that comprises Oxycodone and naloxone |
US8637538B1 (en) | 2012-12-14 | 2014-01-28 | Trevi Therapeutics, Inc. | Methods for treatment of pruritis |
US8987289B2 (en) | 2012-12-14 | 2015-03-24 | Trevi Therapeutics, Inc. | Methods for treating pruritus |
US20140179727A1 (en) | 2012-12-14 | 2014-06-26 | Trevi Therapeutics, Inc. | Methods for treating pruritus |
NZ716267A (en) | 2013-07-23 | 2017-05-26 | Euro Celtique Sa | A combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation |
CN107249327A (en) | 2014-10-17 | 2017-10-13 | 萨利克斯药品公司 | Slow down tumour progression using methyl naltrexone |
EP3826635A4 (en) | 2018-07-23 | 2022-04-27 | Trevi Therapeutics, Inc. | Treatment of chronic cough, breathlessness and dyspnea |
WO2020225395A1 (en) | 2019-05-07 | 2020-11-12 | Bausch Health Ireland Limited | Liquid oral dosage formulations of methylnaltrexone |
EP4142727A1 (en) | 2020-05-02 | 2023-03-08 | Bausch Health Ireland Limited | Methods of reducing mortality risk in subjects suffering from an underlying disease or condition by administration of methylnaltrexone |
Citations (65)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4176186A (en) * | 1978-07-28 | 1979-11-27 | Boehringer Ingelheim Gmbh | Quaternary derivatives of noroxymorphone which relieve intestinal immobility |
US4311833A (en) * | 1979-03-06 | 1982-01-19 | Daicel Chemical Industries Ltd. | Process for preparing ethylcarboxymethylcellulose |
US4322426A (en) * | 1980-04-28 | 1982-03-30 | E. I. Du Pont De Nemours And Company | 17-Substituted-6-desoxy-7,8-dihydro-6α-methylnoroxymorphone narcotic antagonists |
US4377568A (en) * | 1981-08-12 | 1983-03-22 | Merck Sharp & Dohme (I.A.) Corp. | Preparation of aqueous alcoholic dispersions of pH sensitive polymers and plasticizing agents and a method of enteric coating dosage forms using same |
US4385078A (en) * | 1978-09-04 | 1983-05-24 | Shin-Etsu Chemical Co., Ltd. | Method for providing enteric coating on solid dosage forms and aqueous compositions therefor |
US4457907A (en) * | 1982-08-05 | 1984-07-03 | Clear Lake Development Group | Composition and method for protecting a therapeutic drug |
US4462839A (en) * | 1983-06-16 | 1984-07-31 | Fmc Corporation | Enteric coating for pharmaceutical dosage forms |
US4518433A (en) * | 1982-11-08 | 1985-05-21 | Fmc Corporation | Enteric coating for pharmaceutical dosage forms |
US4556552A (en) * | 1983-09-19 | 1985-12-03 | Colorcon, Inc. | Enteric film-coating compositions |
US4606909A (en) * | 1981-11-20 | 1986-08-19 | A/S Alfred Benzon | Pharmaceutical multiple-units formulation |
US4615885A (en) * | 1983-11-01 | 1986-10-07 | Terumo Kabushiki Kaisha | Pharmaceutical composition containing urokinase |
US4670287A (en) * | 1985-07-30 | 1987-06-02 | Washu Kirai Kogyo Kabushiki Kaisha | Method of film-coating hard capsules |
US4719215A (en) * | 1986-03-07 | 1988-01-12 | University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
US4857833A (en) * | 1987-08-27 | 1989-08-15 | Teradyne, Inc. | Diagnosis of faults on circuit board |
US4861781A (en) * | 1986-03-07 | 1989-08-29 | The University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
US4888346A (en) * | 1986-10-07 | 1989-12-19 | Bernard Bihari | Method for the treatment of persons infected with HTLV-III (AIDS) virus |
US4965269A (en) * | 1989-12-20 | 1990-10-23 | Ab Hassle | Therapeutically active chloro substituted benzimidazoles |
US4987136A (en) * | 1982-03-16 | 1991-01-22 | The Rockefeller University | Method for controlling gastrointestinal dysmotility |
US5102887A (en) * | 1989-02-17 | 1992-04-07 | Arch Development Corporation | Method for reducing emesis and nausea induced by the administration of an emesis causing agent |
US5159081A (en) * | 1991-03-29 | 1992-10-27 | Eli Lilly And Company | Intermediates of peripherally selective n-carbonyl-3,4,4-trisubstituted piperidine opioid antagonists |
