WO2011112816A1 - Oral formulations and lipophilic salts of methylnaltrexone - Google Patents
Oral formulations and lipophilic salts of methylnaltrexone Download PDFInfo
- Publication number
- WO2011112816A1 WO2011112816A1 PCT/US2011/027913 US2011027913W WO2011112816A1 WO 2011112816 A1 WO2011112816 A1 WO 2011112816A1 US 2011027913 W US2011027913 W US 2011027913W WO 2011112816 A1 WO2011112816 A1 WO 2011112816A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- methylnaltrexone
- pharmaceutically acceptable
- acceptable excipient
- certain embodiments
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 337
- 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 class 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 192
- 229960002921 methylnaltrexone Drugs 0.000 title claims abstract description 188
- 238000009472 formulation Methods 0.000 title claims abstract description 163
- 150000003839 salts Chemical class 0.000 title claims abstract description 51
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 105
- 239000007884 disintegrant Substances 0.000 claims description 76
- 238000000034 method Methods 0.000 claims description 72
- 125000001931 aliphatic group Chemical group 0.000 claims description 51
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 claims description 48
- 208000002193 Pain Diseases 0.000 claims description 47
- 230000000694 effects Effects 0.000 claims description 42
- 230000036407 pain Effects 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 38
- 238000011282 treatment Methods 0.000 claims description 38
- 150000002500 ions Chemical class 0.000 claims description 36
- 238000005192 partition Methods 0.000 claims description 36
- 206010010774 Constipation Diseases 0.000 claims description 35
- 239000002738 chelating agent Substances 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 229920006395 saturated elastomer Polymers 0.000 claims description 31
- 238000002560 therapeutic procedure Methods 0.000 claims description 30
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 28
- 239000011230 binding agent Substances 0.000 claims description 27
- 239000000080 wetting agent Substances 0.000 claims description 25
- 230000003211 malignant effect Effects 0.000 claims description 24
- 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 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 239000003963 antioxidant agent Substances 0.000 claims description 22
- 235000006708 antioxidants Nutrition 0.000 claims description 22
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 22
- 125000002015 acyclic group Chemical group 0.000 claims description 21
- 229960002834 methylnaltrexone bromide Drugs 0.000 claims description 21
- 238000004090 dissolution Methods 0.000 claims description 20
- 239000000314 lubricant Substances 0.000 claims description 20
- 230000001684 chronic effect Effects 0.000 claims description 18
- 238000000576 coating method Methods 0.000 claims description 18
- 239000011248 coating agent Substances 0.000 claims description 17
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 17
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 15
- 229960000913 crospovidone Drugs 0.000 claims description 15
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 15
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 15
- 150000001450 anions Chemical class 0.000 claims description 14
- 125000004122 cyclic group Chemical group 0.000 claims description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 13
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 13
- 229920000053 polysorbate 80 Polymers 0.000 claims description 13
- 229940043264 dodecyl sulfate Drugs 0.000 claims description 12
- 230000007160 gastrointestinal dysfunction Effects 0.000 claims description 12
- 230000001965 increasing effect Effects 0.000 claims description 12
- 229960005181 morphine Drugs 0.000 claims description 12
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 12
- 229940068968 polysorbate 80 Drugs 0.000 claims description 12
- 230000003078 antioxidant effect Effects 0.000 claims description 11
- 235000019359 magnesium stearate Nutrition 0.000 claims description 11
- 238000005550 wet granulation Methods 0.000 claims description 11
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 10
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000945 filler Substances 0.000 claims description 10
- 238000005469 granulation Methods 0.000 claims description 10
- 230000003179 granulation Effects 0.000 claims description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 10
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 10
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 10
- 229940083575 sodium dodecyl sulfate Drugs 0.000 claims description 10
- 206010047700 Vomiting Diseases 0.000 claims description 9
- 230000005764 inhibitory process Effects 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 8
- 206010028813 Nausea Diseases 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 230000008693 nausea Effects 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims description 7
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 claims description 6
- 102000003840 Opioid Receptors Human genes 0.000 claims description 6
- 108090000137 Opioid Receptors Proteins 0.000 claims description 6
- 208000003251 Pruritus Diseases 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- 210000005070 sphincter Anatomy 0.000 claims description 6
- 239000000454 talc Substances 0.000 claims description 6
- 229910052623 talc Inorganic materials 0.000 claims description 6
- 235000010323 ascorbic acid Nutrition 0.000 claims description 5
- 229960005070 ascorbic acid Drugs 0.000 claims description 5
- 239000011668 ascorbic acid Substances 0.000 claims description 5
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 5
- 230000008991 intestinal motility Effects 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 206010000060 Abdominal distension Diseases 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical group OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 4
- 206010021518 Impaired gastric emptying Diseases 0.000 claims description 4
- 206010046555 Urinary retention Diseases 0.000 claims description 4
- 239000003945 anionic surfactant Substances 0.000 claims description 4
- 235000010216 calcium carbonate Nutrition 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 206010013954 Dysphoria Diseases 0.000 claims description 3
- 230000030136 gastric emptying Effects 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 208000024330 bloating Diseases 0.000 claims description 2
- 230000005176 gastrointestinal motility Effects 0.000 claims description 2
- 238000003801 milling Methods 0.000 claims description 2
- SHWNNYZBHZIQQV-UHFFFAOYSA-J EDTA monocalcium diisodium salt Chemical group [Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-J 0.000 claims 3
- IFGIYSGOEZJNBE-LHJYHSJWSA-N (3s,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;bromide Chemical compound [Br-].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 IFGIYSGOEZJNBE-LHJYHSJWSA-N 0.000 claims 1
- 206010052405 Gastric hypomotility Diseases 0.000 claims 1
- 208000008454 Hyperhidrosis Diseases 0.000 claims 1
- 238000011010 flushing procedure Methods 0.000 claims 1
- 230000001404 mediated effect Effects 0.000 claims 1
- 230000035900 sweating Effects 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 66
- 229940005483 opioid analgesics Drugs 0.000 description 39
- 235000002639 sodium chloride Nutrition 0.000 description 35
- 239000003814 drug Substances 0.000 description 31
- -1 polycyclic aliphatic hydrocarbons Chemical class 0.000 description 29
- IFGIYSGOEZJNBE-NQMNLMSRSA-N (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;bromide Chemical compound [Br-].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 IFGIYSGOEZJNBE-NQMNLMSRSA-N 0.000 description 28
- 239000002775 capsule Substances 0.000 description 26
- 239000002552 dosage form Substances 0.000 description 22
- 229940079593 drug Drugs 0.000 description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 19
- 230000036470 plasma concentration Effects 0.000 description 19
- 210000002784 stomach Anatomy 0.000 description 19
- 239000013543 active substance Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 15
- 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 14
- 208000030053 Opioid-Induced Constipation Diseases 0.000 description 14
- 210000001035 gastrointestinal tract Anatomy 0.000 description 14
- 229960001797 methadone Drugs 0.000 description 14
- 238000012423 maintenance Methods 0.000 description 13
- 238000010521 absorption reaction Methods 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 12
- 125000000304 alkynyl group Chemical group 0.000 description 12
- 239000007916 tablet composition Substances 0.000 description 12
- 230000002496 gastric effect Effects 0.000 description 11
- 239000008141 laxative Substances 0.000 description 11
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
- NVTRPRFAWJGJAJ-UHFFFAOYSA-L EDTA monocalcium salt Chemical compound [Ca+2].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O NVTRPRFAWJGJAJ-UHFFFAOYSA-L 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 10
- 239000007909 solid dosage form Substances 0.000 description 10
- 241000282472 Canis lupus familiaris Species 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- JTESKNWFQRABFY-UHFFFAOYSA-M sodium;tetracosyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCCCCCCCOS([O-])(=O)=O JTESKNWFQRABFY-UHFFFAOYSA-M 0.000 description 9
- 235000014113 dietary fatty acids Nutrition 0.000 description 8
- 239000002702 enteric coating Substances 0.000 description 8
- 238000009505 enteric coating Methods 0.000 description 8
- 239000000194 fatty acid Substances 0.000 description 8
- 229930195729 fatty acid Natural products 0.000 description 8
- 208000008384 ileus Diseases 0.000 description 8
- JVLBPIPGETUEET-GAAHOAFPSA-O methylnaltrexone Chemical compound C[N+]1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)CC1CC1 JVLBPIPGETUEET-GAAHOAFPSA-O 0.000 description 8
- 238000012216 screening Methods 0.000 description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 7
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 230000002378 acidificating effect Effects 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 238000007726 management method Methods 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 229940032147 starch Drugs 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 6
- 241000283073 Equus caballus Species 0.000 description 6
- 208000014540 Functional gastrointestinal disease Diseases 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000001154 acute effect Effects 0.000 description 6
- 201000007637 bowel dysfunction Diseases 0.000 description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000002354 daily effect Effects 0.000 description 6
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 6
- 238000007453 hemicolectomy Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 6
- 230000002209 hydrophobic effect Effects 0.000 description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 6
- 230000002475 laxative effect Effects 0.000 description 6
- 230000002093 peripheral effect Effects 0.000 description 6
- 230000002980 postoperative effect Effects 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 238000013459 approach Methods 0.000 description 5
- 239000012736 aqueous medium Substances 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 239000001569 carbon dioxide Substances 0.000 description 5
- 238000002648 combination therapy Methods 0.000 description 5
- 238000001125 extrusion Methods 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical group 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 5
- 230000008629 immune suppression Effects 0.000 description 5
- 229940125722 laxative agent Drugs 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 235000021317 phosphate Nutrition 0.000 description 5
- 235000012239 silicon dioxide Nutrition 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- YFSUTJLHUFNCNZ-UHFFFAOYSA-M 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctane-1-sulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F YFSUTJLHUFNCNZ-UHFFFAOYSA-M 0.000 description 4
- 208000004998 Abdominal Pain Diseases 0.000 description 4
- 208000000094 Chronic Pain Diseases 0.000 description 4
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 4
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 4
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- 125000000129 anionic group Chemical group 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000012321 colectomy Methods 0.000 description 4
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 102000051367 mu Opioid Receptors Human genes 0.000 description 4
- 239000000014 opioid analgesic Substances 0.000 description 4
- 229960000482 pethidine Drugs 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 229940082004 sodium laurate Drugs 0.000 description 4
- 159000000000 sodium salts Chemical group 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005563 spheronization Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 230000008673 vomiting Effects 0.000 description 4
- 108020001612 μ-opioid receptors Proteins 0.000 description 4
- WRRSFOZOETZUPG-FFHNEAJVSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;hydrate Chemical compound O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC WRRSFOZOETZUPG-FFHNEAJVSA-N 0.000 description 3
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 3
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 3
- 208000008035 Back Pain Diseases 0.000 description 3
- 208000002881 Colic Diseases 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 229910002651 NO3 Inorganic materials 0.000 description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 3
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 3
- 108010079943 Pentagastrin Proteins 0.000 description 3
- 206010054048 Postoperative ileus Diseases 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 230000003042 antagnostic effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 description 3
- 229960001113 butorphanol Drugs 0.000 description 3
- 125000002091 cationic group Chemical group 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 229960004126 codeine Drugs 0.000 description 3
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Natural products C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 3
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 3
- 229960004193 dextropropoxyphene Drugs 0.000 description 3
- 229960002069 diamorphine Drugs 0.000 description 3
- DSAJRCNSPOSHPL-UHFFFAOYSA-N didodecyl sulfate Chemical compound CCCCCCCCCCCCOS(=O)(=O)OCCCCCCCCCCCC DSAJRCNSPOSHPL-UHFFFAOYSA-N 0.000 description 3
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 description 3
- 229960000920 dihydrocodeine Drugs 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 229960002428 fentanyl Drugs 0.000 description 3
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 3
- 229960000240 hydrocodone Drugs 0.000 description 3
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 description 3
- 150000002433 hydrophilic molecules Chemical class 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 230000004899 motility Effects 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 239000003887 narcotic antagonist Substances 0.000 description 3
- 208000004296 neuralgia Diseases 0.000 description 3
- 208000021722 neuropathic pain Diseases 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 229960002085 oxycodone Drugs 0.000 description 3
- 238000002638 palliative care Methods 0.000 description 3
- ANRIQLNBZQLTFV-DZUOILHNSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 description 3
- 229960000444 pentagastrin Drugs 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 230000035807 sensation Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 238000010254 subcutaneous injection Methods 0.000 description 3
- 239000007929 subcutaneous injection Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 229960004380 tramadol Drugs 0.000 description 3
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 3
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 3
- 230000032258 transport Effects 0.000 description 3
- 238000002211 ultraviolet spectrum Methods 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- LGFMXOTUSSVQJV-NEYUFSEYSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;(4r,4ar,7s,7ar,12bs)-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol;1-[(3,4-dimethoxyphenyl)methyl]-6 Chemical compound Cl.Cl.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 LGFMXOTUSSVQJV-NEYUFSEYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 208000007848 Alcoholism Diseases 0.000 description 2
- KHOITXIGCFIULA-UHFFFAOYSA-N Alophen Chemical compound C1=CC(OC(=O)C)=CC=C1C(C=1N=CC=CC=1)C1=CC=C(OC(C)=O)C=C1 KHOITXIGCFIULA-UHFFFAOYSA-N 0.000 description 2
- 229930003347 Atropine Natural products 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- QZKRHPLGUJDVAR-UHFFFAOYSA-K EDTA trisodium salt Chemical compound [Na+].[Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O QZKRHPLGUJDVAR-UHFFFAOYSA-K 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 208000001640 Fibromyalgia Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- JAQUASYNZVUNQP-USXIJHARSA-N Levorphanol Chemical compound C1C2=CC=C(O)C=C2[C@]23CCN(C)[C@H]1[C@@H]2CCCC3 JAQUASYNZVUNQP-USXIJHARSA-N 0.000 description 2
- 208000021642 Muscular disease Diseases 0.000 description 2
- 201000009623 Myopathy Diseases 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical compound C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 2
- 206010031149 Osteitis Diseases 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 description 2
- 208000006735 Periostitis Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 208000017442 Retinal disease Diseases 0.000 description 2
- 206010038923 Retinopathy Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 238000012084 abdominal surgery Methods 0.000 description 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 201000007930 alcohol dependence Diseases 0.000 description 2
- 229960001391 alfentanil Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229940087168 alpha tocopherol Drugs 0.000 description 2
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003466 anti-cipated effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 2
- 229960000396 atropine Drugs 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229960000503 bisacodyl Drugs 0.000 description 2
- 208000018339 bone inflammation disease Diseases 0.000 description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 239000007963 capsule composition Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical compound [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 description 2
- 208000037976 chronic inflammation Diseases 0.000 description 2