US5202159A (en) * | 1990-12-27 | 1993-04-13 | Standard Chemical & Pharmaceutical Corp., Ltd. | Preparation method of microdispersed tablet formulation of spray-dried sodium diclofenac enteric-coated microcapsules |
US5270328A (en) * | 1991-03-29 | 1993-12-14 | Eli Lilly And Company | Peripherally selective piperidine opioid antagonists |
US5391372A (en) * | 1993-06-28 | 1995-02-21 | Campbell; Elizabeth | Methods of treating colic and founder in horses |
US5426112A (en) * | 1984-04-09 | 1995-06-20 | Scully, Scott, Murphy & Presser, P.C. | Growth regulation and related applications of opioid antagonists |
US5472943A (en) * | 1992-09-21 | 1995-12-05 | Albert Einstein College Of Medicine Of Yeshiva University, | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists |
US5512578A (en) * | 1992-09-21 | 1996-04-30 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists |
US5536507A (en) * | 1994-06-24 | 1996-07-16 | Bristol-Myers Squibb Company | Colonic drug delivery system |
US5567423A (en) * | 1986-08-28 | 1996-10-22 | Enzacor Properties, Ltd. | Animal growth promotant |
US5591433A (en) * | 1991-06-21 | 1997-01-07 | University Of Cincinnati | Oral administration of immunologically active biomolecules and other therapeutic proteins |
US5597564A (en) * | 1986-08-28 | 1997-01-28 | Enzacor Properties Limited | Method of administering a microgranular preparation to the intestinal region of animals |
US5609871A (en) * | 1991-06-21 | 1997-03-11 | Michael; J. Gabriel | Oral administration of therapeutic proteins for treatment of infectious disease |
US5614222A (en) * | 1994-10-25 | 1997-03-25 | Kaplan; Milton R. | Stable aqueous drug suspensions and methods for preparation thereof |
US5614219A (en) * | 1991-12-05 | 1997-03-25 | Alfatec-Pharma Gmbh | Oral administration form for peptide pharmaceutical substances, in particular insulin |
US5626875A (en) * | 1995-02-01 | 1997-05-06 | Esteve Quimica, S.A. | Stabilized galenic formulations comprising an acid labile benzimidazole compound and its preparation |
US5656290A (en) * | 1993-02-26 | 1997-08-12 | The Procter & Gamble Company | Bisacodyl dosage form with multiple enteric polymer coatings for colonic delivery |
US5767125A (en) * | 1992-09-21 | 1998-06-16 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
US5804595A (en) * | 1995-12-05 | 1998-09-08 | Regents Of The University Of Minnesota | Kappa opioid receptor agonists |
US5811451A (en) * | 1994-05-24 | 1998-09-22 | Minoia; Paolo | Pharmaceutical compositions comprising an opiate antagonist and calcium salts, their use for the treatment of endorphin-mediated pathologies |
US5866164A (en) * | 1996-03-12 | 1999-02-02 | Alza Corporation | Composition and dosage form comprising opioid antagonist |
US5866154A (en) * | 1994-10-07 | 1999-02-02 | The Dupont Merck Pharmaceutical Company | Stabilized naloxone formulations |
US5958452A (en) * | 1994-11-04 | 1999-09-28 | Euro-Celtique, S.A. | Extruded orally administrable opioid formulations |
US5972954A (en) * | 1997-11-03 | 1999-10-26 | Arch Development Corporation | Use of methylnaltrexone and related compounds |
US5981185A (en) * | 1994-05-05 | 1999-11-09 | Beckman Coulter, Inc. | Oligonucleotide repeat arrays |
USRE36547E (en) * | 1992-09-21 | 2000-02-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists |
US6025154A (en) * | 1995-06-06 | 2000-02-15 | Human Genome Sciences, Inc. | Polynucleotides encoding human G-protein chemokine receptor HDGNR10 |
US6096756A (en) * | 1992-09-21 | 2000-08-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
US6194382B1 (en) * | 1999-03-03 | 2001-02-27 | Albert Einstein College Of Medicine Of Yeshiva University | Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists |
US6274591B1 (en) * | 1997-11-03 | 2001-08-14 | Joseph F. Foss | Use of methylnaltrexone and related compounds |
US20010036951A1 (en) * | 1999-11-29 | 2001-11-01 | Farrar John J. | Novel methods for the treatment and prevention of ileus |
US20010047005A1 (en) * | 1999-09-29 | 2001-11-29 | Farrar John J. | Novel methods and compositions involving opioids and antagonists thereof |
US6353004B1 (en) * | 1997-07-14 | 2002-03-05 | Adolor Coporation | Peripherally acting anti-pruritic opiates |
US20020064771A1 (en) * | 2000-04-07 | 2002-05-30 | Weidong Zhong | HCV replicase complexes |
US6419959B1 (en) * | 1996-12-11 | 2002-07-16 | Klinge Pharma Gmbh | Galenic composition containing opioid antagonists |
US6455537B1 (en) * | 1999-08-25 | 2002-09-24 | Barrett R. Cooper | Methods for treating opiate intolerance |
US20030022909A1 (en) * | 2001-06-05 | 2003-01-30 | University Of Chicago | Use of methylnaltrexone to treat immune suppression |
US20030026801A1 (en) * | 2000-06-22 | 2003-02-06 | George Weiner | Methods for enhancing antibody-induced cell lysis and treating cancer |
US6559158B1 (en) * | 1997-11-03 | 2003-05-06 | Ur Labs, Inc. | Use of methylnaltrexone and related compounds to treat chronic opioid use side affects |
US20030124086A1 (en) * | 2001-10-18 | 2003-07-03 | Shearwater Corporation | Polymer conjugates of opioid antagonists |
US20030191147A1 (en) * | 2002-04-09 | 2003-10-09 | Barry Sherman | Opioid antagonist compositions and dosage forms |
US20040162307A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnaltrexone and related compounds to induce laxation in chronic opioid users |
US20040259899A1 (en) * | 2003-04-08 | 2004-12-23 | Sanghvi Suketu P. | Combination therapy for constipation |
US20040266806A1 (en) * | 2003-04-08 | 2004-12-30 | Sanghvi Suketu P. | Pharmaceutical formulation |
US20050004155A1 (en) * | 2003-04-08 | 2005-01-06 | Boyd Thomas A. | Use of methylnaltrexone to treat irritable bowel syndrome |
US20050124885A1 (en) * | 2003-10-29 | 2005-06-09 | Vuesonix Sensors, Inc. | Method and apparatus for determining an ultrasound fluid flow centerline |
US20060205753A1 (en) * | 2005-01-20 | 2006-09-14 | Israel Robert J | Use of methylnaltrexone and related compounds to treat post-operative gastrointestinal dysfunction |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US222911A (en) * | 1879-12-23 | Improvement in book-cases | ||
US2003A (en) * | 1841-03-12 | Improvement in horizontal windivhlls | ||
US1047726A (en) * | 1912-03-12 | 1912-12-17 | Anthony J Yoggerst | Pipe-cleaner. |
US2625457A (en) * | 1951-07-26 | 1953-01-13 | Bernard J Baecher | Course recorder |
EP0103636B1 (en) | 1982-03-16 | 1990-09-12 | Rockefeller University | Use of opium antagonists for the manufacture of medicaments for controlling gastrointestinal dysmotility |
FR2609632B1 (en) | 1987-01-21 | 1991-03-29 | Shelly Marc | NOVEL THERAPEUTIC APPLICATION OF 17- (CYCLOPROPYLMETHYL) -4,5-EPOXY-3,14-DIHYDROXYMORPHINON-6-ONE AND PHARMACEUTICAL COMPOSITIONS FOR THIS USE |
CA1315689C (en) | 1987-09-03 | 1993-04-06 | Leon I. Goldberg | Quarternary derivatives of noroxymorphone which relieve nausea and emesis |
ES2051742T3 (en) * | 1987-09-10 | 1994-07-01 | Univ Chicago | QUARTERLY DERIVATIVES OF NOROXI-MORPHINE THAT MITIGATE NAUSEA AND EMESIS. |
EP0352361A1 (en) | 1988-07-29 | 1990-01-31 | The Rockefeller University | Method of treating patients suffering from chronic pain or chronic cough |
US5585348A (en) | 1993-02-10 | 1996-12-17 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Use of excitatory opioid receptor antagonists to prevent growth factor-induced hyperalgesia |
AU4136901A (en) | 1999-11-29 | 2001-06-18 | Adolor Corporation | Novel methods for the treatment and prevention of dizziness and pruritus |
MXPA02005335A (en) | 1999-11-29 | 2003-01-28 | Adolor Corp | Novel methods and compositions involving opioids and antagonists thereof. |
DE60042282D1 (en) | 1999-11-29 | 2009-07-09 | Adolor Corp | NEW METHODS AND METHODS FOR TREATING AND AVOIDING ILEUS |
AU5945801A (en) | 2000-05-05 | 2001-11-20 | Pain Therapeutics Inc | Opoid antagonist compositions and dosage forms |
-
1998