- 230000006020 chronic inflammation Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000011443 conventional therapy Methods 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 229960003461 dezocine Drugs 0.000 description 2
- VTMVHDZWSFQSQP-VBNZEHGJSA-N dezocine Chemical compound C1CCCC[C@H]2CC3=CC=C(O)C=C3[C@]1(C)[C@H]2N VTMVHDZWSFQSQP-VBNZEHGJSA-N 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 229940018602 docusate Drugs 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229940113960 edetate calcium Drugs 0.000 description 2
- 229940095629 edetate calcium disodium Drugs 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- MIHVYISIUZTFER-UHFFFAOYSA-N heptyl hydrogen sulfate Chemical compound CCCCCCCOS(O)(=O)=O MIHVYISIUZTFER-UHFFFAOYSA-N 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 229960001410 hydromorphone Drugs 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- 229960003406 levorphanol Drugs 0.000 description 2
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 2
- 229960001571 loperamide Drugs 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000002623 mu opiate receptor antagonist Substances 0.000 description 2
- 229960000805 nalbuphine Drugs 0.000 description 2
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 description 2
- 230000003533 narcotic effect Effects 0.000 description 2
- HNDXBGYRMHRUFN-CIVUWBIHSA-N nicomorphine Chemical compound O([C@H]1C=C[C@H]2[C@H]3CC=4C5=C(C(=CC=4)OC(=O)C=4C=NC=CC=4)O[C@@H]1[C@]52CCN3C)C(=O)C1=CC=CN=C1 HNDXBGYRMHRUFN-CIVUWBIHSA-N 0.000 description 2
- 229960004300 nicomorphine Drugs 0.000 description 2
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229960005118 oxymorphone Drugs 0.000 description 2
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229960003294 papaveretum Drugs 0.000 description 2
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 2
- 229960005301 pentazocine Drugs 0.000 description 2
- 229960003330 pentetic acid Drugs 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229950008882 polysorbate Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- ZBAFFZBKCMWUHM-UHFFFAOYSA-N propiram Chemical compound C=1C=CC=NC=1N(C(=O)CC)C(C)CN1CCCCC1 ZBAFFZBKCMWUHM-UHFFFAOYSA-N 0.000 description 2
- 229950003779 propiram Drugs 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000002271 resection Methods 0.000 description 2
- IPQVTOJGNYVQEO-KGFNBKMBSA-N sennoside A Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=CC2=C1C(=O)C1=C(O)C=C(C(O)=O)C=C1[C@@H]2[C@H]1C2=CC(C(O)=O)=CC(O)=C2C(=O)C2=C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C=CC=C21 IPQVTOJGNYVQEO-KGFNBKMBSA-N 0.000 description 2
- 229940063651 senokot Drugs 0.000 description 2
- 208000007056 sickle cell anemia Diseases 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- REFMEZARFCPESH-UHFFFAOYSA-M sodium;heptane-1-sulfonate Chemical compound [Na+].CCCCCCCS([O-])(=O)=O REFMEZARFCPESH-UHFFFAOYSA-M 0.000 description 2
- GRNNMEITWDFPOL-UHFFFAOYSA-M sodium;heptyl sulfate Chemical compound [Na+].CCCCCCCOS([O-])(=O)=O GRNNMEITWDFPOL-UHFFFAOYSA-M 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 2
- 229960004739 sufentanil Drugs 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229960000984 tocofersolan Drugs 0.000 description 2
- 229940042585 tocopherol acetate Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 239000002076 α-tocopherol Substances 0.000 description 2
- WGVKWNUPNGFDFJ-DQCZWYHMSA-N β-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C WGVKWNUPNGFDFJ-DQCZWYHMSA-N 0.000 description 2
- GZIFEOYASATJEH-VHFRWLAGSA-N δ-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-VHFRWLAGSA-N 0.000 description 2
- JKQXZKUSFCKOGQ-JLGXGRJMSA-N (3R,3'R)-beta,beta-carotene-3,3'-diol Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-JLGXGRJMSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- URDCARMUOSMFFI-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(2-hydroxyethyl)amino]acetic acid Chemical compound OCCN(CC(O)=O)CCN(CC(O)=O)CC(O)=O URDCARMUOSMFFI-UHFFFAOYSA-N 0.000 description 1
- YXSJRZBKSLLIOM-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O YXSJRZBKSLLIOM-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- LORDFXWUHHSAQU-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid [2-(dimethylamino)-2-phenylbutyl] ester Chemical compound C=1C=CC=CC=1C(CC)(N(C)C)COC(=O)C1=CC(OC)=C(OC)C(OC)=C1 LORDFXWUHHSAQU-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- LXAHHHIGZXPRKQ-UHFFFAOYSA-N 5-fluoro-2-methylpyridine Chemical group CC1=CC=C(F)C=N1 LXAHHHIGZXPRKQ-UHFFFAOYSA-N 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010004663 Biliary colic Diseases 0.000 description 1
- ZTHQBROSBNNGPU-UHFFFAOYSA-N Butyl hydrogen sulfate Chemical compound CCCCOS(O)(=O)=O ZTHQBROSBNNGPU-UHFFFAOYSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 102000010970 Connexin Human genes 0.000 description 1
- 108050001175 Connexin Proteins 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- GZIFEOYASATJEH-UHFFFAOYSA-N D-delta tocopherol Natural products OC1=CC(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-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
- OGDVEMNWJVYAJL-LEPYJNQMSA-N Ethyl morphine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OCC OGDVEMNWJVYAJL-LEPYJNQMSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- OGDVEMNWJVYAJL-UHFFFAOYSA-N Ethylmorphine Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OCC OGDVEMNWJVYAJL-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- OZYUPQUCAUTOBP-QXAKKESOSA-N Levallorphan Chemical compound C([C@H]12)CCC[C@@]11CCN(CC=C)[C@@H]2CC2=CC=C(O)C=C21 OZYUPQUCAUTOBP-QXAKKESOSA-N 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 102000001621 Mucoproteins Human genes 0.000 description 1
- 108010093825 Mucoproteins Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 description 1
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Nalorphine Chemical compound C([C@@H](N(CC1)CC=C)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 UIQMVEYFGZJHCZ-SSTWWWIQSA-N 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- HLMSIZPQBSYUNL-IPOQPSJVSA-N Noroxymorphone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4 HLMSIZPQBSYUNL-IPOQPSJVSA-N 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 229940049937 Pgp inhibitor Drugs 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- ZTVQQQVZCWLTDF-UHFFFAOYSA-N Remifentanil Chemical compound C1CN(CCC(=O)OC)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 ZTVQQQVZCWLTDF-UHFFFAOYSA-N 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 239000004902 Softening Agent Substances 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- HVWGGPRWKSHASF-UHFFFAOYSA-N Sulfuric acid, monooctadecyl ester Chemical compound CCCCCCCCCCCCCCCCCCOS(O)(=O)=O HVWGGPRWKSHASF-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- JKQXZKUSFCKOGQ-LQFQNGICSA-N Z-zeaxanthin Natural products C([C@H](O)CC=1C)C(C)(C)C=1C=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-LQFQNGICSA-N 0.000 description 1
- QOPRSMDTRDMBNK-RNUUUQFGSA-N Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCC(O)C1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C QOPRSMDTRDMBNK-RNUUUQFGSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009056 active transport Effects 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 238000011374 additional therapy Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- JKQXZKUSFCKOGQ-LOFNIBRQSA-N all-trans-Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C JKQXZKUSFCKOGQ-LOFNIBRQSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229960002512 anileridine Drugs 0.000 description 1
- LKYQLAWMNBFNJT-UHFFFAOYSA-N anileridine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC1=CC=C(N)C=C1 LKYQLAWMNBFNJT-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229950002202 asimadoline Drugs 0.000 description 1
- JHLHNYVMZCADTC-LOSJGSFVSA-N asimadoline Chemical compound C([C@@H](N(C)C(=O)C(C=1C=CC=CC=1)C=1C=CC=CC=1)C=1C=CC=CC=1)N1CC[C@H](O)C1 JHLHNYVMZCADTC-LOSJGSFVSA-N 0.000 description 1
- 125000002511 behenyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 229940066595 beta tocopherol Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- ZDXGFIXMPOUDFF-XLIONFOSSA-N bremazocine Chemical compound C([C@]1(C2=CC(O)=CC=C2C[C@@H]2C1(C)C)CC)CN2CC1(O)CC1 ZDXGFIXMPOUDFF-XLIONFOSSA-N 0.000 description 1
- 229950008841 bremazocine Drugs 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- JCQNARRMQCMKAN-UHFFFAOYSA-J calcium;disodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate;dihydrate Chemical compound O.O.[Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O JCQNARRMQCMKAN-UHFFFAOYSA-J 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- OCHFNTLZOZPXFE-JEDNCBNOSA-N carbonic acid;(2s)-2,6-diaminohexanoic acid Chemical compound OC(O)=O.NCCCC[C@H](N)C(O)=O OCHFNTLZOZPXFE-JEDNCBNOSA-N 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 235000021466 carotenoid Nutrition 0.000 description 1
- 150000001747 carotenoids Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 125000003901 ceryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- CSMFSDCPJHNZRY-UHFFFAOYSA-M decyl sulfate Chemical compound CCCCCCCCCCOS([O-])(=O)=O CSMFSDCPJHNZRY-UHFFFAOYSA-M 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 235000010389 delta-tocopherol Nutrition 0.000 description 1
- WDEFBBTXULIOBB-WBVHZDCISA-N dextilidine Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C WDEFBBTXULIOBB-WBVHZDCISA-N 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- KYQODXQIAJFKPH-UHFFFAOYSA-N diazanium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [NH4+].[NH4+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O KYQODXQIAJFKPH-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 229940099212 dilaudid Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 description 1
- 229960004192 diphenoxylate Drugs 0.000 description 1
- QLBHNVFOQLIYTH-UHFFFAOYSA-L dipotassium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [K+].[K+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O QLBHNVFOQLIYTH-UHFFFAOYSA-L 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- RRPFCKLVOUENJB-UHFFFAOYSA-L disodium;2-aminoacetic acid;carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O.NCC(O)=O RRPFCKLVOUENJB-UHFFFAOYSA-L 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- LGFIRJFZBSYRDL-UHFFFAOYSA-N docosyl hydrogen sulfate Chemical compound CCCCCCCCCCCCCCCCCCCCCCOS(O)(=O)=O LGFIRJFZBSYRDL-UHFFFAOYSA-N 0.000 description 1
- 229960000878 docusate sodium Drugs 0.000 description 1
- 238000011833 dog model Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 229940058180 edetate dipotassium anhydrous Drugs 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960004578 ethylmorphine Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- MVKIWCDXKCUDEH-QFIPXVFZSA-N fedotozine Chemical compound C([C@](CC)(N(C)C)C=1C=CC=CC=1)OCC1=CC(OC)=C(OC)C(OC)=C1 MVKIWCDXKCUDEH-QFIPXVFZSA-N 0.000 description 1
- 229950008449 fedotozine Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000012395 formulation development Methods 0.000 description 1
- 235000010382 gamma-tocopherol Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 210000003976 gap junction Anatomy 0.000 description 1
- 230000030135 gastric motility Effects 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 230000036397 gastrointestinal physiology Effects 0.000 description 1
- 208000001288 gastroparesis Diseases 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000014617 hemorrhoid Diseases 0.000 description 1
- KGIBGHABTNQVJX-UHFFFAOYSA-N heptadecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCCCCCCOS(O)(=O)=O KGIBGHABTNQVJX-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004405 heteroalkoxy group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000005368 heteroarylthio group Chemical group 0.000 description 1
- UTPTVVAYSIVPFA-UHFFFAOYSA-M hexacosyl sulfate Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCOS([O-])(=O)=O UTPTVVAYSIVPFA-UHFFFAOYSA-M 0.000 description 1
- LPTIRUACFKQDHZ-UHFFFAOYSA-N hexadecyl sulfate;hydron Chemical compound CCCCCCCCCCCCCCCCOS(O)(=O)=O LPTIRUACFKQDHZ-UHFFFAOYSA-N 0.000 description 1
- IDUWTCGPAPTSFB-UHFFFAOYSA-N hexyl hydrogen sulfate Chemical compound CCCCCCOS(O)(=O)=O IDUWTCGPAPTSFB-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000009802 hysterectomy Methods 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003871 intestinal function Effects 0.000 description 1
- 210000002011 intestinal secretion Anatomy 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- XBMIVRRWGCYBTQ-AVRDEDQJSA-N levacetylmethadol Chemical compound C=1C=CC=CC=1C(C[C@H](C)N(C)C)([C@@H](OC(C)=O)CC)C1=CC=CC=C1 XBMIVRRWGCYBTQ-AVRDEDQJSA-N 0.000 description 1
- 229960000263 levallorphan Drugs 0.000 description 1
- 125000002463 lignoceryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000012680 lutein Nutrition 0.000 description 1
- 229960005375 lutein Drugs 0.000 description 1
- 239000001656 lutein Substances 0.000 description 1
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 description 1
- ORAKUVXRZWMARG-WZLJTJAWSA-N lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C ORAKUVXRZWMARG-WZLJTJAWSA-N 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 229940021770 methylnaltrexone bromide 150 mg Drugs 0.000 description 1
- 229940026048 methylnaltrexone injection Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 125000002819 montanyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000001802 myricyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- UZZYXUGECOQHPU-UHFFFAOYSA-M n-octyl sulfate Chemical compound CCCCCCCCOS([O-])(=O)=O UZZYXUGECOQHPU-UHFFFAOYSA-M 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960005297 nalmefene Drugs 0.000 description 1
- 229960000938 nalorphine Drugs 0.000 description 1
- 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 1
- 229960004127 naloxone Drugs 0.000 description 1
- 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 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 1
- 230000003880 negative regulation of appetite Effects 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KETHQOOVMIVLCH-UHFFFAOYSA-M nonyl sulfate(1-) Chemical compound CCCCCCCCCOS([O-])(=O)=O KETHQOOVMIVLCH-UHFFFAOYSA-M 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- RLCFWHWTFGYKGQ-UHFFFAOYSA-N octacosyl hydrogen sulfate Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCOS(O)(=O)=O RLCFWHWTFGYKGQ-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- HGASFNYMVGEKTF-UHFFFAOYSA-N octan-1-ol;hydrate Chemical compound O.CCCCCCCCO HGASFNYMVGEKTF-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940067739 octyl sulfate Drugs 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229940105606 oxycontin Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- COUMKTRLCGRAAA-UHFFFAOYSA-M pentadecyl sulfate Chemical compound CCCCCCCCCCCCCCCOS([O-])(=O)=O COUMKTRLCGRAAA-UHFFFAOYSA-M 0.000 description 1
- ZIRHAFGGEBQZKX-UHFFFAOYSA-N pentyl hydrogen sulfate Chemical compound CCCCCOS(O)(=O)=O ZIRHAFGGEBQZKX-UHFFFAOYSA-N 0.000 description 1
- 229940079358 peripheral opioid receptor antagonist Drugs 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000001141 propulsive effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960003394 remifentanil Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 239000008147 saline laxative Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- BWAUQTFFVCLSOS-UHFFFAOYSA-N sodiosodium hydrate Chemical compound O.[Na].[Na] BWAUQTFFVCLSOS-UHFFFAOYSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- URLJMZWTXZTZRR-UHFFFAOYSA-N sodium myristyl sulfate Chemical compound CCCCCCCCCCCCCCOS(O)(=O)=O URLJMZWTXZTZRR-UHFFFAOYSA-N 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229910000031 sodium sesquicarbonate Inorganic materials 0.000 description 1
- 235000018341 sodium sesquicarbonate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229960000776 sodium tetradecyl sulfate Drugs 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 210000004514 sphincter of oddi Anatomy 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- CSMFSDCPJHNZRY-UHFFFAOYSA-N sulfuric acid monodecyl ester Natural products CCCCCCCCCCOS(O)(=O)=O CSMFSDCPJHNZRY-UHFFFAOYSA-N 0.000 description 1
- UZZYXUGECOQHPU-UHFFFAOYSA-N sulfuric acid monooctyl ester Natural products CCCCCCCCOS(O)(=O)=O UZZYXUGECOQHPU-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- OXYOPNBYVLUFAF-UHFFFAOYSA-M tetracosyl sulfate Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCOS([O-])(=O)=O OXYOPNBYVLUFAF-UHFFFAOYSA-M 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000000779 thoracic wall Anatomy 0.000 description 1
- 229960001402 tilidine Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- NDAYWZNRRYDNNQ-UHFFFAOYSA-N triacontyl hydrogen sulfate Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCOS(O)(=O)=O NDAYWZNRRYDNNQ-UHFFFAOYSA-N 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QTUIJRIDZOSXHJ-UHFFFAOYSA-N tridecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCCOS(O)(=O)=O QTUIJRIDZOSXHJ-UHFFFAOYSA-N 0.000 description 1
- 229960005345 trimebutine Drugs 0.000 description 1
- FYZXEMANQYHCFX-UHFFFAOYSA-K tripotassium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [K+].[K+].[K+].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O FYZXEMANQYHCFX-UHFFFAOYSA-K 0.000 description 1
- 229940048198 trisodium hedta Drugs 0.000 description 1
- WHNXAQZPEBNFBC-UHFFFAOYSA-K trisodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(2-hydroxyethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].OCCN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O WHNXAQZPEBNFBC-UHFFFAOYSA-K 0.000 description 1
- WCTAGTRAWPDFQO-UHFFFAOYSA-K trisodium;hydrogen carbonate;carbonate Chemical compound [Na+].[Na+].[Na+].OC([O-])=O.[O-]C([O-])=O WCTAGTRAWPDFQO-UHFFFAOYSA-K 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- OBYIEPMKXIBQEV-UHFFFAOYSA-N undecyl hydrogen sulfate Chemical compound CCCCCCCCCCCOS(O)(=O)=O OBYIEPMKXIBQEV-UHFFFAOYSA-N 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
- 235000010930 zeaxanthin Nutrition 0.000 description 1
- 229940043269 zeaxanthin Drugs 0.000 description 1
- 239000001775 zeaxanthin Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 235000007680 β-tocopherol Nutrition 0.000 description 1
- 239000011590 β-tocopherol Substances 0.000 description 1
- 239000002478 γ-tocopherol Substances 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
- QUEDXNHFTDJVIY-DQCZWYHMSA-N γ-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-DQCZWYHMSA-N 0.000 description 1
- 239000002446 δ-tocopherol Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- 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
-
- 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
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- 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
- A61P1/10—Laxatives
-
- 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
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
Definitions
- Opioids are widely used in treating patients with pain. Such patients include those with advanced cancers and other terminal diseases and also those with chronic non-malignant pain and acute non-malignant pain.