- 1998-07-22 US US09/120,703 patent/US6274591B1/en not_active Expired - Lifetime
- 1998-11-03 CA CA002312234A patent/CA2312234C/en not_active Expired - Lifetime
- 1998-11-03 AU AU13802/99A patent/AU758416B2/en not_active Expired
- 1998-11-03 WO PCT/US1998/023485 patent/WO1999022737A1/en active IP Right Grant
- 1998-11-03 EP EP98957573A patent/EP1047426B1/en not_active Expired - Lifetime
-
2001
- 2001-05-21 US US09/862,169 patent/US6608075B2/en not_active Expired - Lifetime
-
2002
- 2002-10-23 US US10/278,630 patent/US20030065003A1/en not_active Abandoned
-
2004
- 2004-02-12 US US10/779,129 patent/US20040162308A1/en not_active Abandoned
- 2004-10-12 US US10/962,729 patent/US20050048117A1/en not_active Abandoned
-
2008
- 2008-12-12 US US12/333,912 patent/US20090312359A1/en not_active Abandoned
Patent Citations (82)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4176186A (en) * | 1978-07-28 | 1979-11-27 | Boehringer Ingelheim Gmbh | Quaternary derivatives of noroxymorphone which relieve intestinal immobility |
US4385078A (en) * | 1978-09-04 | 1983-05-24 | Shin-Etsu Chemical Co., Ltd. | Method for providing enteric coating on solid dosage forms and aqueous compositions therefor |
US4311833A (en) * | 1979-03-06 | 1982-01-19 | Daicel Chemical Industries Ltd. | Process for preparing ethylcarboxymethylcellulose |
US4322426A (en) * | 1980-04-28 | 1982-03-30 | E. I. Du Pont De Nemours And Company | 17-Substituted-6-desoxy-7,8-dihydro-6α-methylnoroxymorphone narcotic antagonists |
US4377568A (en) * | 1981-08-12 | 1983-03-22 | Merck Sharp & Dohme (I.A.) Corp. | Preparation of aqueous alcoholic dispersions of pH sensitive polymers and plasticizing agents and a method of enteric coating dosage forms using same |
US4606909A (en) * | 1981-11-20 | 1986-08-19 | A/S Alfred Benzon | Pharmaceutical multiple-units formulation |
US4987136A (en) * | 1982-03-16 | 1991-01-22 | The Rockefeller University | Method for controlling gastrointestinal dysmotility |
US4457907A (en) * | 1982-08-05 | 1984-07-03 | Clear Lake Development Group | Composition and method for protecting a therapeutic drug |
US4518433A (en) * | 1982-11-08 | 1985-05-21 | Fmc Corporation | Enteric coating for pharmaceutical dosage forms |
US4462839A (en) * | 1983-06-16 | 1984-07-31 | Fmc Corporation | Enteric coating for pharmaceutical dosage forms |
US4556552A (en) * | 1983-09-19 | 1985-12-03 | Colorcon, Inc. | Enteric film-coating compositions |
US4615885A (en) * | 1983-11-01 | 1986-10-07 | Terumo Kabushiki Kaisha | Pharmaceutical composition containing urokinase |
US5426112A (en) * | 1984-04-09 | 1995-06-20 | Scully, Scott, Murphy & Presser, P.C. | Growth regulation and related applications of opioid antagonists |
US4670287A (en) * | 1985-07-30 | 1987-06-02 | Washu Kirai Kogyo Kabushiki Kaisha | Method of film-coating hard capsules |
US4719215A (en) * | 1986-03-07 | 1988-01-12 | University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
US4861781A (en) * | 1986-03-07 | 1989-08-29 | The University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
US5597564A (en) * | 1986-08-28 | 1997-01-28 | Enzacor Properties Limited | Method of administering a microgranular preparation to the intestinal region of animals |
US5567423A (en) * | 1986-08-28 | 1996-10-22 | Enzacor Properties, Ltd. | Animal growth promotant |
US4888346A (en) * | 1986-10-07 | 1989-12-19 | Bernard Bihari | Method for the treatment of persons infected with HTLV-III (AIDS) virus |
US4857833A (en) * | 1987-08-27 | 1989-08-15 | Teradyne, Inc. | Diagnosis of faults on circuit board |
US5102887A (en) * | 1989-02-17 | 1992-04-07 | Arch Development Corporation | Method for reducing emesis and nausea induced by the administration of an emesis causing agent |
US4965269A (en) * | 1989-12-20 | 1990-10-23 | Ab Hassle | Therapeutically active chloro substituted benzimidazoles |