- Opioids are narcotic medications that activate opioid receptors located in the central nervous system to relieve pain. Opioids, however, also react with receptors outside of the central nervous system, resulting in side effects including constipation, nausea, vomiting, urinary retention, and severe itching. Notable are the effects of opioids in the gastrointestinal (GI) tract where these drugs inhibit gastric emptying and peristalsis in the intestines, thereby decreasing the rate of intestinal transit and producing constipation.
- GI gastrointestinal
- the use of opioids in treating pain is often limited due to these undesired side effects, which can be debilitating and often cause patients to refuse the use of opioid analgesics.
- GI gastrointestinal
- an abnormal physiological level of endogenous opioids and/or receptor activity may also lead to bowel dysfunction.
- patients who have undergone surgical procedures, especially surgery of the abdomen often suffer from a particular bowel dysfunction, termed post-operative ileus, that may be caused by fluctuations in natural opioid levels.
- post-operative ileus a particular bowel dysfunction
- women who have recently given birth commonly suffer from post partum ileus, which may be caused by similar fluctuations in natural opioid levels as a result of birthing stress.
- Gastrointestinal dysfunction associated with post-operative or post-partum ileus can typically last for 3 to 5 days, with some severe cases lasting more than a week.
- opioids to a patient after surgery to treat pain, which is now an almost universal practice, may exacerbate bowel dysfunction, thereby delaying recovery of normal bowel function, prolonging hospital stays, and increasing medical care costs.
- Opioid receptor antagonists such as naloxone, naltrexone, and nalmefene, have been studied as a means of antagonizing the undesirable peripheral side effects of opioids.
- these agents not only act on peripheral opioid receptors but also on opioid receptors in the central nervous system, sometimes reversing the beneficial and desired analgesic effects of opioids or causing symptoms of opioid withdrawal.
- Preferable approaches for use in controlling opioid-induced side effects include administration of peripheral acting opioid receptor antagonists that do not readily cross the blood-brain barrier.
- peripheral ⁇ opioid receptor antagonist methylnaltrexone has been studied since the late 1970s. It has been used in patients to reduce opioid-induced side effects such as constipation, pruritus, nausea, and urinary retention(see, e.g., U.S.
- the dosage form of methylnaltrexone used most often in these studies has been a solution of methylnaltrexone for intravenous injection.
- Methylnaltrexone subcutaneous injection was explored and has been clinically approved in the United States to treat opioid-induced constipation in patients with advanced medical illness who are receiving palliative care.
- the subcutaneous injection dose found to be effective was 0.15 or 0.3 mg/kg. This dose did not induce "immediate” laxation, but rather induced laxation within 4 hours in a significant number of patients treated.
- Aattempts have been made to make an oral dosage form of certain opioid antagonists, including methylnaltrexone.
- an oral dosage form is constructed so as to release certain compounds "over the whole gastrointestinal tract.” According to the '959 patent, opioid antagonists are not always suitable for
- opioid-induced constipation was believed to result from the direct and local effects of opioids on receptors across the entire gastrointestinal tract.
- the '959 patent suggests dosing certain opioid antagonists, including
- methylnaltrexone in a controlled-release dosage form, thereby delivering these antagonists at acceptable doses locally across the entire gastrointestinal tract. Data respecting methylnaltrexone specifically, however, was not reported.
- Capsules containing enterically coated spheroids of a formulation of methylnaltrexone were tested in patients suffering from opioid-induced constipation.
- the patients in this study were receiving opioids for non-malignant pain. (They were not chronic methadone maintenance patients.)
- Patients were administered 300 mg or mg/kg, respectively), which were doses within the ranges reported to be effective in the '591 patent.
- the average peak plasma level of methylnaltrexone resulting from the 300 mg dose was less than 10 ng/mL and the average peak plasma level of methylnaltrexone resulting from the 450 mg dose was less than 20 ng/mL.
- Tablets containing spheroids of a formulation of methylnaltrexone, without an enteric coating were tested in patients receiving opioids for non-malignant pain. Doses of 150 mg, 300 mg, 450 mg, and 600 mg were tested. These doses resulted in average peak plasma levels of between about 7 and 40 ng/ml, similar to the peak plasma levels achieved with the uncoated capsules. These tablets without an enteric coating showed activity with statistical significance at one dose, but did not consistently induce laxation across all doses. That there was activity with a tablet but not a capsule would have been surprising to one of ordinary skill in the art based on the information available in the prior art.
- the prior art did not make clear what would be required to create an oral methylnaltrexone effective for treating opioid induced constipation in patients receiving opioids for non-malignant pain.
- the prior art did not make clear whether achieving laxation depended on the overall plasma levels of the drug, the peak plasma levels of the drug, or the timing of achieving the plasma levels of the drug.
- the prior art did not make clear formulation methodology for predictably controlling the pharmacokinetics of oral methylnaltrexone, other than via dose alterations and coatings. Because of the desire to further improve the performance of the non-enteric coated tablet, further formulation development studies were undertaken.
- Methylnaltrexone is hydrophilic and quite soluble in aqueous solutions.
- methylnaltrexone causes methylnaltrexone to be poorly absorbed in the gastrointestinal tract. In general, less than about 5% of methylnaltrexone is absorbed into the bloodstream when delivered orally.
- Ion pairing has been investigated to reduce the apparent ionic charge on a molecule.
- the interaction between a hydrophilic, charged molecule and an amphiphilic counter ion can make the hydrophilic molecule sufficiently lipophilic to enable (or increase) solubility of the molecule in a non-aqueous solvent.
- ion pairing increases partitioning of the molecule into an organic phase, much of the work in this area has been directed towards extraction of ionic molecules into organic solvents, separation of molecules by chromatography, reaction of hydrophilic molecules in organic solvents, and so forth.
- drug absorption most of the work has been limited to delivery of a drug to the skin, eyes, nasal cavity, or vaginal cavity (see, e.g., J. Hadgraft, "Skin Deep,” European Journal of Pharmaceutics and
- methylnaltrexone and anions One such ion pair was formed between methylnaltrexone and dodecyl (lauryl) sulfate.
- amphiphilic pharmaceutically acceptable excipient that forms an ion pair or salt with methylnaltrexone when dissolved in solution, in a solid dosage form together with a rapid-acting disintegrant (e.g. , a carbon dioxide- generating disintegrant) was effective to induce laxation.
- a rapid-acting disintegrant e.g. , a carbon dioxide- generating disintegrant
- the present invention relates to ion pairs of methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient, methods for forming such ion pairs, methods for selecting such ion pairs, use of such ion pairs, compositions including such ion pairs, solid oral formulations of methylnaltrexone and an amphiphilic
- compositions and formulations thereof including formulations containing a rapid-acting disintegrant (e.g. , effervescent or carbon dioxide-producing disintegrant), as well as methods of using such compositions and formulations thereof.
- a rapid-acting disintegrant e.g. , effervescent or carbon dioxide-producing disintegrant
- the present invention provides a salt of methylnaltrexone of the formula:
- methylnaltrexone is the cation of the salt, and A " is an anion of an amphiphilic pharmaceutically acceptable excipient.
- the methylnaltrexone is (R)-N-methylnaltrexone as shown in the formula above.
- pharmaceutically acceptable excipient is acidic.
- the amine salt of the formula (1) is acidic.
- amphiphilic pharmaceutically acceptable excipient has a pK a of about 3 or less.
- the amphiphilic pharmaceutically acceptable excipient may include a sulfate, sulfonate, nitrate, nitrite, phosphate, or phosphonate moiety.
- the pharmaceutically acceptable excipient comprises an (-OSO 3 ) group.
- such chemical functional groups with pK a values at or below about 3 allow for the ion pair to remain bound together at the acidic pH found in the stomach. This is because the conjugate base of the excipient remains deprotonated and negatively charged, and methylnaltrexone is quaternary amine that is positively charged.
- the pharmaceutically acceptable excipient also includes a hydrophobic portion.
- the hydrophobic portion is a branched or unbranched, saturated or unsaturated, cyclic or acyclic C4-30 aliphatic chain, which may be optionally substituted.
- the pharmaceutically acceptable excipient is, for example, a saturated or unsaturated, branched or unbranched, cyclic or acyclic C 4 _3o aliphatic group that is optionally substituted. In some embodiments it is a saturated, unbranched, acyclic, unsubstituted C 4 _3o alkyl group.
- it is a saturated, unbranched, acyclic, unsubstituted C 7-1 5 alkyl group. In some embodiments it is a C 12 w-alkyl group. In some embodiments, it is dodecyl (lauryl) sulfate.
- the aliphatic chain makes the excipients amphiphilic and surface active in nature, which helps transport of the ion pair through the unstirred diffusion layer lining the inner surface of the GI tract, thus increasing availability of methylnaltrexone to the GI membrane for local effects on receptor sites and/or absorption across lipophilic barriers such as the lining of the GI tract, e.g., the stomach and upper duodenum.
- the aliphatic chain makes the excipients amphiphilic and surface active in nature, which helps transport of the ion pair through the unstirred diffusion layer lining the inner surface of the GI tract, thus increasing availability of methylnaltrexone to the GI membrane for local effects on receptor sites and/or absorption across lipophilic barriers such as the lining of the GI tract, e.g., the stomach and upper duodenum.
- the aliphatic chain makes the excipients amphiphilic and surface active in nature, which helps transport of the ion pair through the un
- methylnaltrexone ion pair is a salt that is solid at room temperature.
- composition is provided.
- the composition is the salt or ion pair described above.
- the salt or ion pair may comprise at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 50%, at least 75%, at least 90%, at least 95% or at least 99% of the methylnaltrexone in the composition.
- the composition is a pharmaceutical composition.
- a composition for oral administration is provided.
- the composition includes methylnaltrexone and an amphiphilic
- the methylnaltrexone when dissolved in solution, thereby increasing the octanol/water partition coefficient of methylnaltrexone.
- the methylnaltrexone When the composition is dissolved in an aqueous solution, the methylnaltrexone has an apparent octanol/water partition coefficient of at least 0.25 in acidic conditions, and in some embodiments at a pH between 1 and 4. A pH of between 1 and 4 is used to simulate the physiological conditions of the stomach.
- the apparent octanol/water partition coefficient of methylnaltrexone is at least 0.5, 1.0, 5.0, 10, 20, or 30 at a pH between 1 and 4.
- the pharmaceutically acceptable excipient has a pKa of about 3 or less so that the conjugate base of the amphiphilic pharmaceutically acceptable excipient remains deprotonated and will be noncovalently bound to the cationic methylnaltrexone under physiological conditions found in the stomach (i.e., a solution at acidic pH).
- the composition also may include a rapid-acting disintegrant, wherein the composition dissolves within about 15 minutes in the stomach.
- a rapid-acting disintegrant wherein the composition dissolves within about 15 minutes in the stomach.
- at least 50% of the methylnaltrexone in the composition is dissolved in 15 minutes.
- at least 75%, 80%, 85%, 90%, 95%, or even 99% of the methylnaltrexone in the composition is dissolved in 15 minutes.
- the methylnaltrexone in the composition can dissolve within 10 minutes or even within 5 minutes.
- the dissolution of the composition in the stomach may be simulated by in vitro studies in a dissolution apparatus with paddles at 100 rpm in 900 ml 0.1 N HC1 at 37 °C.
- the disintegrant is a fast-acting disintegrant.
- the composition has a dissolution profile substantially similar to the one depicted in Figure 2.
- the disintegrant is an effervescent disintegrant (i.e., one that evolves a gas). By creating gas bubbles within the composition, the composition is more readily broken down thereby releasing methylnaltrexone. Effervescent disintegrants were found to be particularly useful in aiding in the dissolution tablets containing methylnaltrexone and dodecyl sulfate.
- the disintegrant is an effervescent disintegrant that is capable of generating carbon dioxide when the composition is contacted with an aqueous medium.
- the effervescent disintegrant can be a bicarbonate or carbonate. In any of the embodiments, the effervescent disintegrant can be sodium bicarbonate.
- a method of preparing a methylnaltrexone formulation includes combining a solid pharmaceutically acceptable salt of methylnaltrexone (that is not an ion pair of methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient), such as methylnaltrexone bromide or iodide, with a solid pharmaceutically acceptable salt of the amphiphilic excipient (that is not the ion pair of methylnaltrexone and the amphiphilic pharmaceutically acceptable excipient) to form a mixture.
- the mixture may be wet granulated.
- a wet granulation of methylnaltrexone or a pharmaceutically acceptable salt thereof, an amphiphilic pharmaceutically acceptable excipient, at least one disintegrant, at least one binder, at least one chelating agent, at least one wetting agent, and optionally at least one filler is prepared and formed into a solid dosage form.
- a wet granulation is formed by dry blending the methylnaltrexone or a pharmaceutically acceptable salt thereof, a binder, an amphiphilic pharmaceutically acceptable excipient, and optionally a disintegrant; and granulating the dry blend with a solution of a chelating agent and/or a wetting agent to form a wet granulation.
- the wet granulation may be dried and milled, and the milled dried granulation blended with an additional disintegrant (e.g. , sodium bicarbonate) and optionally a lubricant and/or a glidant before a solid dosage form is prepared.
- an additional disintegrant e.g. , sodium bicarbonate
- a lubricant and/or a glidant optionally a lubricant and/or a glidant before a solid dosage form is prepared.
- the present invention provides compositions for oral administration comprising a salt of the cation methylnaltrexone and the anion of the amphiphilic pharmaceutically acceptable excipient (e.g. , dodecyl sulfate).
- the compositions for oral administration are tablet formulations.
- the compositions for oral administration are capsule formulations.
- formulations for oral administration comprise
- methylnaltrexone an amphiphilic pharmaceutically acceptable excipient as described above, and a disintegrant, and further optionally comprise one or more other
- oral formulations are tablet formulations.
- the present invention provides a unit dosage form comprising a formulation or composition described herein.
- the present invention also provides methods of oral administration of methylnaltrexone in any context in which such administration is desirable.
- formulations are useful for preventing, treating, or reducing the severity of side effects resulting from administration of opioids, including inhibition of intestinal motility or gastrointestinal dysfunction (e.g. , constipation, GI sphincter constriction), nausea, emesis, and pruritus.
- compositions and formulations are useful for administration to patients receiving acute opioid treatment (e.g., patients suffering from post operative ileus or gastrointestinal dysfunction resulting from acute opioid administration). Such formulations are also useful for administration to subjects receiving chronic opioid administration (e.g. , terminally ill patients receiving opioid therapy (e.g., an AIDS patient, a cancer patient, a patient with cardiovascular disease); subjects receiving chronic opioid therapy for pain management; subjects receiving opioid therapy for maintenance of opioid withdrawal).
- the subject is undergoing opioid therapy for chronic pain management.
- the subject is undergoing opioid therapy for acute pain management.
- the pain is non-malignant pain (e.g., back pain, neuropathic pain, pain associated with
- the pain is chronic non- malignant pain. In certain embodiments, the pain is malignant pain.
- the present invention provides a method comprising the step of reducing one or more side effects of opioid therapy in a subject receiving opioid treatment comprising administering to the subject a provided tablet formulation, as described herein. In other embodiments, the present invention provides a method for reducing one of more effects of endogenous opioid activity in a subject (e.g. , post partum ileus) comprising administering to the subject a formulation. In some embodiments the subject is not a methadone maintenance patient. In any of the foregoing embodiments, the subject can be fasted or fed. In one important embodiment, the subject is fasted overnight. .
- Figure 1 shows the dissolution profile of methylnaltrexone tablets and capsules in 900 ml 0.1 N HC1, at 37 degrees C, 100 rpm Paddle.
- Figure 2 shows the dissolution profile of methylnaltrexone (150 mg) tablets formulated with sodium dodecyl sulfate and an effervescent disintegrant, sodium bicarbonate (as described in Example 5), at 37 degrees C, 100 rpm Paddle, analyzed using a Cary 50 spectrophotometer.
- Figures 3 shows a plot of the time and the percentage of patients having a first laxation response in patients with chronic malignant pain administered an (R)-N- methylnaltrexone bromide (300 mg or 450 mg) SDS tablet formulation after a 10 hour fast.
- Figure 4 includes characterization data for MNTX-heptyl sulfate.
- FIG. 4A is the 1H NMR spectrum of MNTX-heptyl sulfate.
- Figure 4B is an HPLC chromatogram for MNTX-heptyl sulfate.
- Figure 4C is the UV spectrum of MNTX- heptyl sulfate.
- Figure 5 includes characterization data for MNTX-dodecyl sulfate.
- Figure 5A is the 1H NMR spectrum of MNTX-dodecyl sulfate.
- Figure 5B is an HPLC chromatogram for MNTX-dodecyl sulfate.
- Figure 5C is the UV spectrum of MNTX- dodecyl sulfate.
- Figure 6 includes characterization data for MNTX-sodium laurate.
- Figure 6A is the 1H NMR spectrum of MNTX- sodium laurate.
- Figure 6B is an HPLC chromatogram for MNTX- sodium laurate.
- Figure 6C is the UV spectrum of MNTX- sodium laurate.
- aliphatic includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
- aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
- alkyl includes straight, branched, and cyclic alkyl groups.
- alkyl alkenyl
- alkynyl alkynyl
- the terms “alkyl,” “alkenyl,” “alkynyl,” and the like encompass both substituted and unsubstituted groups.
- lower alkyl is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1-6 carbon atoms.
- the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-30 aliphatic carbon atoms.
- the alkyl, alkenyl, and alkynyl groups employed in the invention contain 10-30 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 5-25 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 5-20 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 10-20 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 15-25 aliphatic carbon atoms.
- the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4 carbon atoms.
- Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, vinyl, allyl, n-butyl, sec -butyl, isobutyl, tert-butyl, cyclobutyl, -CH 2 -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, - CH 2 -cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH 2 -cyclohexyl, heptyl, octyl (capryl), nonyl, decyl (capric), undecyl, dodecyl (lauryl), tridecyl, tetradec
- substituents of the above-described aliphatic moieties include, but are not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;
- heteroaliphatic, arylalkyl, or heteroarylalkyl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted.
- amphiphilic refers to the molecule' s dual hydrophobic and hydrophilic properties.
- amphiphilic molecules have a polar, water soluble group (e.g., a phosphate, carboxylic acid, sulfate) attached to a nonpolar, water- insoluble group (e.g. , a hydrocarbon).
- a polar, water soluble group e.g., a phosphate, carboxylic acid, sulfate
- nonpolar, water- insoluble group e.g. , a hydrocarbon
- amphiphilic is synonymous with amphipathic.
- amphiphilic molecules include sodium dodecyl (lauryl) sulfate, fatty acids, phospholipids, and bile acids.
- Amphiphilic molecules may be uncharged, cationic, or anionic.
- dissolution rate refers to the amount of time it takes for an active ingredient or composition thereof (e.g., a salt methylnaltrexone) to dissolve in a solvent.
- the dissolution rate may depend on a variety of factors including mixing, temperature, pH, solvent, particle size, etc.
- the dissolution rate of a drug or composition thereof affects the bioavailability of the drug. In certain circumstances, dissolution rate is used to determine drug availability from solid dosage forms.
- an "effective amount" is at least a minimal amount of a compound, or formulation or composition containing a compound, which is sufficient for treating one or more symptoms of a disorder or condition associated with modulation of peripheral ⁇ opioid receptors, such as side effects associated with opioid analgesic therapy (e.g. , gastrointestinal dysfunction (e.g., dysmotility constipation, etc.), nausea, emesis, etc.).
- opioid analgesic therapy e.g. , gastrointestinal dysfunction (e.g., dysmotility constipation, etc.), nausea, emesis, etc.).
- an "effective amount" of a compound, composition, or formulation containing a compound is sufficient for treating symptoms associated with, a disease associated with aberrant endogenous peripheral opioid or ⁇ opioid receptor activity (e.g., idiopathic constipation, ileus, etc.).
- a disease associated with aberrant endogenous peripheral opioid or ⁇ opioid receptor activity e.g., idiopathic constipation, ileus, etc.
- the term "effective amount,” as used in connection with an amount of methylnaltrexone or salt of methylnaltrexone means an amount of methylnaltrexone or salt of methylnaltrexone sufficient to achieve laxation in a patient.
- effervescent disintegrant refers to a material that causes effervescence resulting in quick disintegration of the dosage form following contact with aqueous medium.
- the effervescent disintegrant is a base (e.g., carbonate) which reacts with an acid (e.g., HC1 in the stomach) to form carbon dioxide. Therefore, such effervescent disintegrants include carbon dioxide producing
- Carbonate sources include, but are not limited to, carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate, sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate, and calcium carbonate.
- Effervescent disintegrants are known in the art for achieving fast-disintegrating dosage forms.
- lipophilicity refers to a compound's ability to associate with or dissolve in a fat, lipid, oil, or non-polar solvent. Lipophilicity and hydrophobicity may be used to describe the same tendency of a molecule to dissolve in fats, oils, lipids, and non-polar solvents.
- non-functional coating is a coating that does not significantly affect release characteristics of a therapeutically active compound or compounds from a formulation when administered.
- examples of a non-functional coat include a seal coat (e.g. , hydroxypropyl cellulose, hypromellose or polyvinyl alcohol).
- a non-functional coating is a polish coat or seal coat.
- non-malignant pain refers to “non-cancer pain.”
- the term "apparent partition coefficient,” as used herein, refers to the ratio of concentrations of a compound in any form in the two phases of a mixture of two immiscible solvents at equilibrium.
- the two immiscible solvents are octanol and water.
- the apparent partition coefficient may be determined under various conditions, for example, temperature, pH, concentration, etc. Apparent partition coefficients have been found useful in estimating the distribution of compounds in the body. Higher apparent partition coefficients denote a more hydrophobic (more lipophilic) compound, while lower apparent partition coefficients denote a hydrophilic compound.
- the apparent partition coefficient of a compound may be determined by procedures known in the art, for example, in the U.S. Pharmacopeia.
- the apparent partition coefficient may be determined by the procedure used to determine the apparent partition coefficients of methylnaltrexone dodecyl sulfate and methylnaltrexone heptyl sulfate in the Examples.
- subject means a mammal and includes human and animal subjects, such as domesticated animals (e.g., horses, dogs, cats, etc.) and experimental animals (e.g., mice, rats, dogs, chimpanzees, apes, etc.).
- domesticated animals e.g., horses, dogs, cats, etc.
- experimental animals e.g., mice, rats, dogs, chimpanzees, apes, etc.
- shuffer or “suffering” as used herein refers to one or more conditions that a patient has been diagnosed with, or is suspected to have.
- spheroids has its art understood meaning of a substantially spherical particulate.
- spheroids prepared or utilized according to the present invention have a size within the range of about 1- 1500 microns. In some embodiments, such spheroids have a size within the range of about 20- 1500 microns. In some embodiments, such spheroids have a size within the range of about 20-1000 microns. In some embodiments, such spheroids have a size within the range of about 20-500 microns. In some embodiments, such spheroids have a size within the range of about 20-300 microns.
- the spheroids have a size range wherein at least 80% of the spheroids fall within the range of about 20-325 microns. In some embodiments, the spheroids have a size range wherein at least 50% of the spheroids fall within the range of about 45-120 microns.
- treat refers to partially or completely alleviating, inhibiting, delaying onset of, reducing the incidence of, ameliorating and/or relieving a disorder or condition, or one or more symptoms of the disorder, disease or condition.
- “Therapeutically active agent” or “active agent” refers to a substance, including a biologically active substance, that is useful for therapy (e.g., human therapy, veterinary therapy), including prophylactic and therapeutic treatment.
- Therapeutically active agents include organic molecules that are drug compounds, peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoprotein, mucoprotein, lipoprotein, synthetic polypeptide or protein, small molecules linked to a protein, glycoprotein, steroid, nucleic acid, DNA, RNA, nucleotide, nucleoside, oligonucleotides, antisense oligonucleotides, lipid, hormone, and vitamin.
- Therapeutically active agents include any substance used as a medicine for treatment, prevention, delay, reduction or amelioration of a disease, condition, or disorder.
- therapeutically active agents useful in the formulations of the present invention are opioid receptor antagonist compounds, opioid analgesic compounds, and the like.
- a therapeutically active agent includes a compound that increases the effect or effectiveness of a second compound, for example, by enhancing potency or reducing adverse effects of a second compound.
- unit dosage form refers to a physically discrete unit of a provided formulation appropriate for the subject to be treated. It will be understood, however, that the total daily usage of provided formulation will be decided by the attending physician within the scope of sound medical judgment.
- the specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active agent employed; specific formulation employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.
- K a refers to the -logioK a , wherein K a is the acid dissociation constant. pK a measures the strength of an acid in solution on a logarithmic scale.
- the acid dissociation constant K a is the equilibrium constant for the dissociation of a compound into a proton and its conjugate base, symbolically written as:
- methylnaltrexone refers to (R)-N-methylnaltrexone. (R)-
- N-methylnaltrexone a peripherally acting ⁇ opioid receptor antagonist, has been studied and used to treat bowel dysfunction in patients being administered opioids.
- enterically coated preparations of methylnaltrexone do not consistently demonstrate a substantial effect in treating opioid-induced constipation. Contrary to the suggestions of the prior art concerning oral methylnaltrexone, local concentrations of methylnaltrexone in the intestinal tract remote from the stomach, are not effective to induce laxation and treat constipation.
- the present invention provides a composition comprising methylnaltrexone and a pharmaceutically acceptable excipient, wherein the composition in solution yields an octanol/water apparent partition coefficient for methylnaltrexone of at least 0.25 under acidic conditions, in certain embodiments at a pH between 1 and 4.
- such compositions are formulated for oral administration.
- a composition for oral administration is formulated into a tablet. Methylnatrexone for use in such compositions and
- formulations may be in any of a variety of forms.
- methylnaltrexone suitable for use in the inventive compositions and formulations include pharmaceutically acceptable salts, prodrugs, polymorphs (i.e., crystal forms), co- crystals, hydrates, solvates, and the like. Any form of methylnaltrexone may be used in the compositions or formulations, but the form should allow for ion pairing with the amphiphilic pharmaceutically acceptable excipient.
- compositions, and formulations thereof comprise a salt of formula I:
- a " is a suitable anion.
- a " is the anion of a Br0nsted acid.
- Exemplary Br0nsted acids include hydrogen halides, carboxylic acids, sulfonic acids, sulfuric acid, and phosphoric acid.
- a " is chloride, bromide, iodide, fluoride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate sulfonate, methylsulfonate, formate, carboxylate, sulfate, methylsulfate or succinate salt.
- a " is trifluoroacetate.
- a " is bromide. In certain embodiments, A " is an anion of an amphiphilic pharmaceutically acceptable excipient. In certain embodiments, A " is an acidic amphiphilic pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutically acceptable excipient has a pK a of about 3 or less. In certain embodiments, the pharmaceutically acceptable excipient has a pK a of about 2 or less. In certain embodiments, the pharmaceutically acceptable excipient has a pK a between about 1 and about 2. In certain embodiments, the pharmaceutically acceptable excipient has a pK a of about 1 or less.
- the anion of the pharmaceutically acceptable excipient include a sulfate, sulfonate, phosphate, phosphonate, nitrate, or nitrite moiety.
- the anion of the pharmaceutically acceptable excipient includes a sulfate (-OSO 3 ) group.
- the anion is butyl sulfate, pentyl sulfate, hexyl sulfate, heptyl sulfate, octyl sulfate, nonyl sulfate, decyl sulfate, undecyl sulfate, dodecyl sulfate, tridecyl sulphate, tetradecyl sulfate, pentadecyl sulfate, hexadecyl sulfate, heptadecyl sulfate, octadecyl sulfate, eicosyl sulfate, docosyl sulfate, tetracosyl sulfate, hexacosyl sulfate, octacosyl sulfate, and triacontyl sulphate.
- compositions, and formulations thereof comprise (R)-N-methylnaltrexone bromide.
- (R)-N-methylnaltrexone bromide which is also known as "MNTX” and is described in international PCT patent application publication number, WO2006/12789, which is incorporated herein by reference.
- the chemical name for (R)-N-methylnaltrexone bromide is (R)-N-(cyclopropylmethyl) noroxymorphone methobromide.
- (R)-N-methylnaltrexone bromide has the molecular formula C 2 iH 26 N0 4 Br and a molecular weight of 436.36 g/mol.
- (R)-N-methylnaltrexone bromide has the following structu
- the compound is in the (R) configuration with respect to the quaternary nitrogen.
- at least about 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or 99.95% of the compound is in the (R) configuration with respect to nitrogen.
- a composition, or formulation thereof comprises from about 7% to about 75%, about 25% to about 55%, about 40%, or to about 50% (R)- /V-methylnaltrexone cation, based upon total weight of the formulation.
- a provided composition, or formulation thereof comprises from about 7%, about 8%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 75% (R)-N-methylnaltrexone cation, based upon the total weight of the given composition or formulation.
- the (R)-N- methylnaltrexone cation and the anion of the amphiphilic pharmaceutically acceptable excipient may exist in the composition as an ion pair or may exist as separate salts paired with other counter ions such as bromide and sodium, or mixtures thereof.
- a composition, or formulation thereof comprises from about 7% to about 75%, about 25% to about 55%, about 40%, or to about 50% (R)- N-methylnaltrexone cation and dodecyl sulfate anion, based upon the total weight of the composition or formulation.
- a composition, or formulation thereof comprises from about 7%, about 8%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 75% (R)-N-methylnaltrexone cation and dodecyl sulfate anion, based upon total weight of the composition or formulation.
- the present invention provides a composition comprising methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient.
- the amphiphlic pharmaceutically acceptable excipient increases the lipophilicity of the composition thereby allowing for increased transport through the unstirred diffusion layer in the GI tract, resulting in increased permeation through biological membranes.
- the excipient increases the lipophilicity of the drug.
- the excipient is a surfactant.
- the excipient is an anionic surfactant.
- the excipient is an anionic surfactant that forms an ion pair or salt with positively charged methylnaltrexone.
- anionic surfactants are known in the art and are typically characterized by having a lipophilic end and an anionic portion.
- exemplary excipients useful in the present invention include aliphatic sulfates (e.g. , sodium dodecyl (lauryl) sulfate), aliphatic phosphates, fatty acids, and salts and derivatives thereof.
- a solution of the composition yields an apparent octanol/water partition coefficient for methylnaltrexone of at least 0.25 at a pH between 1 and 4.
- the apparent octanol/water partition coefficient as used herein is determined at room temperature at a concentration of approximately 0.5 mg/mL. Exemplary methods for the determination of apparent octanol/water partition coefficient of methylnaltrexone salts are described in the
- Particularly useful amphiphilic pharmaceutically acceptable excipient includes those that increase the oral absorption of methylnaltrexone.
- the excipient increases the absorption of methylnaltrexone in the stomach.
- the excipient increases the ability of methylnaltrexone to cross lipophilic barriers.
- the excipient increases the lipophilicity of methylnaltrexone by forming an ion pair with cationic methylnaltrexone. Ion pairing increases the partitioning of methylnaltrexone into an organic phase such as a lipid bilayer.
- the excipient forms an ion pair with methylnaltrexone such that when the composition is in solution, the methylnaltrexone has an apparent octanol/water partition coefficient of at least 0.25 at a pH between 1 and 4.
- the apparent octanol/water partition coefficient is at least 0.5 at a pH between 1 and 4.
- the apparent octanol/water partition coefficient is at least 0.75 at a pH between 1 and 4.
- the apparent octanol/water partition coefficient is at least 1.0 at a pH between 1 and 4.
- the apparent octanol/water partition coefficient is at least 10 at a pH between 1 and 4.
- the apparent octanol/water partition coefficient is at least 15 at a pH between 1 and 4. In certain embodiments, the apparent octanol/water partition coefficient is at least 20 at a pH between 1 and 4. In certain embodiments, the apparent octanol/water partition coefficient is at least 25 at a pH between 1 and 4. In certain embodiments, the apparent octanol/water partition coefficient is at least 30 at a pH between 1 and 4.
- aliphatic sulfate refers to a compound having a sulfate moiety at one end and an aliphatic tail, which is straight or branched, and saturated or unsaturated.
- the aliphatic tail may be substituted and may also include cyclic groups.
- the aliphatic tail is a C 4 to C30 aliphatic group.
- the aliphatic tail is a C 7 to C 20 aliphatic group.
- the aliphatic tail is a C 10 to C 20 aliphatic group.
- the aliphatic tail is a C 10 , Cn, C 12 , C 13 , C 14 , or C 15 aliphatic group.
- the aliphatic group is an w-alkyl group, which is saturated, not branched, and not substituted. In certain embodiments, the aliphatic group is C 7 -C 2 o n-alkyl. In certain embodiments, the aliphatic group is Cw-Qs w-alkyl.
- amphiphilic pharmaceutically acceptable excipient is a compound of formula:
- R 1 is a C 4 _ 3 o aliphatic group that is saturated or unsaturated, unbranched or branched, and cyclic or acyclic, and the aliphatic group is optionally substituted with one or more halogen or hydroxyl groups.
- each R 1 is a C 4 _ 1 o aliphatic group.
- each R 1 is a Cw-is aliphatic group.
- each R 1 is a Ci 5 -2o aliphatic group.
- each R 1 is a C20-30 aliphatic group.
- R 1 is unsaturated.
- R 1 is saturated.