US5202159A (en) * | 1990-12-27 | 1993-04-13 | Standard Chemical & Pharmaceutical Corp., Ltd. | Preparation method of microdispersed tablet formulation of spray-dried sodium diclofenac enteric-coated microcapsules |
US5270328A (en) * | 1991-03-29 | 1993-12-14 | Eli Lilly And Company | Peripherally selective piperidine opioid antagonists |
US5159081A (en) * | 1991-03-29 | 1992-10-27 | Eli Lilly And Company | Intermediates of peripherally selective n-carbonyl-3,4,4-trisubstituted piperidine opioid antagonists |
US5629001A (en) * | 1991-06-21 | 1997-05-13 | University Of Cincinnati | Oral administration of therapeutic proteins for treatment of infectious disease |
US5591433A (en) * | 1991-06-21 | 1997-01-07 | University Of Cincinnati | Oral administration of immunologically active biomolecules and other therapeutic proteins |
US5609871A (en) * | 1991-06-21 | 1997-03-11 | Michael; J. Gabriel | Oral administration of therapeutic proteins for treatment of infectious disease |
US5614219A (en) * | 1991-12-05 | 1997-03-25 | Alfatec-Pharma Gmbh | Oral administration form for peptide pharmaceutical substances, in particular insulin |
US5472943A (en) * | 1992-09-21 | 1995-12-05 | Albert Einstein College Of Medicine Of Yeshiva University, | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists |
US5512578A (en) * | 1992-09-21 | 1996-04-30 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists |
USRE36547E (en) * | 1992-09-21 | 2000-02-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists |
US5767125A (en) * | 1992-09-21 | 1998-06-16 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
US6096756A (en) * | 1992-09-21 | 2000-08-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
US5656290A (en) * | 1993-02-26 | 1997-08-12 | The Procter & Gamble Company | Bisacodyl dosage form with multiple enteric polymer coatings for colonic delivery |
US5391372A (en) * | 1993-06-28 | 1995-02-21 | Campbell; Elizabeth | Methods of treating colic and founder in horses |
US5981185A (en) * | 1994-05-05 | 1999-11-09 | Beckman Coulter, Inc. | Oligonucleotide repeat arrays |
US5811451A (en) * | 1994-05-24 | 1998-09-22 | Minoia; Paolo | Pharmaceutical compositions comprising an opiate antagonist and calcium salts, their use for the treatment of endorphin-mediated pathologies |
US5536507A (en) * | 1994-06-24 | 1996-07-16 | Bristol-Myers Squibb Company | Colonic drug delivery system |
US5866154A (en) * | 1994-10-07 | 1999-02-02 | The Dupont Merck Pharmaceutical Company | Stabilized naloxone formulations |
US5614222A (en) * | 1994-10-25 | 1997-03-25 | Kaplan; Milton R. | Stable aqueous drug suspensions and methods for preparation thereof |
US5958452A (en) * | 1994-11-04 | 1999-09-28 | Euro-Celtique, S.A. | Extruded orally administrable opioid formulations |
US6261599B1 (en) * | 1994-11-04 | 2001-07-17 | Euro-Celtique, S.A. | Melt-extruded orally administrable opioid formulations |
US20010036476A1 (en) * | 1994-11-04 | 2001-11-01 | Euro-Celtique S.A. | Melt-extruded orally administrable opioid formulations |
US20010033865A1 (en) * | 1994-11-04 | 2001-10-25 | Benjamin Oshlack | Melt-extrusion multiparticulates |
US5626875A (en) * | 1995-02-01 | 1997-05-06 | Esteve Quimica, S.A. | Stabilized galenic formulations comprising an acid labile benzimidazole compound and its preparation |
US6025154A (en) * | 1995-06-06 | 2000-02-15 | Human Genome Sciences, Inc. | Polynucleotides encoding human G-protein chemokine receptor HDGNR10 |
US5804595A (en) * | 1995-12-05 | 1998-09-08 | Regents Of The University Of Minnesota | Kappa opioid receptor agonists |
US5866164A (en) * | 1996-03-12 | 1999-02-02 | Alza Corporation | Composition and dosage form comprising opioid antagonist |
US6419959B1 (en) * | 1996-12-11 | 2002-07-16 | Klinge Pharma Gmbh | Galenic composition containing opioid antagonists |
US6353004B1 (en) * | 1997-07-14 | 2002-03-05 | Adolor Coporation | Peripherally acting anti-pruritic opiates |
US5972954A (en) * | 1997-11-03 | 1999-10-26 | Arch Development Corporation | Use of methylnaltrexone and related compounds |