- R 1 is unbranched. In certain embodiments, R 1 is branched. In certain embodiments, Rl is substituted. In certain embodiments, R 1 is unsubstituted. In certain embodiments, R 1 is saturated, unbranched, and unsubstituted. In certain embodiments, R 1 is C 4 _3o w-alkyl. In certain embodiments, R 1 is C 5 5 w-alkyl. In certain embodiments, R 1 is Cs-io w-alkyl. In certain embodiments, R 1 is Cio-15 w-alkyl. In certain embodiments, R 1 is C 6 w-alkyl. In certain embodiments, R 1 is C 7 w-alkyl.
- R 1 is w-alkyl. In certain embodiments, R 1 is C 9 w-alkyl. In certain embodiments, R 1 is C 10 w-alkyl. In certain embodiments, R 1 is Cn w-alkyl. In certain embodiments, R 1 is C 12 w-alkyl. In certain embodiments, R 1 is C 13 w-alkyl. In certain embodiments, R 1 is C 14 w-alkyl. In certain embodiments, R 1 is C 15 w-alkyl. In certain embodiments, the excipient is a sodium salt form.
- amphiphilic pharmaceutically acceptable excipient is a compound of formula:
- R 1 is a C 4 _ 3 o aliphatic group that is saturated or unsaturated, unbranched or branched, and cyclic or acyclic, and the aliphatic group is optionally substituted with one or more halogen or hydroxyl groups.
- each R 1 is a C 4-1 o aliphatic group.
- each R 1 is a Cw-15 aliphatic group.
- each R 1 is a Ci 5 -2o aliphatic group.
- each R 1 is a C20-30 aliphatic group.
- R 1 is unsaturated.
- R 1 is saturated.
- R 1 is unbranched. In certain embodiments, R 1 is branched. In certain embodiments, Rl is substituted. In certain embodiments, R 1 is unsubstituted. In certain embodiments, R 1 is saturated, unbranched, and unsubstituted. In certain embodiments, R 1 is C 4 _ 3 o w-alkyl. In certain embodiments, R 1 is C 5 5 w-alkyl. In certain embodiments, R 1 is C 5-1 o n-alkyl. In certain embodiments, R 1 is Cio-15 w-alkyl. In certain embodiments, R 1 is C 6 w-alkyl. In certain embodiments, R 1 is C 7 w-alkyl.
- R 1 is Cg w-alkyl. In certain embodiments, R 1 is C 9 w-alkyl. In certain embodiments, R 1 is C 10 w-alkyl. In certain embodiments, R 1 is Cn w-alkyl. In certain embodiments, R 1 is C 12 w-alkyl. In certain embodiments, R 1 is C 13 w-alkyl. In certain embodiments, R is C 14 w-alkyl. In certain embodiments, R is C 15 w-alkyl. In certain embodiments, the excipient is a sodium salt form.
- amphiphilic pharmaceutically acceptable excipient is a compound of formula:
- R 1 is a C 4 _ 3 o aliphatic group that is saturated or unsaturated, unbranched or branched, and cyclic or acyclic, and the aliphatic group is optionally substituted with one or more halogen or hydroxyl groups.
- each R 1 is a C 4-1 o aliphatic group.
- each R 1 is a Cw-is aliphatic group.
- each R 1 is a C 1 5_ 2 o aliphatic group.
- each R 1 is a C 20 - 3 o aliphatic group.
- R 1 is unsaturated.
- R 1 is saturated.
- R 1 is unbranched. In certain embodiments, R 1 is branched. In certain embodiments, Rl is substituted. In certain embodiments, R 1 is unsubstituted. In certain embodiments, R 1 is saturated, unbranched, and unsubstituted. In certain embodiments, R 1 is C 4 _ 3 o w-alkyl. In certain embodiments, R 1 is C5 5 w-alkyl. In certain embodiments, R 1 is C 5-1 o n-alkyl. In certain embodiments, R 1 is Cio-15 w-alkyl. In certain embodiments, R 1 is C 6 w-alkyl. In certain embodiments, R 1 is C 7 w-alkyl.
- R 1 is Cg w-alkyl. In certain embodiments, R 1 is C9 w-alkyl. In certain embodiments, R 1 is C 10 w-alkyl. In certain embodiments, R 1 is Cn w-alkyl. In certain embodiments, R 1 is C 12 w-alkyl. In certain embodiments, R 1 is C 13 w-alkyl. In certain embodiments, R 1 is C 14 w-alkyl. In certain embodiments, R 1 is C 15 w-alkyl. In certain embodiments, the excipient is a sodium salt form.
- amphiphilic pharmaceutically acceptable excipient is a compound of formula:
- R 1 is a C 4 _ 3 o aliphatic group that is saturated or unsaturated, unbranched or branched, and cyclic or acyclic, and the aliphatic group is optionally substituted with one or more halogen or hydroxyl groups.
- each R 1 is a C 4-1 o aliphatic group.
- each R 1 is a Cm-is aliphatic group.
- each R 1 is a C 1 5_ 2 o aliphatic group.
- each R 1 is a C 2 o_ 3 o aliphatic group.
- R 1 is unsaturated.
- R 1 is saturated.
- R 1 is unbranched. In certain embodiments, R 1 is branched. In certain embodiments, Rl is substituted. In certain embodiments, R is unsubstituted. In certain embodiments, R is saturated, unbranched, and unsubstituted. In certain embodiments, R 1 is C 4 _3o w-alkyl. In certain embodiments, R 1 is C5 5 w-alkyl. In certain embodiments, R 1 is C 5-1 o n-alkyl. In certain embodiments, R 1 is Cio-is w-alkyl. In certain embodiments, R 1 is C 6 w-alkyl. In certain embodiments, R 1 is C 7 w-alkyl.
- R 1 is Cg w-alkyl. In certain embodiments, R 1 is C9 w-alkyl. In certain embodiments, R 1 is C 10 n-alkyl. In certain embodiments, R 1 is Cn w-alkyl. In certain embodiments, R 1 is C 12 n-alkyl. In certain embodiments, R 1 is C 13 n-alkyl. In certain embodiments, R 1 is C 14 n-alkyl. In certain embodiments, R 1 is C 15 n-alkyl. In certain embodiments, the excipient is a sodium salt form.
- methylnaltrexone may form an ion pair or salt with an anionic amphiphilic pharmaceutically acceptable excipient.
- the present invention provides a compound of formula II:
- a " is an anionic amphiphilic pharmaceutically acceptable excipient.
- methylnaltrexone may form an ion pair with any of formulae R ⁇ COOH, R ⁇ SC ⁇ OH, R ⁇ OSC ⁇ OH, R ⁇ PCO ⁇ OH, R 1 -OP(0) 2 OH, or a salt thereof, as described herein.
- the present invention provides a compound of any of formula III, formula IV, formula V, formula VI, or formula VII:
- R 1 is a C 4 _3o aliphatic group that is saturated or unsaturated, unbranched or branched, and cyclic or acyclic, and the aliphatic group is optionally substituted with one or more halogen or hydroxyl groups.
- the amphiphilic pharmaceutically acceptable excipient is sodium dodecyl (lauryl) sulfate (also known as SDS or SLS), sodium heptyl sulfate, sodium heptyl sulfonate, perfluorooctanesulfonate (PFOS), and the like.
- compositions i.e., pharmaceutical compositions comprising methylnaltrexone and sodium dodecyl (lauryl) sulfate (also known as SDS or SLS), are provided.
- a provided composition, or formulation thereof comprises from about 5% to about 80% of the amphiphilic pharmaceutically acceptable excipient, based upon total weight of the composition, or formulation thereof. In certain embodiments, about 5% to about 25% of amphiphilic pharmaceutically acceptable excipient is used in the composition or formulation. In some embodiments, a provided composition, or formulation thereof, comprises about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% of the excipient, based upon total weight of the composition, or formulation thereof.
- the present invention provides a composition or formulation comprising methylnaltrexone, or a salt thereof, an amphiphilic pharmaceutically acceptable excipient, and a disintegrant.
- incorpora suitable rapid-acting disintegrant into compositions and formulations facilitates the breakdown of tablets or other solid dosage forms, in particular, the rapid breakdown of tablets or other solid dosage forms in the stomach.
- rapid-acting disintegrants is desired in solid dosage forms, such as tablets, that contain active ingredient.
- the amount of the disintegrant will vary, depending on the nature and amount of the amphiphilic pharmaceutically acceptable excipient (and, optionally, other ingredients).
- USP United States Pharmacopeia
- At least 50% of the methylnaltrexone in the composition dissolves in 15 minutes. In other embodiments, at least 75%, 80%, 85%, 90%, 95%, or even 99% of the methylnaltrexone in the composition dissolves in 15 minutes. In some embodiments, the amounts of methylnaltrexone indicated above dissolve in about 10 minutes, or even about 5 minutes.
- the percent of the methylnaltrexone, as a cation or as a salt such as an ion pair, in the composition that will convert from a solid into solution when the composition is placed in 900 ml of 1 N HC1 at 37 °C, 100 rpm Paddle.
- Suitable disintegrants include, but are not limited to, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, sodium bicarbonate, crospovidone (cross-linked PVP), sodium carboxymethyl starch (sodium starch glycolate), cross-linked sodium carboxymethyl cellulose (croscarmellose), pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), and combinations thereof.
- the disintegrant is crospovidone.
- the disintegrant is an effervescent disintegrant.
- Effervescent disintegrants are capable of generating carbon dioxide in an aqueous medium, particularly acidic aqueous medium such as the contents of the stomach.
- the disintegrant is a bicarbonate, such as sodium bicarbonate (NaHC0 3 ) or potassium bicarbonate (KHC0 3 ).
- the disintegrant is a bicarbonate, such as sodium bicarbonate (NaHC0 3 ) or potassium bicarbonate (KHC0 3 ).
- the disintegrant is a bicarbonate, such as sodium bicarbonate (NaHC0 3 ) or potassium bicarbonate (KHC0 3 ).
- disintegrants is a carbonate.
- the disintegrant is sodium carbonate (Na 2 C0 3 ).
- the disintegrant is calcium carbonate (CaC0 3 ).
- the composition or formulation comprises at least two disintegrants.
- the composition or formulation may include one effervescent disintegrant and one disintegrant that is not effervescent.
- the compositions or formulation comprises sodium bicarbonate and crospovidone as disintegrants.
- provided formulations comprise from about 1% to about 25%, about 1% to about 15%, about 1% to about 10%, or about 2% to about 5% disintegrant, based upon total weight of the formulation.
- provided formulations comprise from about 1%, about 2%, about 3%, about 4%, about 5%, about 7%, about 8%, about 10%, about 12%, or about 15% disintegrant, based upon total weight of the formulation.
- the composition or formulation includes a material and/or coating that retards or prevents dissolution of the solid dosage form in the oral cavity.
- the solid dosage form breaks down or disintegrates rapidly in the stomach, not in the oral cavity.
- the present invention provides a formulation of methylnatrexone which further comprises one or more additional components, such as, for example, binders, carriers, disintegrants, chelating agents, antioxidants, fillers, wetting agents, or combinations thereof.
- a composition is formulated into a tablet which further comprises one or more additional components, such as, for example, binders, carriers, disintegrants, chelating agents, antioxidants, fillers, wetting agents, lubricants, or combinations thereof.
- a composition is formulated into a tablet which further comprises an antioxidant and one or more components, such as, for example, binders, carriers, chelating agents, fillers, wetting agents, or combinations thereof.
- a composition is formulated into a tablet which further comprises a disintegrant and one or more components, such as, for example, binders, carriers, chelating agents, antioxidants, fillers, wetting agents, or combinations thereof.
- a composition is formulated into a tablet which further comprises an antioxidant, a disintegrant, and one or more components, such as, for example, binders, carriers, chelating agents, fillers, wetting agents, or combinations thereof.
- additional components are described in detail herein, infra.
- pharmaceutically acceptable formulations of the present invention are provided as tablets which comprise a composition comprising methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient, and a disintegrant, and, optionally, one or more of a binder, a chelating agent, and a wetting agent.
- such tablets comprise a composition comprising methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient, a binder, a chelating agent, a disintegrant, and a wetting agent.
- such tablets comprise a composition comprising methylnaltrexone and an amphiphilic
- provided formulations comprise tablets that have a non-functional coating. In some embodiments, provided formulations further comprise an antioxidant.
- wetting agents are well known in the art and typically facilitate the interaction of an active agent, such as one that is hydrophobic, with water molecules in a surrounding aqueous environment.
- exemplary wetting agents include poloxamer, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polysorbates, such as polysorbate 80, cetyl alcohol, glycerol fatty acid esters (e.g.
- provided tablets comprise from about 1% to about 25% wetting agent, based upon total weight of the tablets. In some embodiments, provided tablets comprise from about 1%, about 3%, about 4%, about 5%, about 10%, about 15%, or about 20% of wetting agent, based upon total weight of given tablets.
- a wetting agent is a polysorbate.
- a wetting agent is polysorbate 80, also known as Tween 80, and is available from Sigma- Aldrich, among other sources.
- provided tablets comprise from about 1% to about 25% polysorbate 80, about 1% to about 5%, about 2% to about 5%, about 3%, or to about 4% based upon total weight of given tablet.
- provided tablets comprise from about 1%, about 3%, about 4%, about 5%, about 10%, about 15%, or about 20% polysorbate 80, based upon total weight of given tablets.
- polysorbate 80 can also act as an absorption enhancer.
- polysorbate 80 may facilitate thinning of the mucus layer created in the gastrointestinal tract so that remaining methylnaltrexone in the mucous layer is more readily released for rapid absorption.
- Addition of one or more chelating agents may be particularly useful in formulations that include methylnaltrexone, and such agents may provide protection from metal-catalyzed degradation and/or from precipitation of methylnaltrexone.
- chelating agents are known to those skilled in the art, and include any pharmaceutically acceptable chelating agent.
- Common chelating agents include, but are not limited to ethylenediaminetetraacetic acid (EDTA) and derivatives thereof, ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraaceticacid (EGTA) and derivatives thereof, diethylenetriaminepentaacetic acid (DTPA) and derivatives thereof, N,N- bis(carboxymethyl)glycine (NTA) and derivatives thereof, nitrilotriacetic acid and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, and sodium desoxycholate and derivatives thereof.
- EDTA ethylenediaminetetraacetic acid
- EGTA ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraaceticacid
- DTPA diethylenetriaminepent
- the chelating agent is selected from the group consisting of EDTA or derivatives thereof. In some embodiments, the chelating agent is selected from the group consisting of calcium EDTA disodium, diammonium EDTA, dipotassium EDTA, disodium EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium EDTA, HEDTA, and trisodium HEDTA, and related salts thereof. In some embodiments, the chelating agent is EDTA disodium, EDTA trisodium, or calcium EDTA disodium.
- the chelating agent is calcium EDTA (edetate calcium) or a calcium salt EDTA derivative or calcium EGTA or a calcium salt EGTA derivative.
- the chelating agent is calcium EDTA disodium, such as, for example, calcium EDTA disodium hydrate (edetate calcium disodium dihydrate). Calcium EDTA is available from Sigma- Aldrich, among other sources.
- provided formulations comprise from about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, 0.01% to about 2%, 0.01% to about 1%, about 0.1% to about 5%, about 0.1% to about 4%, 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, or about 0.1% to about 0.5% of the chelating agent, based upon total weight of the formulation.
- provided formulations comprise from about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, or about 0.6% of the chelating agent, based upon total weight of formulation.
- Suitable binders are known in the art.
- suitable binders include but are not limited to starch, PVP (polyvinyl pyrrolidone), low molecular weight HPC (hydroxypropyl cellulose), microcrystalline cellulose (e.g. , Avicel ® ), silicified microcrystalline cellulose (Prosolv 50), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxymethyl cellulose, ethylcellulose, alginates, gelatin, polyethylene oxide, acacia, dextrin, sucrose, magnesium aluminum silicate, and polymethacrylates.
- PVP polyvinyl pyrrolidone
- HPC hydroxypropyl cellulose
- microcrystalline cellulose e.g. , Avicel ®
- Prosolv 50 silicified microcrystalline cellulose
- HPMC hydroxypropyl methylcellulose
- carboxymethyl cellulose ethylcellulose
- ethylcellulose alginates
- gelatin polyethylene oxide
- Fillers include agents selected from the group consisting of microcrystalline cellulose (e.g., Avicel ® ), starch, lactitol, lactose, a suitable inorganic calcium salt, sucrose, glucose, mannitol, silicic acid, or a combination thereof.
- formulations comprise from about 5%, to about 90%, or about 10% to about 50% ,or about 10% to about 40%, or about 10% to about 45% binder, based upon total weight of the formulation.
- formulations comprise from about 10%, about 15%, about 16%, about 20%, about 24%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% binder, based upon total weight of the tablets.
- formulations comprise microcrystalline cellulose as a binder.
- formulations comprise the binders, microcrystalline cellulose and silicified microcrystalline cellulose.
- provided formulations may comprise one or more antioxidants.
- antioxidants include those known to one of ordinary skill in the art.
- Exemplary antioxidants include ascorbic acid, and salts and esters thereof; citric acid, and salts and esters thereof; butylated hydroxyanisole (“BHA”); butylated hydroxytoluene (“BHT”); tocopherols (e.g., -alpha tocopherol, /-alpha tocopherol, d- alpha tocopherol acetate, /-alpha tocopherol acetate, beta tocopherol, delta tocopherol, gamma tocopherol, and the like), and carotenoids (e.g., vitamin A, lutein, and zeaxanthin).
- BHA butylated hydroxyanisole
- BHT butylated hydroxytoluene
- tocopherols e.g., -alpha tocopherol, /-alpha tocopherol,
- a formulation comprises ascorbic acid. In some embodiments, aformulation comprises up to about 10% one or more antioxidants by weight. In some embodiments, a provided formulation comprises about 0.01 to about 5% one or more antioxidants by weight. In some embodiments, a provided formulation comprises about 1.0% to about 10% one or more antioxidants by weight. In certain embodiments, a provided formulation comprises about 1%, about 2%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% of one or more antioxidants by weight.
- formulations may comprise a lubricant.
- Lubricants generally, are substances used in solid dosage formulations to reduce friction during compression. Such compounds include, by way of example and without limitation, sodium oleate, sodium stearate, calcium stearate, zinc stearate, magnesium stearate, polyethylene glycol, talc, mineral oil, stearic acid, sodium benzoate, sodium acetate, sodium chloride, and other materials known to one of ordinary skill in the art.
- the lubricant is a stearate salt.
- formulations comprise from about 0.1% to about 7%, or about 0.2% to about 1% lubricant, based upon total weight of given formulation.
- the lubricant is magnesium stearate and is available from Sigma- Aldrich, among other sources.
- formulations may comprise a non-functional coating.
- the tablet may comprise a non-functional coating.
- the non-functional coating is a seal coat.
- a suitable seal coating can be applied as a solution (e.g., HPMC solution) at a
- initial seal coating is in the range of about 1% w/w to about 3% w/w, or about 2% w/w, of the uncoated tablet.
- a seal coating may comprise a polymer (e.g., HPMC) and may be a commercially available seal coating seal such as Opadry ® Clear (Colorcon, Inc.), or HPMC E3.
- seal coating may be from about 1% to about 10% of weight gain of the total coated formulation.
- the formulation may comprise a coating to prevent disintegration of the dosage form in the oral cavity.
- the formulation for oral administration comprises (a) about 7% to about 75% of methylnaltrexone bromide, based upon the total weight of the formulation; (b) about 5% to about 80% of an amphiphilic
- the methylnaltrexone bromide of the formulation is (R)-N-methylnaltrexone bromide.
- the amphiphilic pharmaceutically acceptable excipient is sodium dodecyl (lauryl) sulfate.
- the chelating agent is a salt of EDTA (e.g., calcium EDTA).
- the wetting agent is polysorbate 80.
- the disintegrant is sodium bicarbonate.
- the disintegrant is crospovidone.
- the disintegrant is a combination of sodium bicarbonate and crospovidone.
- the lubricant is magnesium stearate.
- the antioxidant is ascorbic acid.
- the invention provides a tablet formulation for oral administration comprising about 30% methylnaltrexone bromide, about 10% sodium dodecyl sulfate, about 11% microcrystalline cellulose, about 5% crospovidone, about 0.25% calcium EDTA, about 2% polysorbate 80, about 30% Prosolv 50, about 11% sodium
- the methylnaltrexone may exist paired with bromide, paired with the anion of the amphiphilic pharmaceutically acceptable excipient, or some combination thereof.
- compositions and formulations are prepared by methods which include an extrusion/spheronization step.
- formulations are manufactured via wet-granulation of a provided formulation followed by extrusion/spheronization to form spheroids. Given spheroids are then dried and milled to form a powder which is blended with suitable binder(s) and disintegrant(s). The resulting mixture is then milled and blended with a suitable lubricant and pressed into tablets. In certain embodiments, a non-functional coating is applied.
- tablets are prepared by methods which do not include extrusion/spheronization steps and, in accordance with such methods, are manufactured via wet- granulation.
- the granulation is milled to form a granular powder which is blended with suitable binder(s) and disintegrant(s).
- the resulting mixture is then milled and blended with a suitable lubricant and pressed into tablets.
- a non-functional coating is applied.
- Formulations of methylnatrexone may be prepared as a unit dosage form.
- a tablet is typically a unit dosage form.
- a unit dosage form contains 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, or 1500 mg of methylnaltre
- a unit dosage form contains between 50 mg and 900 mg, inclusive, or between 150 mg and 450 mg, inclusive, of methylnaltrexone bromide. In some embodiments, a unit dosage form contains 50 mg, 75 mg, 150 mg, 225 mg, 300 mg, 450 mg, 600 mg, or 900 mg of methylnaltrexone bromide. In some embodiments, the unit dosage form comprises methylnaxtrexone and an amphiphilic pharmaceutically acceptable excipient, e.g., sodium dodecyl (lauryl) sulfate (also known as SDS or SLS).
- an amphiphilic pharmaceutically acceptable excipient e.g., sodium dodecyl (lauryl) sulfate (also known as SDS or SLS).
- compositions and formulations may be administered to a patient as required to provide an effective amount of methylnaltrexone.
- the patient is orally administered methylnaltrexone or a formulation thereof at least once a day.
- the patient is orally administered methylnaltrexone or a formulation thereof up to once a day.
- the patient is orally administered methylnaltrexone or a formulation thereof not more than once a day.
- the patient is orally administered methylnaltrexone or a formulation thereof as needed.
- the patient is orally administered methylnaltrexone or a formulation thereof as needed, but not more than once a day.
- a unit dosage form of a provided formulation may be orally administered to a patient in a single day, for example, a unit dosage of about 150 mg, 300 mg, or 450 mg methylnaltrexone bromide or an equivalent molar amount of methylnaltrexone.
- the present invention provides a method for treating an opioid-induced side effect in a patient in need thereof, comprising the step of orally administering to said patient one or more tablets of the present invention wherein said tablet provides about 150 mg, 300 mg, or 450 mg of methylnaltrexone or an equivalent molar amount of methylnaltrexone bromide, e.g., methylnaltrexone and a amphiphilic pharmaceutically acceptable excipient such as sodium dodecyl (lauryl) sulfate (also known as SDS or SLS), sodium heptyl sulfate, sodium heptyl sulfonate, perfluorooctanesulfonate (PFOS), and the like.
- a amphiphilic pharmaceutically acceptable excipient such as sodium dodecyl (lauryl) sulfate (also known as SDS or SLS), sodium heptyl sulfate, sodium heptyl sulfonate, per
- a single tablet formulation of the present invention provides about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 300 mg, or about 450 mg of methylnaltrexone bromide, or equivalent moles of another salt form, or
- methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient such as sodium dodecyl (lauryl) sulfate (also known as SDS or SLS).
- an amphiphilic pharmaceutically acceptable excipient such as sodium dodecyl (lauryl) sulfate (also known as SDS or SLS).
- an effective amount means an amount of methylnaltrexone sufficient to achieve laxation in a patient.
- an effective amount means an amount of methylnaltrexone sufficient to achieve laxation in a patient within about 24 hours, within about 12 hours, within about 8 hours, within about 5 hours, within about 4 hours, within about 3 hours, within about 2 hours, or within about 1 hours of administration to said patient.
- effective amount means an amount of methylnaltrexone sufficient to achieve laxation within about 4 hours of administration to the patient.
- effective amount means an amount of methylnaltrexone sufficient to achieve laxation within about 4 hours of administration to the patient for at least 99%, at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, or at least 50% of all doses administered. In some embodiments, effective amount means an amount of methylnaltrexone sufficient to achieve laxation within about 4 hours of administration to the patient for all doses administered during first four weeks of dosing. [0093] In some embodiments, the formulations are administered to a fasted patient.
- the term “fasted” means that the patient has not eaten any food for at least 2 hours, at least 4 hours, for at least 6 hours, for at least 8 hours, for at least 10 hours, or for at least 12 hours prior to administration of a provided formulation.
- the term “fasted” means an overnight fast. It is believed that improved effects will be seen in fasted patients than in fed patients. These effects may be magnified in patients administered methylnatrexone in a provided tablet as compared with patients administered the same dose in capsule form. Thus, administration of a provided methylnaltrexone tablet formulation to a patient in a fasted state is believed to be advantageous.
- the formulations are administered to a patient that has not fasted. Therefore, there is no requirement that the patient not have eaten before methylnaltrexone is administered.
- compositions and formulations can be employed in combination therapies, that is, provided formulations can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
- Particular combination therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
- therapies employed may achieve a desired effect for the same disorder (for example, a formulation may be administered concurrently with another compound used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects).
- additional therapeutic compounds which are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated.”
- methylnaltrexone or an ion pair or formulation of the invention and one or more other active agents may be administered together in a single formulation (e.g., unit dosage form); in other embodiments, methylnaltrexone and one or more other active agents may be administered as separate formulations. In certain embodiments, methylnaltrexone and/or one or more other active agent may be administered in multiple doses.
- the other active agent administered in combination with a methylnaltrexone ion pair or formulation of the invention is an opioid.
- the present invention provides a unit dosage form comprising a combination of methylnaltrexone with an opioid together in a single layer dosage form (e.g. , tablet).
- a unit dosage form may be a bi-layer tablet comprising methylnaltrexone in one layer and an opioid in another layer.
- the combination unit dosage form is suitable for oral administration.
- opioid compounds include, but are not limited to, alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, ethylmorphine, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6- glucoronide, nalbuphine, nalorphine, nicomorphine, opium, oxycodone, oxymorphone, papaveretum, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil
- dihydrocodeine fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, nicomorphine, oxycodone,
- the opioid is selected from morphine, codeine, oxycodone, hydrocodone, dihydrocodeine, propoxyphene, fentanyl, tramadol, and mixtures thereof.
- the opioid is loperamide.
- the opioid is a mixed agonist such as butorphanol.
- the subjects are administered more than one opioid, for example, morphine and heroin or methadone and heroin.
- combination therapy may be no more than the amount that would normally be administered in monotherapy with the relevant agent(s).
- the amount of other active agent administered in combination therapy may be less than that normally administered in monotherapy with the relevant agent(s).
- the amount of additional active agent can range from about 50% to 100% of the amount normally present in a formulation comprising that compound as the only therapeutic agent.
- formulations may also be used in conjunction with and/or in combination with conventional therapies for gastrointestinal dysfunction to aid in the amelioration of constipation and bowel dysfunction.
- conventional therapies include, but may not be limited to functional stimulation of the intestinal tract, stool softening agents, laxatives (e.g., diphelymethane laxatives, cathartic laxatives, osmotic laxatives, saline laxatives), bulk forming agents and laxatives, lubricants, intravenous hydration, and nasogastric decompression.
- the present invention provides pharmaceutically acceptable formulations as described herein comprising methylnaltrexone for oral administration useful for the delivery of such compounds in any context in which such delivery is desirable.
- provided formulations are useful for the delivery of
- formulations may be used as to treat subjects having disease states that are ameliorated by binding ⁇ opioid receptors, or in any treatment wherein temporary suppression of the ⁇ opioid receptor system is desired (e.g., ileus).
- opioid analgesic therapy e.g., gastrointestinal effects (e.g., delayed gastric emptying, altered GI tract motility)
- formulations may be used as to treat subjects having disease states that are ameliorated by binding ⁇ opioid receptors, or in any treatment wherein temporary suppression of the ⁇ opioid receptor system is desired (e.g., ileus).
- compositions of the present invention methods of use of provided formulations are in human subjects.
- opioid use such as, for example, gastrointestinal dysfunction (e.g., inhibition of intestinal motility, constipation, GI sphincter constriction, nausea, emesis (vomiting)), biliary spasm, opioid bowel dysfunction, colic, dysphoria, pruritis, urinary retention, depression of respiration, papillary constriction, cardiovascular effects, chest wall rigidity and cough suppression, depression of stress response, and immune suppression associated with use of narcotic analgesia, or combinations thereof.
- gastrointestinal dysfunction e.g., inhibition of intestinal motility, constipation, GI sphincter constriction, nausea, emesis (vomiting)
- opioid bowel dysfunction colic, dysphoria, pruritis, urinary retention, depression of respiration, papillary constriction, cardiovascular effects, chest wall rigidity and cough suppression, depression of stress response, and immune suppression associated with use of narcotic analgesia, or combinations thereof.
- formulation may thus be beneficial from a quality of life standpoint for subjects undergoing use of opioids, as well as to reduce complications arising from chronic constipation, such as hemorrhoids, appetite suppression, mucosal breakdown, sepsis, colon cancer risk, and myocardial infarction.
- provided formulations are useful for:
- provided formulations are useful for administration to patients suffering from postoperative gastrointestinal dysfunction.
- provided formulations are also useful for administration to subjects undergoing chronic opioid use (e.g. , terminally ill patients receiving opioid therapy such as an AIDS patient, a cancer patient, a cardiovascular patient; subjects receiving chronic opioid therapy for pain management; subjects undergoing opioid therapy for maintenance of opioid withdrawal).
- opioid therapy such as an AIDS patient, a cancer patient, a cardiovascular patient
- subjects receiving chronic opioid therapy for pain management subjects undergoing opioid therapy for maintenance of opioid withdrawal.
- the subject is a subject using opioid therapy for chronic pain management.
- the pain is non-malignant pain (e.g. , back pain, neuropathic pain, pain associated with fibromyalgia, osteoarthritis).
- the subject is a terminally ill patient. In other embodiments the subject is a person undergoing opioid withdrawal maintenance therapy.
- formulations provided herein are:
- the subject is selected based on the subject having an increased risk for developing one or more of the conditions set forth above.
- the subject is selected based on the use of opioid therapy for pain management, or based on having one or more of the conditions set forth herein.
- the subject is constipated or has a history of constipation due to opioid therapy.
- a constipated subject has not had a bowel movement in the previous three days.
- a constipated subject has had less than three bowel movements in the previous week.
- a constipated subject has had less than three rescue-free bowel movements per week on average over the last four consecutive weeks, and one or more of the following: (a) hard or lumpy stools, (b) straining during bowel movements, and/or (c) sensation of incomplete evacuation after bowel movements.
- the subject is selected for treatment with a methylnaltrexone formulation described herein based on the use of opioids, e.g., for non- malignant pain.
- the subject may be using opioids intermittently or regularly.
- the subject that is selected has been taking opioids as needed.
- the subject that is selected has been taking opioids for less than one week.
- the subject that is selected has been taking opioids over the course of at least one week.
- the subject that is selected has been taking opioids over the course of at least two weeks.
- the subject that is selected has been taking opioids over the course of at least three weeks.
- the subject that is selected has been taking opioids over the course of at least four weeks.
- the subject that is selected has been taking opioids over the course of at least three months. In another embodiment, the subject that is selected has been taking opioids over the course of at least six months. In another embodiment, the subject that is selected has been taking opioids over the course of at least twelve months. In another embodiment, the subject that is selected has been taking opioids over the course of more than one year. In another embodiment, the subject that is selected has been taking opioids at least every other day over the course of at least two weeks. In one embodiment, the subject that is selected has been receiving at least 7 doses >25 mg of oral morphine equivalents over at least 14 days. In one embodiment, the subject that is selected has been receiving a daily dose of >50 mg of oral morphine equivalents for at least 14 days.
- the subject that is selected is constipated due to opioid therapy and has been receiving a daily dose of >50 mg of oral morphine equivalents for at least 14 days.
- the subject has been receiving a daily dose of >50 mg of oral morphine equivalents for at least 14 days; and has had less than three (3) rescue-free bowel movements per week on average over the least four consecutive weeks that were associated with one or more of the following: (a) a Bristol Stool Form Scale type 1 or 2 for at least 25% of the rescue-free bowel movements, (b) straining during at least 25% of the rescue-free bowel movements; and/or (c) a sensation of incomplete evacuation after at least 25% of the rescue-free bowel movements.
- a rescue-free bowel movement refers to a bowel movement associated with no laxative use within the 24 hours prior to the bowel movement.
- the subject selected for treatment with a methylnaltrexone formulation described herein is a subject suffering from opioid- induced constipation.
- the subject selected for treatment with a methylnaltrexone formulation described herein is a subject with advanced illness who is receiving palliative care and is suffering from opioid-induced constipation.