US20040167148A1 (en) * | 1997-11-03 | 2004-08-26 | Foss Joseph F. | Oral use of methylnaltrexone and related compounds to treat constipation in chronic opioid users |
US20030065003A1 (en) * | 1997-11-03 | 2003-04-03 | The University Of Chicago | Use of methylnaltrexone and related compounds |
US6559158B1 (en) * | 1997-11-03 | 2003-05-06 | Ur Labs, Inc. | Use of methylnaltrexone and related compounds to treat chronic opioid use side affects |
US20040162307A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnaltrexone and related compounds to induce laxation in chronic opioid users |
US20020028825A1 (en) * | 1997-11-03 | 2002-03-07 | Foss Joseph F. | Use of methylnaltrexone and related compounds |
US6274591B1 (en) * | 1997-11-03 | 2001-08-14 | Joseph F. Foss | Use of methylnaltrexone and related compounds |
US20050048117A1 (en) * | 1997-11-03 | 2005-03-03 | Foss Joseph F. | Use of methylnaltrexone and related compounds |
US6608075B2 (en) * | 1997-11-03 | 2003-08-19 | The University Of Chicago | Use of methylnaltrexone and related compounds |
US20030187010A1 (en) * | 1997-11-03 | 2003-10-02 | Foss Joseph F. | Use of methylnaltrexone and related compounds to treat chronic opioid use side effects |
US20040162306A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnal trexone and related compounds to treat constipation in chronic opioid users |
US20040167147A1 (en) * | 1997-11-03 | 2004-08-26 | Foss Joseph F. | Oral use of methylnaltrexone and related compounds to induce laxation in chronic opioid users |
US6395705B2 (en) * | 1999-03-03 | 2002-05-28 | Albert Einstein College Of Medicine Of Yeshiva University | Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists |
US6194382B1 (en) * | 1999-03-03 | 2001-02-27 | Albert Einstein College Of Medicine Of Yeshiva University | Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists |
US20010018413A1 (en) * | 1999-03-03 | 2001-08-30 | Crain Stanley M. | Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists |
US6455537B1 (en) * | 1999-08-25 | 2002-09-24 | Barrett R. Cooper | Methods for treating opiate intolerance |
US20010047005A1 (en) * | 1999-09-29 | 2001-11-29 | Farrar John J. | Novel methods and compositions involving opioids and antagonists thereof |
US6451806B2 (en) * | 1999-09-29 | 2002-09-17 | Adolor Corporation | Methods and compositions involving opioids and antagonists thereof |
US20010036951A1 (en) * | 1999-11-29 | 2001-11-01 | Farrar John J. | Novel methods for the treatment and prevention of ileus |
US6469030B2 (en) * | 1999-11-29 | 2002-10-22 | Adolor Corporation | Methods for the treatment and prevention of ileus |
US20020064771A1 (en) * | 2000-04-07 | 2002-05-30 | Weidong Zhong | HCV replicase complexes |
US20020188005A1 (en) * | 2000-04-27 | 2002-12-12 | Adolor Corporation | Novel methods for the treatment and prevention of ileus |
US20030026801A1 (en) * | 2000-06-22 | 2003-02-06 | George Weiner | Methods for enhancing antibody-induced cell lysis and treating cancer |
US20030022909A1 (en) * | 2001-06-05 | 2003-01-30 | University Of Chicago | Use of methylnaltrexone to treat immune suppression |
US20030124086A1 (en) * | 2001-10-18 | 2003-07-03 | Shearwater Corporation | Polymer conjugates of opioid antagonists |
US20030191147A1 (en) * | 2002-04-09 | 2003-10-09 | Barry Sherman | Opioid antagonist compositions and dosage forms |
US20040259899A1 (en) * | 2003-04-08 | 2004-12-23 | Sanghvi Suketu P. | Combination therapy for constipation |
US20040266806A1 (en) * | 2003-04-08 | 2004-12-30 | Sanghvi Suketu P. | Pharmaceutical formulation |
US20050004155A1 (en) * | 2003-04-08 | 2005-01-06 | Boyd Thomas A. | Use of methylnaltrexone to treat irritable bowel syndrome |
US20050124885A1 (en) * | 2003-10-29 | 2005-06-09 | Vuesonix Sensors, Inc. | Method and apparatus for determining an ultrasound fluid flow centerline |