- the subject selected for treatment with a methylnaltrexone formulation described herein is a subject with advanced illness who is receiving palliative care and is suffering from opioid-induced constipation where response to laxative therapy (e.g., bisacodyl, senokot, docusate) has not been sufficient.
- laxative therapy e.g., bisacodyl, senokot, docusate
- the subject selected for treatment with a methylnaltrexone formulation described herein is a subject with non-malignant pain who is suffering from opioid-induced constipation. In certain embodiments, the subject selected for treatment with a methylnaltrexone formulation described herein is a subject with non-malignant pain who is suffering from opioid-induced constipation where response to laxative therapy (e.g., bisacodyl, senokot, docusate) has not been sufficient. In certain embodiments, the subject selected for treatment with a methylnaltrexone formulation described herein has not responded to standard laxative therapy. In certain embodiments, the subject selected for treatment with a methylnaltrexone formulation described herein has responded to standard laxative therapy. In certain embodiments, the subject selected for treatment with a
- methylnaltrexone formulation described herein is concurrently administered laxative therapy.
- angiogenesis and increase in lethal factor production from opportunistic infectious agents (e.g., Pseudomonas aeruginosa).
- Additional advantageous uses of provided formulations include treatment of opioid-induced immune suppression, inhibition of angiogenesis, inhibition of vascular proliferation, treatment of pain, treatment of inflammatory conditions such as inflammatory bowel syndrome, treatment of infectious diseases and diseases of the musculoskeletal system such as osteoporosis, arthritis, osteitis, periostitis, myopathies, and treatment of autoimmune diseases.
- provided formulations may be used in methods for preventing, inhibiting, reducing, delaying, diminishing or treating gastrointestinal dysfunction, including, but not limited to, irritable bowel syndrome, opioid-induced bowel dysfunction, colitis, post-operative or postpartum ileus, nausea and/or vomiting, decreased gastric motility and emptying, inhibition of the stomach, and small and/or large intestinal propulsion, increased amplitude of non-propulsive segmental
- formulations are also useful in treatment of conditions including cancers involving angiogenesis, immune suppression, sickle cell anemia, vascular wounds, and retinopathy, treatment of inflammation associated disorders (e.g. , irritable bowel syndrome), immune suppression, chronic inflammation.
- conditions including cancers involving angiogenesis, immune suppression, sickle cell anemia, vascular wounds, and retinopathy, treatment of inflammation associated disorders (e.g. , irritable bowel syndrome), immune suppression, chronic inflammation.
- provided formulations and unit dose forms are useful in preparation of medicaments, including, but not limited to medicaments useful in the treatment of side effects of opioid use, including gastrointestinal side effects (e.g. , inhibition of intestinal motility, GI sphincter constriction, constipation), nausea, emesis, vomiting, dysphoria, pruritis, or a combination thereof.
- Provided formulations are useful for preparations of medicaments, useful in treatment of patients receiving acute opioid therapy (e.g., patients suffering from post-operative gastrointestinal dysfunction receiving acute opioid administration) or subjects using opioids chronically (e.g.
- terminally ill patients receiving opioid therapy such as an AIDS patient, a cancer patient, a patient with cardiovascular disease; subjects receiving chronic opioid therapy for pain management (malignant or non-malignant pain); or subjects undergoing opioid therapy for maintenance of opioid withdrawal).
- preparation of medicaments useful in the treatment of pain treatment of inflammatory conditions such as inflammatory bowel syndrome, treatment of infectious diseases, treatment of diseases of the musculokeletal system such as osteoporosis, arthritis, osteitis, periostitis, myopathies, treatment of autoimmune diseases and immune suppression, therapy of post-operative gastrointestinal dysfunction following abdominal surgery (e.g., colectomy (e.g., right hemicolectomy, left hemicolectomy, transverse hemicolectomy, colectomy takedown, low anterior resection), idiopathic constipation, and ileus (e.g., post operative ileus, post partum ileus), and treatment of disorders such as cancers involving angiogenesiss, chronic inflammation and/or chronic pain, sickle cell angiogenesiss
- veterinary applications e.g., treatment of domestic animals, e.g., horse, dogs, cats
- use of provided formulations in veterinary applications analogous to those discussed above for human subjects is contemplated.
- equine gastrointestinal motility such as colic and constipation
- kits comprising formulations described herein, and a container (e.g., a foil or plastic package, or other suitable container).
- a container e.g., a foil or plastic package, or other suitable container.
- instructions for use are additionally provided in such kits.
- Methylnaltrexone bromide may be prepared according to the methods described in detail in international PCT Patent Application publication number, WO 2006/127899, or obtained from commercial sources such as Covidien, Saint Louis, Mo. Formulations containing methylnaltrexone were prepared using pharmaceutically acceptable excipients. Spheroids containing methylnaltrexone were prepared. Capsules were prepared by filling capsules with spheroids. Some capsules were prepared to contain enterically coated spheroids, which spheroids dissolve only after passing through the stomach. The capsules, without an enteric coat, or after dissolution of the enteric coat, will dissolve over 10-30 minutes. Tablets also were prepared from spheroids, using conventional techniques. The tablets dissolve in under 10 minutes.
- the spheroids were prepared by a wet granulation process followed by extrusion and spheronization, as described in the following general method.
- Methylnaltrexone bromide and pharmaceutically acceptable excipients were combined in an aqueous solution. Water was added until wet mass suitable for extrusion was obtained. The wet mass was passed through an extruder, and the extrudate was spheronized in a spheronizer. The resulting spheroids were dried in a fluid bed drier and passed through a screen. The uncoated spheroids were stored in appropriate container.
- Capsules containing enterically coated spheroids of methylnaltrexone as described in Example 1 were tested in patients suffering from opioid-induced constipation.
- the patients in this study were not chronic methadone maintenance patients.
- the patients had chronic non-malignant (not cancer) pain where the non- malignant condition underlying the chronic pain (e.g., osteoarthritis, back pain, neuropathic pain) had a documented history of at least 2 months before screening, stable pain for at least 1 month.
- the patients were on opioids for at least one month and at a daily dose of greater than or equal to 20 mg of morphine equivalents per day for at least two weeks before the screening visit and during the screening visit period with no anticipated changes during the study.
- Constipation defined as less than 3 bowel movements per week on average and 1 or more of the following: (i) hard or lumpy stools for at least 25% of bowel movements, (ii) a sensation of incomplete evacuation following at least 25% of bowel movements, (iii) straining during at least 25% of bowel movements.
- Patients were administered enterically coated methylnaltrexone capsules containing 10 mg , 50 mg , 150 mg , 300 mg or 450 mg of methylnaltrexone.
- the average peak plasma level of methylnaltrexone resulting from the doses was as follows: (i) for 10 mg, less than 1 ng/ml, (ii) for 50 mg, less than 5 ng/ml, (iii) for 150 mg, less than 5 ng/ml, (iv) for 300 mg, less than 10 ng/mL, amd (v) for 450 mg, less than 20 ng/mL.
- These capsules containing enterically coated preparations of methylnaltrexone were not effective for treating opioid-induced constipation. They did not induce laxation and did not cause more bowel movements in patients relative to controls.
- Capsules containing spheroids of methylnaltrexone, but without the enteric coating, prepared as described in Example l, were tested in patients receiving opioids for non-malignant pain.
- the patients in this study were not chronic methadone maintenance patients.
- the patients were selected on the basis of the same criteria as the criteria used in Example 2, except the minimum daily dose of opioids was equal to or greater than 30 mg, instead of 20 mg of morphine equivalents.
- Doses of 150 mg, 300 mg, 450 mg, and 600 mg were tested. These doses resulted in average peak plasma levels of between about 15 and 40 ng/ml, on the order of 3 or more times lower than the average peak plasma levels associated with effective doses of subcutaneous
- Tablets containing spheroids of methylnaltrexone, without an enteric coating, prepared as described in Example 1, were tested in patients receiving opioids for non-malignant pain.
- the patients in this study were not chronic methadone maintenance patients.
- the patients were selected on the basis of the same criteria as the criteria used in Example 3.
- Doses of 150 mg, 300 mg, 450 mg, and 600 mg were tested. These doses resulted in average peak plasma levels of between about 7 and 40 ng/ml.
- These tablets without an enteric coating showed statistically significant activity at one dose, but did not consistently induce laxation across all doses.
- Both tablets and capsules containing uncoated spheroids had similar compositions except that spheroids were compressed with pharmaceutically acceptable excipients to form tablets, while spheroids were encapsulated into hard gelatine shells to prepare capsules. Once contacted with an aqueous medium, the tablets disintegrated immediately and almost all the drug dissolved in less than 10 minutes. In contrast, it took 10 minutes for the capsule shells to dissolve and at least 30 minutes for the complete dissolution of the drug from the capsules.
- Plasma levels associated with both dosage forms containing uncoated spheroids were variable (tablets produced more consistent average peak plasma levels relative to the capsule) and overlapping among the subjects.
- Ion pairs of methylnaltrexone with amphiphilic pharmaceutically acceptable excipients were prepared and the apparent octanol- water partition coefficient (APC) was measured and compared to that of methylnaltrexone bromide.
- a predetermined amount of each of MNTX-heptyl sulfate and MNTX-dodecyl sulfate was dissolved in 2 mL of 1-octanol that was saturated with water. Two mL of water that was saturated with 1-octanol was added to each MNTX salt solution.
- the present Example describes the preparation of tablets containing methylnaltrexone, sodium dodecyl sulfate (SDS), and an effervescent disintegrant (sodium bicarbonate).
- SDS sodium dodecyl sulfate
- effervescent disintegrant sodium bicarbonate
- Polysorbate 80 (vegetable grade) 2.07 10.73
- microcrystalline cellulose based on actual potency, with corresponding adjustments made to microcrystalline cellulose.
- disodium/polysorbate 80 solution for approximately 4 minutes. Additional water might be added to obtain proper granulation. Note: the granulation steps may be completed in sub-batches to obtain larger batch sizes.
- Step 13 Take a portion of the blend, add to the magnesium stearate and bag blend. Note: Step 13 may not be required for batches larger than 50 kg.
- Tablets including methylnaltrexone bromide (150 mg), sodium dodecyl sulfate (SDS), and sodium bicarbonate were manufactured using the method described in Example 5.
- the tablet was placed in a dissolution apparatus with paddles at 100 rpm in 900 mL of 0.1 N HC1 at 37 °C. Samples were then removed at specified times points and analyzed by HPLC. The dissolution rates of two tablets were determined. The dissolution profile of the SDS tablet with sodium bicarbonate is shown in Figure 2. Greater than 90% of the methylnaltrexone from the tablets was dissolved within 11 minutes.
- the formulations (150 mg MNTX) were dosed to six dogs (9.4 - 13.7 kg) via oral administration following an overnight fast and blood samples were drawn at 0 (predose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after dosing; plasma was separated and assayed for methylnaltrexone content.
- This example reports on the efficacy of methylnaltrexone in the SDS tablet formulation at a dose of 300 and 450 mg administered orally to subjects with chronic non-malignant pain.
- Subjects enrolled in this study had to have a history of constipation due to opioid use for at least one month before the screening visit.
- the study was a phase 1, open-label, single dose, inpatient studies.
- Subjects received methylnaltrexone as a single dose (2x150 mg or 3x150 mg) of the SLS tablet formulation after an overnight fast of at least 10 hours.
- the dose was taken orally with 240 mL of room temperature water at approximately 0800 hours on day 1.
- Opioid medication was provided at approximately the same time every day.
- Each subject participated in the study for approximately 3 weeks. This included a screening evaluation within 3 weeks before test article administration and a 2 day/1 night inpatient period.
- FIG. 3 This figures shows a plot of the comparison between time and the percentage of patients having a first laxation response in patients with chronic malignant pain administered a methylnaltrexone (300 mg and 450 mg) SDS tablet after a 10 hour fast.
- the SLS tablet formulation resulted in increases in percentage laxation within 4 hours and within 24 hours in subject patients.
- Example 8 the percentage of patients who laxated within 4 hours of receiving a single initial dose of 450 mg of the SDS formulation of the invention was approximately 41%. In Example 8, the percentage of patients who laxated within 24 hours of receiving a single initial dose of 450 mg of the SDS formulation of the invention was approximately 72%.
- the percentage of subjects receiving placebo who laxated within 4 hours was on the order of about 9%-13%.
- the placebo response in the present study could be different from the previous studies due to such factors as the smaller study size and different inclusion/exclusion criteria.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Emergency Medicine (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Inorganic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Otolaryngology (AREA)
- Hospice & Palliative Care (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2789798A CA2789798C (en) | 2010-03-11 | 2011-03-10 | Oral formulations and lipophilic salts of methylnaltrexone |
MA35290A MA34146B1 (en) | 2010-03-11 | 2011-03-10 | ORAL FORMULATIONS AND LIPOPHILIC SALTS OF METHYLNALTREXONE |
MX2012009125A MX349145B (en) | 2010-03-11 | 2011-03-10 | Oral formulations and lipophilic salts of methylnaltrexone. |
AU2011224275A AU2011224275B2 (en) | 2010-03-11 | 2011-03-10 | Oral formulations and lipophilic salts of methylnaltrexone |
NZ601595A NZ601595A (en) | 2010-03-11 | 2011-03-10 | Oral formulations and lipophilic salts of methylnaltrexone |
SG2012057261A SG183133A1 (en) | 2010-03-11 | 2011-03-10 | Oral formulations and lipophilic salts of methylnaltrexone |
KR1020127026488A KR101913102B1 (en) | 2010-03-11 | 2011-03-10 | Oral formulations and lipophilic salts of methylnaltrexone |
CN201180013511.1A CN102918039B (en) | 2010-03-11 | 2011-03-10 | The oral formulations and lipophilic salt of methyl naltrexone |
BR112012022873-0A BR112012022873B1 (en) | 2010-03-11 | 2011-03-10 | PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION INCLUDING METHYLTREXONE BROMIDE AND SODIUM DODECYL SULFATE |
EA201270741A EA029096B1 (en) | 2010-03-11 | 2011-03-10 | Solid dosage form for oral administration comprising methylnaltrexone |
KR1020187030676A KR101982482B1 (en) | 2010-03-11 | 2011-03-10 | Oral formulations and lipophilic salts of methylnaltrexone |
UAA201211733A UA111717C2 (en) | 2010-03-11 | 2011-10-03 | ORAL INTRODUCTION AND METHYLNALTREXON LIPOPHILIC SALTS |
TNP2012000392A TN2012000392A1 (en) | 2010-03-11 | 2012-08-02 | Oral formulations and lipophilic salts of methylnaltrexone |
IL221452A IL221452A (en) | 2010-03-11 | 2012-08-14 | Oral formulations and lipophilic salts of methylnaltrexone |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US31301810P | 2010-03-11 | 2010-03-11 | |
US61/313,018 | 2010-03-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2011112816A1 true WO2011112816A1 (en) | 2011-09-15 |
Family
ID=44148539
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2011/027913 WO2011112816A1 (en) | 2010-03-11 | 2011-03-10 | Oral formulations and lipophilic salts of methylnaltrexone |
Country Status (32)
Country | Link |
---|---|
US (8) | US8524276B2 (en) |
EP (2) | EP3178472B1 (en) |
JP (4) | JP6143409B2 (en) |
KR (2) | KR101982482B1 (en) |
CN (2) | CN107308125B (en) |
AR (1) | AR080491A1 (en) |
AU (1) | AU2011224275B2 (en) |
BR (1) | BR112012022873B1 (en) |
CA (1) | CA2789798C (en) |
CL (1) | CL2012002192A1 (en) |
CO (1) | CO6630134A2 (en) |
CR (1) | CR20120476A (en) |
EA (1) | EA029096B1 (en) |
EC (1) | ECSP12012208A (en) |
ES (1) | ES2623926T3 (en) |
GE (1) | GEP201606550B (en) |
GT (1) | GT201200247A (en) |
HK (1) | HK1245673A1 (en) |
HU (1) | HUE033133T2 (en) |
IL (1) | IL221452A (en) |
MA (1) | MA34146B1 (en) |
MX (2) | MX368805B (en) |
MY (1) | MY160727A (en) |
NZ (3) | NZ702826A (en) |
PE (1) | PE20130063A1 (en) |
PL (2) | PL2371357T3 (en) |
SG (3) | SG183133A1 (en) |
TN (1) | TN2012000392A1 (en) |
TW (2) | TWI605814B (en) |
UA (2) | UA123856C2 (en) |
WO (1) | WO2011112816A1 (en) |
ZA (1) | ZA201808498B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013096444A1 (en) * | 2011-12-19 | 2013-06-27 | Salix Pharmaceuticals, Ltd. | Methods for treatment and prevention of opioid induced constipation using oral compositions of methylnaltrexone |
EP3718404A1 (en) | 2014-10-17 | 2020-10-07 | Salix Pharmaceuticals, Inc. | Use of methylnaltrexone to attenuate tumor progession |
WO2020225395A1 (en) * | 2019-05-07 | 2020-11-12 | Bausch Health Ireland Limited | Liquid oral dosage formulations of methylnaltrexone |
WO2023031955A1 (en) * | 2021-08-28 | 2023-03-09 | Redasani Vijayendrakumar Virendrakumar Ji | Oral pharmaceutical compositions of methylnaltrexone and salt thereof |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104383542B (en) | 2003-04-08 | 2017-09-26 | 普罗热尼奇制药公司 | Pharmaceutical formulation comprising methyl naltrexone |
MX351611B (en) | 2007-03-29 | 2017-10-20 | Wyeth Llc | Crystal forms of (r) -n-methylnaltrexone bromide and uses thereof. |
US9061076B2 (en) | 2007-05-25 | 2015-06-23 | North Carolina State University | Viral nanoparticle cell-targeted delivery platform |
AU2011224275B2 (en) | 2010-03-11 | 2015-10-01 | Wyeth Llc | Oral formulations and lipophilic salts of methylnaltrexone |
US8627816B2 (en) | 2011-02-28 | 2014-01-14 | Intelliject, Inc. | Medicament delivery device for administration of opioid antagonists including formulations for naloxone |
US8939943B2 (en) | 2011-01-26 | 2015-01-27 | Kaleo, Inc. | Medicament delivery device for administration of opioid antagonists including formulations for naloxone |
WO2015191686A1 (en) * | 2014-06-10 | 2015-12-17 | Salix Pharmaceuticals, Inc. | Methods of administering methylnaltrexone |
US10617686B2 (en) * | 2014-07-08 | 2020-04-14 | Hikma Pharmaceuticals Usa Inc. | Liquid naloxone spray |
US9642848B2 (en) * | 2014-07-08 | 2017-05-09 | Insys Development Company, Inc. | Sublingual naloxone spray |
US10441538B2 (en) * | 2014-07-08 | 2019-10-15 | Hikma Pharmaceuticals Usa Inc. | Liquid naloxone spray |
US11135155B2 (en) | 2014-07-08 | 2021-10-05 | Hikma Pharmaceuticals Usa Inc. | Liquid naloxone spray |
US10722510B2 (en) * | 2014-07-08 | 2020-07-28 | Hikma Pharmaceuticals Usa Inc. | Liquid naloxone spray |
CA3142214A1 (en) | 2019-06-03 | 2020-12-10 | Bausch Health Ireland Limited | Use of methylnaltrexone and rifaximin for treatment of increased gut permeability or associated disorders |
CA3177250A1 (en) | 2020-05-02 | 2021-11-11 | Bausch Health Ireland Limited | Methods of reducing mortality risk in subjects suffering from an underlying disease or condition by administration of methylnaltrexone |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030144510A1 (en) * | 2001-11-29 | 2003-07-31 | Schering Corporation | Preparation of pharmaceutical salts |
WO2008121860A1 (en) * | 2007-03-29 | 2008-10-09 | Wyeth | Peripheral opioid receptor and antagonists and uses thereof |
Family Cites Families (44)
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 |
US4861781A (en) | 1986-03-07 | 1989-08-29 | The University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
US4719215A (en) | 1986-03-07 | 1988-01-12 | University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
CA1297218C (en) | 1986-03-14 | 1992-03-10 | Edward David Weil | Thermally stable diphosphonate-type flame retardant additive for plastics |
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 |
US5780012A (en) | 1990-06-21 | 1998-07-14 | Huland; Edith | Method for reducing lung afflictions by inhalation of cytokine solutions |
WO1994008599A1 (en) | 1992-10-14 | 1994-04-28 | The Regents Of The University Of Colorado | Ion-pairing of drugs for improved efficacy and delivery |
US5866154A (en) | 1994-10-07 | 1999-02-02 | The Dupont Merck Pharmaceutical Company | Stabilized naloxone formulations |
DE19651551C2 (en) | 1996-12-11 | 2000-02-03 | Klinge Co Chem Pharm Fab | Opioid antagonist-containing galenic formulation |
WO1998035679A1 (en) | 1997-02-14 | 1998-08-20 | Gödecke Aktiengesellschaft | Stabilization of naloxonhydrochlorid |
US6559158B1 (en) | 1997-11-03 | 2003-05-06 | Ur Labs, Inc. | Use of methylnaltrexone and related compounds to treat chronic opioid use side affects |
US6274591B1 (en) | 1997-11-03 | 2001-08-14 | Joseph F. Foss | Use of methylnaltrexone and related compounds |
EP0913152B1 (en) | 1997-11-03 | 2001-12-19 | Stada Arzneimittel Ag | Stabilised combination of drugs comprising naloxone and an opioid analgesic |
US5972954A (en) | 1997-11-03 | 1999-10-26 | Arch Development Corporation | Use of methylnaltrexone and related compounds |
US20030158220A1 (en) | 1997-11-03 | 2003-08-21 | Foss Joseph F. | Use of methylnaltrexone and related compounds to treat chronic opioid use side effects |
GB0100115D0 (en) | 2001-01-04 | 2001-02-14 | Alchemia Pty Ltd | Delivery systems |
CN1525851A (en) * | 2001-05-11 | 2004-09-01 | ������ҩ������˾ | Abuse-resistant controlled-release opioid dosage form |
ATE446751T1 (en) | 2001-06-05 | 2009-11-15 | Univ Chicago | USE OF METHYLNALTREXONE TO TREAT IMMUNOSUPRESSION |
MXPA04003597A (en) | 2001-10-18 | 2004-07-30 | Nektar Therapeutics Al Corp | Polymer conjugates of opioid antagonists. |
CA2478558C (en) | 2002-03-14 | 2012-09-11 | Euro-Celtique, S.A. | Naltrexone hydrochloride compositions |
US20030191147A1 (en) | 2002-04-09 | 2003-10-09 | Barry Sherman | Opioid antagonist compositions and dosage forms |
CN104383542B (en) | 2003-04-08 | 2017-09-26 | 普罗热尼奇制药公司 | Pharmaceutical formulation comprising methyl naltrexone |
US20040259899A1 (en) | 2003-04-08 | 2004-12-23 | Sanghvi Suketu P. | Combination therapy for constipation |
MXPA05010819A (en) | 2003-04-08 | 2006-03-30 | Progenics Pharm Inc | The use of peripheral opiois antagonists, especially methylnaltrexone to treat irritable bowel syndrome. |
US8871269B2 (en) * | 2003-07-15 | 2014-10-28 | Evonik Corporation | Method for the preparation of controlled release formulations |
US8946262B2 (en) | 2003-12-04 | 2015-02-03 | Adolor Corporation | Methods of preventing and treating gastrointestinal dysfunction |
CA2550071A1 (en) | 2003-12-19 | 2005-07-07 | Schering Corporation | Pharmaceutical compositions |
JP2007517015A (en) * | 2003-12-31 | 2007-06-28 | ファイザー・プロダクツ・インク | Stabilized pharmaceutical solid composition of low solubility drug, poloxamer and stabilizing polymer |
CN1294728C (en) | 2004-08-05 | 2007-01-10 | 华为技术有限公司 | Method and system for providing QoS assurance in edge router |
WO2006039705A2 (en) | 2004-09-30 | 2006-04-13 | Becton, Dickinson And Company | Method for reducing or eliminating residue in a glass medical container and container made in accordance therewith |
US20060177380A1 (en) * | 2004-11-24 | 2006-08-10 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse of orally administered pharmaceutical products |
AR057035A1 (en) * | 2005-05-25 | 2007-11-14 | Progenics Pharm Inc | SYNTHESIS OF (R) -N-METHYLNTREXONE, PHARMACEUTICAL COMPOSITIONS AND USES |
TWI489984B (en) * | 2006-08-04 | 2015-07-01 | Wyeth Corp | Formulations for parenteral delivery of compounds and uses thereof |
WO2008021394A2 (en) * | 2006-08-15 | 2008-02-21 | Theraquest Biosciences, Llc | Pharmaceutical formulations of cannabinoids and method of use |
EP2059267B1 (en) * | 2006-08-16 | 2012-04-18 | Novartis AG | Temporal photo-bleaching of colored lens care solutions |
AU2007322269A1 (en) * | 2006-10-11 | 2008-05-29 | Alpharma Pharmaceuticals, Llc | Pharmaceutical compositions |
TW200843802A (en) | 2007-02-09 | 2008-11-16 | Drugtech Corp | Compositions for improving gastrointestinal nutrient and drug absorption |
MX351611B (en) * | 2007-03-29 | 2017-10-20 | Wyeth Llc | Crystal forms of (r) -n-methylnaltrexone bromide and uses thereof. |
JP5178064B2 (en) * | 2007-06-27 | 2013-04-10 | 富士フイルム株式会社 | Metal layer laminate having metal surface roughened layer and method for producing the same |
AU2009244805B2 (en) * | 2008-05-07 | 2013-01-10 | Nektar Therapeutics | Oral administration of peripherally-acting opioid antagonists |
CA2676881C (en) | 2008-09-30 | 2017-04-25 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
JP5525247B2 (en) * | 2009-08-04 | 2014-06-18 | 株式会社神戸製鋼所 | Copper alloy with high strength and excellent bending workability |
AU2011224275B2 (en) | 2010-03-11 | 2015-10-01 | Wyeth Llc | Oral formulations and lipophilic salts of methylnaltrexone |
TW201235609A (en) * | 2010-07-13 | 2012-09-01 | Koninkl Philips Electronics Nv | Low cost mounting of LEDs in TL-retrofit tubes |
-
2011
- 2011-03-10 AU AU2011224275A patent/AU2011224275B2/en active Active
- 2011-03-10 TW TW105105359A patent/TWI605814B/en active
- 2011-03-10 AR ARP110100757A patent/AR080491A1/en unknown
- 2011-03-10 SG SG2012057261A patent/SG183133A1/en unknown
- 2011-03-10 GE GEAP201112868A patent/GEP201606550B/en unknown
- 2011-03-10 MA MA35290A patent/MA34146B1/en unknown
- 2011-03-10 KR KR1020187030676A patent/KR101982482B1/en active IP Right Grant
- 2011-03-10 PE PE2012001538A patent/PE20130063A1/en active IP Right Grant
- 2011-03-10 MY MYPI2012003442A patent/MY160727A/en unknown
- 2011-03-10 NZ NZ702826A patent/NZ702826A/en unknown
- 2011-03-10 CN CN201710321015.1A patent/CN107308125B/en active Active
- 2011-03-10 EA EA201270741A patent/EA029096B1/en unknown
- 2011-03-10 SG SG10201606618PA patent/SG10201606618PA/en unknown
- 2011-03-10 CA CA2789798A patent/CA2789798C/en active Active
- 2011-03-10 SG SG10201501821RA patent/SG10201501821RA/en unknown
- 2011-03-10 WO PCT/US2011/027913 patent/WO2011112816A1/en active Application Filing
- 2011-03-10 TW TW100108143A patent/TWI589293B/en active
- 2011-03-10 NZ NZ601595A patent/NZ601595A/en unknown
- 2011-03-10 MX MX2015010803A patent/MX368805B/en unknown
- 2011-03-10 US US13/045,108 patent/US8524276B2/en active Active
- 2011-03-10 JP JP2011052316A patent/JP6143409B2/en active Active
- 2011-03-10 NZ NZ703564A patent/NZ703564A/en unknown
- 2011-03-10 CN CN201180013511.1A patent/CN102918039B/en active Active
- 2011-03-10 BR BR112012022873-0A patent/BR112012022873B1/en active IP Right Grant
- 2011-03-10 UA UAA201602306A patent/UA123856C2/en unknown
- 2011-03-10 KR KR1020127026488A patent/KR101913102B1/en active IP Right Grant
- 2011-03-10 MX MX2012009125A patent/MX349145B/en active IP Right Grant
- 2011-03-11 EP EP17153285.6A patent/EP3178472B1/en active Active
- 2011-03-11 ES ES11157837.3T patent/ES2623926T3/en active Active
- 2011-03-11 PL PL11157837T patent/PL2371357T3/en unknown
- 2011-03-11 EP EP11157837.3A patent/EP2371357B1/en active Active
- 2011-03-11 HU HUE11157837A patent/HUE033133T2/en unknown
- 2011-03-11 PL PL17153285T patent/PL3178472T3/en unknown
- 2011-10-03 UA UAA201211733A patent/UA111717C2/en unknown
-
2012
- 2012-08-02 TN TNP2012000392A patent/TN2012000392A1/en unknown
- 2012-08-07 CL CL2012002192A patent/CL2012002192A1/en unknown
- 2012-08-14 IL IL221452A patent/IL221452A/en active IP Right Grant
- 2012-08-23 GT GT201200247A patent/GT201200247A/en unknown
- 2012-09-19 CR CR20120476A patent/CR20120476A/en unknown
- 2012-10-02 EC ECSP12012208 patent/ECSP12012208A/en unknown
- 2012-10-10 CO CO12178897A patent/CO6630134A2/en unknown
-
2013
- 2013-07-31 US US13/956,050 patent/US9314461B2/en active Active
- 2013-08-14 US US13/966,779 patent/US8956651B2/en active Active
-
2015
- 2015-09-10 JP JP2015178184A patent/JP2016029054A/en active Pending
-
2016
- 2016-03-15 US US15/070,555 patent/US20160206612A1/en not_active Abandoned
-
2017
- 2017-08-07 JP JP2017152275A patent/JP6429955B2/en active Active
-
2018
- 2018-04-27 HK HK18105478.0A patent/HK1245673A1/en unknown
- 2018-10-30 JP JP2018203748A patent/JP6647368B2/en active Active
- 2018-12-13 US US16/219,159 patent/US10376505B2/en active Active
- 2018-12-13 US US16/219,681 patent/US10307417B2/en active Active
- 2018-12-18 ZA ZA2018/08498A patent/ZA201808498B/en unknown
-
2019
- 2019-06-24 US US16/450,157 patent/US10507206B2/en active Active
- 2019-10-25 US US16/664,239 patent/US20200121673A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030144510A1 (en) * | 2001-11-29 | 2003-07-31 | Schering Corporation | Preparation of pharmaceutical salts |
WO2008121860A1 (en) * | 2007-03-29 | 2008-10-09 | Wyeth | Peripheral opioid receptor and antagonists and uses thereof |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013096444A1 (en) * | 2011-12-19 | 2013-06-27 | Salix Pharmaceuticals, Ltd. | Methods for treatment and prevention of opioid induced constipation using oral compositions of methylnaltrexone |
CN104254332A (en) * | 2011-12-19 | 2014-12-31 | 萨利克斯药品有限公司 | Methods for treatment and prevention of opioid induced constipation using oral compositions of methylnaltrexone |
CN110384701A (en) * | 2011-12-19 | 2019-10-29 | 萨利克斯药品有限公司 | The method for treating and preventing opiates induction type constipation using methyl naltrexone Orally administered composition |
EP3718404A1 (en) | 2014-10-17 | 2020-10-07 | Salix Pharmaceuticals, Inc. | Use of methylnaltrexone to attenuate tumor progession |
WO2020225395A1 (en) * | 2019-05-07 | 2020-11-12 | Bausch Health Ireland Limited | Liquid oral dosage formulations of methylnaltrexone |
WO2023031955A1 (en) * | 2021-08-28 | 2023-03-09 | Redasani Vijayendrakumar Virendrakumar Ji | Oral pharmaceutical compositions of methylnaltrexone and salt thereof |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10507206B2 (en) | Oral formulations and lipophilic salts of methylnaltrexone | |
AU2016200133B2 (en) | Oral formulations and lipophilic salts of methylnaltrexone | |
AU2013203559B2 (en) | Oral formulations and lipophilic salts of methylnaltrexone |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201180013511.1 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11754078 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011224275 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012002192 Country of ref document: CL Ref document number: MX/A/2012/009125 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2789798 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12012501622 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 221452 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 2011224275 Country of ref document: AU Date of ref document: 20110310 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 001538-2012 Country of ref document: PE |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1201004587 Country of ref document: TH |
|
WWE | Wipo information: entry into national phase |
Ref document number: CR2012-000476 Country of ref document: CR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 8585/CHENP/2012 Country of ref document: IN |
|
ENP | Entry into the national phase |
Ref document number: 20127026488 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: A201211733 Country of ref document: UA Ref document number: 12868 Country of ref document: GE Ref document number: 12178897 Country of ref document: CO Ref document number: 201270741 Country of ref document: EA |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 11754078 Country of ref document: EP Kind code of ref document: A1 |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112012022873 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112012022873 Country of ref document: BR Kind code of ref document: A2 Effective date: 20120911 |