US20060205753A1 (en) * | 2005-01-20 | 2006-09-14 | Israel Robert J | Use of methylnaltrexone and related compounds to treat post-operative gastrointestinal dysfunction |
Cited By (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030065003A1 (en) * | 1997-11-03 | 2003-04-03 | The University Of Chicago | Use of methylnaltrexone and related compounds |
US20040162306A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnal trexone and related compounds to treat constipation in chronic opioid users |
US20040162307A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnaltrexone and related compounds to induce laxation in chronic opioid users |
US20040167148A1 (en) * | 1997-11-03 | 2004-08-26 | Foss Joseph F. | Oral use of methylnaltrexone and related compounds to treat constipation in chronic opioid users |
US10376584B2 (en) | 2003-04-08 | 2019-08-13 | Progenics Pharmaceuticals, Inc. | Stable pharmaceutical formulations of methylnaltrexone |
US20040266806A1 (en) * | 2003-04-08 | 2004-12-30 | Sanghvi Suketu P. | Pharmaceutical formulation |
US20050004155A1 (en) * | 2003-04-08 | 2005-01-06 | Boyd Thomas A. | Use of methylnaltrexone to treat irritable bowel syndrome |
US9669096B2 (en) | 2003-04-08 | 2017-06-06 | Progenics Pharmaceuticals, Inc. | Stable pharmaceutical formulations of methylnaltrexone |
US20040259899A1 (en) * | 2003-04-08 | 2004-12-23 | Sanghvi Suketu P. | Combination therapy for constipation |
US8552025B2 (en) | 2003-04-08 | 2013-10-08 | Progenics Pharmaceuticals, Inc. | Stable methylnaltrexone preparation |
US20060205753A1 (en) * | 2005-01-20 | 2006-09-14 | Israel Robert J | Use of methylnaltrexone and related compounds to treat post-operative gastrointestinal dysfunction |
US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
US9717725B2 (en) | 2005-03-07 | 2017-08-01 | The University Of Chicago | Use of opioid antagonists |
US9675602B2 (en) | 2005-03-07 | 2017-06-13 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US9662390B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US9597327B2 (en) | 2005-05-25 | 2017-03-21 | Progenics Pharmaceuticals, Inc. | Synthesis of (R)-N-methylnaltrexone |
US8916581B2 (en) | 2005-05-25 | 2014-12-23 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone |
US20070265293A1 (en) * | 2005-05-25 | 2007-11-15 | Boyd Thomas A | (S)-N-methylnaltrexone |
US7563899B2 (en) | 2005-05-25 | 2009-07-21 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone |
US7674904B2 (en) | 2005-05-25 | 2010-03-09 | Progenics Pharmaceuticals, Inc. | Synthesis of R-N-methylnaltrexone |
US8343992B2 (en) | 2005-05-25 | 2013-01-01 | Progenics Pharmaceuticals, Inc. | Synthesis of R-N-methylnaltrexone |
US8003794B2 (en) | 2005-05-25 | 2011-08-23 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone |
US8772310B2 (en) | 2007-03-29 | 2014-07-08 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US9102680B2 (en) | 2007-03-29 | 2015-08-11 | Wyeth Llc | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
US9879024B2 (en) | 2007-03-29 | 2018-01-30 | Progenics Pharmaceuticals., Inc. | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
US8853232B2 (en) | 2007-03-29 | 2014-10-07 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US8546418B2 (en) | 2007-03-29 | 2013-10-01 | Progenics Pharmaceuticals, Inc. | Peripheral opioid receptor antagonists and uses thereof |
US8338446B2 (en) | 2007-03-29 | 2012-12-25 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US9061024B2 (en) | 2007-10-18 | 2015-06-23 | Aiko Biotechnology | Combination analgesic employing opioid agonist and neutral antagonist |
US8748448B2 (en) | 2007-10-18 | 2014-06-10 | Aiko Biotechnology | Combination analgesic employing opioid agonist and neutral antagonist |
US20090111844A1 (en) * | 2007-10-18 | 2009-04-30 | Aiko Biotechnology | Combination analgesic employing opioid and neutral antagonist |
US8883817B2 (en) | 2007-10-18 | 2014-11-11 | Aiko Biotechnology | Combination analgesic employing opioid and neutral antagonist |
US8916706B2 (en) | 2008-02-06 | 2014-12-23 | Progenics Pharmaceuticals, Inc. | Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone |
US8471022B2 (en) | 2008-02-06 | 2013-06-25 | Progenics Pharmaceuticals, Inc. | Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone |
US9526723B2 (en) | 2008-03-21 | 2016-12-27 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
US8685995B2 (en) | 2008-03-21 | 2014-04-01 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
US10383869B2 (en) | 2008-03-21 | 2019-08-20 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
US8247425B2 (en) | 2008-09-30 | 2012-08-21 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
US9492445B2 (en) | 2008-09-30 | 2016-11-15 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
US8420663B2 (en) | 2008-09-30 | 2013-04-16 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
US9180125B2 (en) | 2008-09-30 | 2015-11-10 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
US9724343B2 (en) | 2008-09-30 | 2017-08-08 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
US8822490B2 (en) | 2008-09-30 | 2014-09-02 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US8455644B2 (en) | 2008-09-30 | 2013-06-04 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
US10307417B2 (en) | 2010-03-11 | 2019-06-04 | Wyeth, Llc | Oral formulations and lipophilic salts of methylnaltrexone |
US10376505B2 (en) | 2010-03-11 | 2019-08-13 | Wyeth, Llc | Oral formulations and lipophilic salts of methylnaltrexone |
US10507206B2 (en) | 2010-03-11 | 2019-12-17 | Wyeth, Llc | Oral formulations and lipophilic salts of methylnaltrexone |
Also Published As
Publication number | Publication date |
---|---|
AU1380299A (en) | 1999-05-24 |
US20090312359A1 (en) | 2009-12-17 |
EP1047426A1 (en) | 2000-11-02 |
EP1047426A4 (en) | 2004-07-14 |
US6608075B2 (en) | 2003-08-19 |
CA2312234A1 (en) | 1999-05-14 |
US20050048117A1 (en) | 2005-03-03 |
AU758416B2 (en) | 2003-03-20 |
CA2312234C (en) | 2005-03-22 |
EP1047426B1 (en) | 2010-05-12 |
US20020028825A1 (en) | 2002-03-07 |
US20030065003A1 (en) | 2003-04-03 |
US6274591B1 (en) | 2001-08-14 |
WO1999022737A1 (en) | 1999-05-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5972954A (en) | Use of methylnaltrexone and related compounds | |
US20040162308A1 (en) | Use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids | |
EP1225897B1 (en) | Composition for treatment of constipation and irritable bowel syndrome | |
US20120190702A1 (en) | Use of methylnaltrexone and related compounds to treat constipation in chronic opioid users | |
US8039456B2 (en) | Method of stimulating the motility of the gastrointestinal system using ipamorelin | |
JP5985824B2 (en) | Opioid receptor antagonist-containing particles and methods of use | |
EP1105134A2 (en) | Nalmefene in combination with opioid analgesics | |
US20090312358A1 (en) | Method for management of diarrhea | |
JP2004512260A (en) | Local anesthesia / opioid preparation and method of use | |
CN110101702A (en) | System and method for treating bad pharmacodynamics response caused by opioid | |
AU782523B2 (en) | Salts and bases of 17-(cyclopropylmethyl)-4,5 alpha-epoxy-6-methylenemorphinan-3,14 diol for optimizing dopamine homeostasis during administration of opioid analgesics | |
US20050011468A1 (en) | Use of methylnaltrexone in treating gastrointestinal dysfunction in equines | |
AU2003204844B2 (en) | Use of methylnaltrexone and related compounds | |
CA2475305A1 (en) | Use of methylnaltrexone in treating gastrointestinal dysfunction in equines | |
WO2009082426A1 (en) | Method of stimulating the motility of the gastrointestinal system using ipamorelin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: PROGENICS PHARMACEUTICALS NEVADA, INC., NEW YORK Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:UR LABS, INC.;REEL/FRAME:017480/0272 Effective date: 20051222 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |