US20040266806A1 - Pharmaceutical formulation - Google Patents
Pharmaceutical formulation Download PDFInfo
- Publication number
- US20040266806A1 US20040266806A1 US10/821,811 US82181104A US2004266806A1 US 20040266806 A1 US20040266806 A1 US 20040266806A1 US 82181104 A US82181104 A US 82181104A US 2004266806 A1 US2004266806 A1 US 2004266806A1
- Authority
- US
- United States
- Prior art keywords
- methylnaltrexone
- pharmaceutical preparation
- canceled
- solution
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 229960002921 methylnaltrexone Drugs 0.000 claims abstract description 231
- JVLBPIPGETUEET-WIXLDOGYSA-O (3r,4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one Chemical compound C([N@+]1(C)[C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)C1CC1 JVLBPIPGETUEET-WIXLDOGYSA-O 0.000 claims abstract description 227
- 238000000034 method Methods 0.000 claims abstract description 87
- 239000000243 solution Substances 0.000 claims description 152
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 121
- 238000002360 preparation method Methods 0.000 claims description 96
- 239000003795 chemical substances by application Substances 0.000 claims description 88
- 239000007857 degradation product Substances 0.000 claims description 67
- 239000000203 mixture Substances 0.000 claims description 64
- 239000002738 chelating agent Substances 0.000 claims description 57
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 57
- 239000006172 buffering agent Substances 0.000 claims description 55
- 150000003839 salts Chemical class 0.000 claims description 54
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical group OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 46
- -1 alkyl gallate Chemical compound 0.000 claims description 45
- 239000003963 antioxidant agent Substances 0.000 claims description 44
- 235000006708 antioxidants Nutrition 0.000 claims description 44
- 238000009472 formulation Methods 0.000 claims description 39
- 230000003078 antioxidant effect Effects 0.000 claims description 35
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 31
- 230000015556 catabolic process Effects 0.000 claims description 28
- 238000006731 degradation reaction Methods 0.000 claims description 28
- 230000002401 inhibitory effect Effects 0.000 claims description 23
- 239000000047 product Substances 0.000 claims description 22
- 239000007979 citrate buffer Substances 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 238000003860 storage Methods 0.000 claims description 17
- 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 claims description 16
- 229930195725 Mannitol Natural products 0.000 claims description 16
- 239000002577 cryoprotective agent Substances 0.000 claims description 16
- 239000000594 mannitol Substances 0.000 claims description 16
- 235000010355 mannitol Nutrition 0.000 claims description 16
- 239000011780 sodium chloride Substances 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims description 14
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound 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 claims description 14
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 claims description 14
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 14
- 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 14
- 229960000482 pethidine Drugs 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 238000001802 infusion Methods 0.000 claims description 11
- 239000001509 sodium citrate Substances 0.000 claims description 11
- 230000001954 sterilising effect Effects 0.000 claims description 11
- 238000004659 sterilization and disinfection 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
- 230000000694 effects Effects 0.000 claims description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000003708 ampul Substances 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- 229920005862 polyol Polymers 0.000 claims description 8
- 150000003077 polyols Chemical group 0.000 claims description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 8
- 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 claims description 7
- 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 claims description 7
- 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 claims description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 7
- 206010010774 Constipation Diseases 0.000 claims description 7
- 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 claims description 7
- 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 claims description 7
- 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 claims description 7
- 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 claims description 7
- 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 claims description 7
- 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 claims description 7
- 239000008896 Opium Substances 0.000 claims description 7
- 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 claims description 7
- 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 claims description 7
- 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 claims description 7
- 229960001391 alfentanil Drugs 0.000 claims description 7
- 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 claims description 7
- 229960002512 anileridine Drugs 0.000 claims description 7
- 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 claims description 7
- 229950002202 asimadoline Drugs 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 229950008841 bremazocine Drugs 0.000 claims description 7
- 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 claims description 7
- 229960001113 butorphanol Drugs 0.000 claims description 7
- 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 claims description 7
- 229960004126 codeine Drugs 0.000 claims description 7
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 7
- 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 claims description 7
- 229960004193 dextropropoxyphene Drugs 0.000 claims description 7
- 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 claims description 7
- 229960003461 dezocine Drugs 0.000 claims description 7
- 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 claims description 7
- 229960000920 dihydrocodeine Drugs 0.000 claims description 7
- 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 claims description 7
- 229960004192 diphenoxylate Drugs 0.000 claims description 7
- 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 claims description 7
- 229950008449 fedotozine Drugs 0.000 claims description 7
- 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 claims description 7
- 229960002428 fentanyl Drugs 0.000 claims description 7
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 claims description 7
- 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 claims description 7
- 229960000240 hydrocodone Drugs 0.000 claims description 7
- 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 claims description 7
- 229960001410 hydromorphone Drugs 0.000 claims description 7
- 239000008101 lactose Substances 0.000 claims description 7
- 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 claims description 7
- 229960000263 levallorphan Drugs 0.000 claims description 7
- 229960003406 levorphanol Drugs 0.000 claims description 7
- 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 claims description 7
- 229960001571 loperamide Drugs 0.000 claims description 7
- 239000012931 lyophilized formulation Substances 0.000 claims description 7
- 229960001797 methadone Drugs 0.000 claims description 7
- 229960005181 morphine Drugs 0.000 claims description 7
- 229960000805 nalbuphine Drugs 0.000 claims description 7
- 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 claims description 7
- 229960000938 nalorphine Drugs 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 229960001027 opium Drugs 0.000 claims description 7
- 229960002085 oxycodone Drugs 0.000 claims description 7
- 229960005118 oxymorphone Drugs 0.000 claims description 7
- 229960005301 pentazocine Drugs 0.000 claims description 7
- 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 claims description 7
- ZBAFFZBKCMWUHM-UHFFFAOYSA-N propiram Chemical compound C=1C=CC=NC=1N(C(=O)CC)C(C)CN1CCCCC1 ZBAFFZBKCMWUHM-UHFFFAOYSA-N 0.000 claims description 7
- 229950003779 propiram Drugs 0.000 claims description 7
- 229960003394 remifentanil Drugs 0.000 claims description 7
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 7
- 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 claims description 7
- 229960004739 sufentanil Drugs 0.000 claims description 7
- 229960001402 tilidine Drugs 0.000 claims description 7
- 229960004380 tramadol Drugs 0.000 claims description 7
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 claims description 7
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 claims description 7
- 229960005345 trimebutine Drugs 0.000 claims description 7
- 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 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 6
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
- 235000010323 ascorbic acid Nutrition 0.000 claims description 5
- 239000011668 ascorbic acid Substances 0.000 claims description 5
- 229960005070 ascorbic acid Drugs 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 5
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 5
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 5
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 5
- 229960005055 sodium ascorbate Drugs 0.000 claims description 5
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 5
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 5
- 229940038773 trisodium citrate Drugs 0.000 claims description 5
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 4
- 239000004471 Glycine Substances 0.000 claims description 4
- 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 claims description 4
- 150000000996 L-ascorbic acids Chemical class 0.000 claims description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 4
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 4
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 4
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims description 4
- 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 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 4
- 229960001484 edetic acid Drugs 0.000 claims description 4
- 235000014304 histidine Nutrition 0.000 claims description 4
- 235000014655 lactic acid Nutrition 0.000 claims description 4
- 239000004310 lactic acid Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 239000011976 maleic acid Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 229960003966 nicotinamide Drugs 0.000 claims description 4
- 235000005152 nicotinamide Nutrition 0.000 claims description 4
- 239000011570 nicotinamide Substances 0.000 claims description 4
- 239000002504 physiological saline solution Substances 0.000 claims description 4
- 238000012545 processing Methods 0.000 claims description 4
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 4
- 235000010234 sodium benzoate Nutrition 0.000 claims description 4
- 239000004299 sodium benzoate Substances 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 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 claims description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 4
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 4
- 239000001540 sodium lactate Substances 0.000 claims description 4
- 235000011088 sodium lactate Nutrition 0.000 claims description 4
- 229940005581 sodium lactate Drugs 0.000 claims description 4
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 4
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- 229940074404 sodium succinate Drugs 0.000 claims description 4
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 claims description 4
- 235000010265 sodium sulphite Nutrition 0.000 claims description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims description 4
- 235000010384 tocopherol Nutrition 0.000 claims description 4
- 239000011732 tocopherol Substances 0.000 claims description 4
- 229960001295 tocopherol Drugs 0.000 claims description 4
- 229930003799 tocopherol Natural products 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 3
- 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 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 3
- 229940095259 butylated hydroxytoluene Drugs 0.000 claims description 3
- 239000008121 dextrose Substances 0.000 claims description 3
- 229960002449 glycine Drugs 0.000 claims description 3
- 229960000448 lactic acid Drugs 0.000 claims description 3
- 229940098895 maleic acid Drugs 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 238000011146 sterile filtration Methods 0.000 claims 1
- 239000008380 degradant Substances 0.000 description 18
- 239000003085 diluting agent Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 13
- 229940005483 opioid analgesics Drugs 0.000 description 13
- 239000000463 material Substances 0.000 description 12
- 229960004106 citric acid Drugs 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 239000002245 particle Substances 0.000 description 10
- 239000008351 acetate buffer Substances 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 208000008384 ileus Diseases 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 230000001684 chronic effect Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000001356 surgical procedure Methods 0.000 description 6
- 239000000499 gel Substances 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 4
- 206010013954 Dysphoria Diseases 0.000 description 4
- 206010052405 Gastric hypomotility Diseases 0.000 description 4
- 206010021518 Impaired gastric emptying Diseases 0.000 description 4
- 206010028813 Nausea Diseases 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 206010054048 Postoperative ileus Diseases 0.000 description 4
- 208000003251 Pruritus Diseases 0.000 description 4
- 206010046555 Urinary retention Diseases 0.000 description 4
- 206010047700 Vomiting Diseases 0.000 description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000008693 nausea Effects 0.000 description 4
- 230000036407 pain Effects 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 229910001220 stainless steel Inorganic materials 0.000 description 4
- 239000010935 stainless steel Substances 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 206010000060 Abdominal distension Diseases 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010004663 Biliary colic Diseases 0.000 description 3
- 208000001953 Hypotension Diseases 0.000 description 3
- 206010062016 Immunosuppression Diseases 0.000 description 3
- HLMSIZPQBSYUNL-IPOQPSJVSA-N Noroxymorphone Chemical group O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4 HLMSIZPQBSYUNL-IPOQPSJVSA-N 0.000 description 3
- 102000003840 Opioid Receptors Human genes 0.000 description 3
- 108090000137 Opioid Receptors Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000019790 abdominal distention Diseases 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000010234 biliary secretion Effects 0.000 description 3
- 208000024330 bloating Diseases 0.000 description 3
- 208000006218 bradycardia Diseases 0.000 description 3
- 230000036471 bradycardia Effects 0.000 description 3
- 238000011010 flushing procedure Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 230000030136 gastric emptying Effects 0.000 description 3
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 3
- 230000007160 gastrointestinal dysfunction Effects 0.000 description 3
- 230000005176 gastrointestinal motility Effects 0.000 description 3
- 230000036543 hypotension Effects 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 208000002551 irritable bowel syndrome Diseases 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 3
- 229960004127 naloxone Drugs 0.000 description 3
- 239000003401 opiate antagonist Substances 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 210000005070 sphincter Anatomy 0.000 description 3
- 230000035900 sweating Effects 0.000 description 3
- 208000004998 Abdominal Pain Diseases 0.000 description 2
- 206010000087 Abdominal pain upper Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 2
- 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 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 208000001640 Fibromyalgia Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010061598 Immunodeficiency Diseases 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 206010027603 Migraine headaches Diseases 0.000 description 2
- 239000012901 Milli-Q water Substances 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010061339 Perineal pain Diseases 0.000 description 2
- 239000004698 Polyethylene Substances 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
- 229930006000 Sucrose Natural products 0.000 description 2
- 206010043269 Tension headache Diseases 0.000 description 2
- 208000008548 Tension-Type Headache Diseases 0.000 description 2
- 238000012084 abdominal surgery Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 150000003842 bromide salts Chemical class 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 229960004926 chlorobutanol Drugs 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000009699 differential effect Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 229940009662 edetate Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000001631 haemodialysis Methods 0.000 description 2
- 239000001307 helium Substances 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 2
- 230000000322 hemodialysis Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 229960002834 methylnaltrexone bromide Drugs 0.000 description 2
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 2
- 239000003887 narcotic antagonist Substances 0.000 description 2
- 230000007823 neuropathy Effects 0.000 description 2
- 201000001119 neuropathy Diseases 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 208000007056 sickle cell anemia Diseases 0.000 description 2
- 208000020431 spinal cord injury Diseases 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 2
- 229960000984 tocofersolan Drugs 0.000 description 2
- 229940042585 tocopherol acetate Drugs 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 239000002076 α-tocopherol Substances 0.000 description 2
- 235000004835 α-tocopherol Nutrition 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
- IFGIYSGOEZJNBE-KNLJMPJLSA-N (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@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)CC1CC1 IFGIYSGOEZJNBE-KNLJMPJLSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 239000004261 Ascorbyl stearate Substances 0.000 description 1
- LITUBCVUXPBCGA-WMZHIEFXSA-N Ascorbyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O LITUBCVUXPBCGA-WMZHIEFXSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-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
- 235000001809 DL-alpha-tocopherylacetate Nutrition 0.000 description 1
- 239000011626 DL-alpha-tocopherylacetate 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
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- SHWNNYZBHZIQQV-UHFFFAOYSA-J EDTA monocalcium diisodium salt Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-J 0.000 description 1
- 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 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010021333 Ileus paralytic Diseases 0.000 description 1
- 201000005081 Intestinal Pseudo-Obstruction Diseases 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000000450 Pelvic Pain Diseases 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001305 Poly(isodecyl(meth)acrylate) Polymers 0.000 description 1
- 229920002319 Poly(methyl acrylate) Polymers 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- FFRKTLXKIPHZTJ-UHFFFAOYSA-N acetic acid 2-hydroxy-2-(2-oxo-2-sulfanylethyl)butanedioic acid 2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound C(C)(=O)O.C(CC(O)(C(=O)O)CC(=O)O)(=O)O.C(CC(O)(C(=O)O)CC(=O)O)(=S)O FFRKTLXKIPHZTJ-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- 230000002547 anomalous effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 238000007486 appendectomy Methods 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 235000019276 ascorbyl stearate Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229940066595 beta tocopherol Drugs 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 235000010376 calcium ascorbate Nutrition 0.000 description 1
- 239000011692 calcium ascorbate Substances 0.000 description 1
- 229940047036 calcium ascorbate Drugs 0.000 description 1
- BLORRZQTHNGFTI-ZZMNMWMASA-L calcium-L-ascorbate Chemical compound [Ca+2].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] BLORRZQTHNGFTI-ZZMNMWMASA-L 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000005323 carbonate salts Chemical class 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000012321 colectomy Methods 0.000 description 1
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003413 degradative effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 235000010389 delta-tocopherol Nutrition 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 229940095629 edetate calcium disodium Drugs 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 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
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- SYUXAJSOZXEFPP-UHFFFAOYSA-N glutin Natural products COc1c(O)cc2OC(=CC(=O)c2c1O)c3ccccc3OC4OC(CO)C(O)C(O)C4O SYUXAJSOZXEFPP-UHFFFAOYSA-N 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000009802 hysterectomy Methods 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 235000000396 iron Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 239000002357 osmotic agent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 201000007620 paralytic ileus Diseases 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001490 poly(butyl methacrylate) polymer Polymers 0.000 description 1
- 229920000212 poly(isobutyl acrylate) Polymers 0.000 description 1
- 229920000205 poly(isobutyl methacrylate) Polymers 0.000 description 1
- 229920000196 poly(lauryl methacrylate) Polymers 0.000 description 1
- 229920000184 poly(octadecyl acrylate) Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000129 polyhexylmethacrylate Polymers 0.000 description 1
- 229920000197 polyisopropyl acrylate Polymers 0.000 description 1
- 229920000182 polyphenyl methacrylate Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 238000007467 rectal resection Methods 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 229940033663 thimerosal Drugs 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229960005066 trisodium edetate Drugs 0.000 description 1
- 239000011590 β-tocopherol Substances 0.000 description 1
- 235000007680 β-tocopherol Nutrition 0.000 description 1
- 239000002478 γ-tocopherol Substances 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
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- 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
- A61P1/12—Antidiarrhoeals
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
-
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
Definitions
- This invention relates to methylnaltrexone pharmaceutical preparations, methylnaltrexone formulations, methylnaltrexone kits, and methods of making the same.
- Quaternary amine opioid antagonist derivatives have been shown to have utility in a number of contexts. They are considered peripherally acting only, and, therefore, find particular utility in reducing the side-effects of opioids without reducing the analgesic effect of opioids. Such side effects include nausea, emesis, dysphoria, pruritis, urinary retention, bowel hypomotility, constipation, gastric hypomotility, delayed gastric emptying and immune suppression.
- the utility of these peripherally acting opioid antagonists is not limited to reducing side-effects stemming from opioid analgesic treatment. Instead, these derivatives also have utility in circumstances where endogenous opioids alone (or in conjunction with exogenous opioid treatment) cause undesirable conditions such as ileus and other such conditions including, but not limited to, those mentioned above.
- Methylnaltrexone is a quaternary amine opioid antagonist derivative, discovered in the mid-70s. Methylnaltrexone and some of its uses are described in U.S. Pat. Nos. 4,176,186, 4,719,215, 4,861,781, 5,102,887, 5,972,954, and 6,274,591. Stable formulations of methylnaltrexone, however, have heretofore not existed. Methylnaltrexone apparently was assumed to have a structure that was inherently stable. The stability of a pharmaceutical composition in solution, however, is not necessarily predictable either over time when stored at room temperature or when autoclaved.
- Naloxone is an opioid antagonist that acts both centrally and peripherally. It differs structurally from methylnaltrexone and would be expected to have a different stability in solution.
- An allegedly stable formulation of naloxone is described in U.S. Pat. No. 5,866,154.
- methylnaltrexone is unusually unstable. It further has been discovered that methylnaltrexone has certain degradation products different from those of naloxone. It also has been discovered that critical parameters and conditions are required for stable formulations of methylnaltrexone.
- the invention provides a composition or preparation that is a solution of methylnaltrexone or a salt thereof, wherein the preparation after autoclaving has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone or salt thereof in the preparation.
- concentration of such degradation products does not exceed 1.5%, 1%, 0.5%, 0.25%, or even 0.125% of the methylnaltrexone or salt thereof in the preparation.
- the composition or preparation can contain one of, any combination of, or all of a chelating agent, a buffering agent, an anti-oxidant, a cryoprotecting agent, an isotonicity agent and an opioid.
- the preferred chelating agent is disodium edetate or a derivative thereof.
- the disodium edetate preferably is at a concentration ranging from between 0.001 and 100 mg/ml, more preferably 0.05 to 25.0 mg/ml, and even more preferably, 0.1 to 2.5 mg/ml.
- a preferred buffering agent is citrate buffer.
- the citrate buffer typically is in a concentration ranging from 0.001 to 100.0 mM, preferably from 0.1 to 10 mM, and more preferably, 0.1 to 5.0 mM.
- a preferred cryoprotecting agent is mannitol.
- the composition or preparation preferably has a pH that does not exceed 4.25. More preferably, the pH ranges from 2.0 to 4.0, 3.0 to 4.0, and most preferably, from 3.0 to 3.5.
- a composition or preparation which includes a solution of methylnaltrexone or a salt thereof, wherein the preparation after storage at about room temperature for six months has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone in the preparation.
- the concentration of the methylnaltrexone degradation products preferably does not exceed 1.5%, 1.0%, 0.5%, 0.25%, and even 0.125% of the methylnaltrexone in the preparation.
- the composition or preparation can contain one of, any combination of, or all of a chelating agent, a buffering agent, an anti-oxidant, a cryoprotecting agent, an isotonicity agent and an opioid.
- the preferred chelating agent and concentrations are as described above.
- the preferred buffering agent and concentrations are as described above.
- the composition or preparation has a pH that does not exceed 4.25. The preferred pHs and ranges are as described above.
- a stable composition or preparation is provided.
- the composition or preparation is a solution of methylnaltrexone or a salt thereof wherein the pH is below 4.25.
- the pH is between 2.75 and 4.25, more preferably, between 3.0 and 4.0, and most preferably, between 3.0 and 3.5.
- pH can be adjusted with an acid.
- acids useful for this purpose include hydrochloric acid, citric acid, sulfuric acid, acetic acid, and phosphoric acid.
- the stable composition or preparation can also include any one of, any combination of, or all of a chelating agent, a buffering agent, an isotonicity agent, an antioxidant, a cryogenic agent, and an opioid.
- a stable composition or preparation is provided.
- the composition or preparation is a solution of methylnaltrexone or salt thereof, wherein the solution further comprises a chelating agent in an amount sufficient to inhibit degradation of the methylnaltrexone or salt thereof, whereby the amount is such that the composition or preparation after autoclaving has a concentration of methylnaltrexone degradation products that does not exceed 0.5%, 0.25% or even 0. 125% of the methylnaltrexone or salt thereof in the composition or preparation.
- the composition or preparation can further include any one of, any combination of, or all of a buffering agent, an isotonicity agent, an antioxidant and an opioid. Preferred chelating agents, buffering agents and pHs are as described above.
- a composition or preparation is provided.
- the composition or preparation is a solution of methylnaltrexone or salt thereof in at least one methylnaltrexone degradation inhibiting agent.
- the agent can be any one of, any combination of, or all of a chelating agent, a buffering agent, and an antioxidant, provided that the solution has a pH ranging from 2.0 to 6.0.
- the degradation inhibiting agent is present in an amount sufficient to render the composition or preparation stable, wherein the composition or preparation is processed under at least one sterilization technique, and wherein the composition or preparation is substantially free of methylnaltrexone degradation products.
- the composition or preparation can be stable to storage for at least six months, at least twelve months, or at least twenty-four months, at about room temperature.
- the composition or preparation is stable after autoclaving.
- the composition or preparation further may include either or both of an isotonicity agent and an opioid.
- the pH of the solution is between 2.75 and 4.25, more preferably, between 3.0 and 4.0, and most preferably, between 3.0 and 3.5.
- the composition or preparation can be a pharmaceutical composition.
- the methylnaltrexone can be present in a therapeutically effective amount.
- the concentration of methylnaltrexone ranges from 0.01 to 100 mg/ml. In other embodiments, the methylnaltrexone concentration ranges between 0.1 and 100.0 mg/ml. In other embodiments, the methylnaltrexone ranges between 1.0 and 50.0 mg/ml.
- the methylnaltrexone can be present in an amount sufficient to treat nausea, emesis, dysphoria, pruritus, urinary retention, ileus, post-operative ileus, post-partum ileus, paralytic ileus, bowel hypomotility, constipation, gastric hypomotility, delayed gastric emptying, decreased biliary secretion, decreased pancreatic secretion, biliary spasm, increased sphincter tone, cutaneous flushing, impaction, sweating, inhibition of gastrointestinal motility, inhibition of gastric emptying, gastrointestinal dysfunction, incomplete evacuation, bloating, abdominal distention, increased gastroesophageal reflux, hypotension, bradycardia, irritable bowel syndrome, or immunosuppression.
- the methylnaltrexone can be present in an amount sufficient to accelerate discharge from hospital post-surgery (including abdominal surgeries such as rectal resection, colectomy, stomach, esophageal, duodenal, appendectomy, hysterectomy, or non-abdominal surgeries such as orthopedic, trauma injuries, thoracic or transplantation), for example, by accelerating bowel sounds after surgery, or speeding the time to first food intake or first bowel movement.
- the amount is sufficient to induce laxation. This has particular application where the subject is a chronic opioid user.
- the solution of methylnaltrexone or salt thereof may be contained in a sealed container such as a bottle, an infusion bag, a syringe, a vial, a vial with a septum, an ampoule, an ampoule with a septum, or a syringe.
- the container may include indicia indicating that the solution has been autoclaved or otherwise subjected to a sterilization technique.
- any of the foregoing embodiments is lyophilized, preferably in the presence of a cryoprotecting agent.
- the invention therefore provides a lyophilized preparation of methylnaltrexone.
- the lyophilized preparation is a stable preparation, containing less than 1%, less than 0.5%, less than 0.25% and even less than 0.125% methylnaltrexone degradation product.
- the preparation can contain a cryoprotecting agent, which preferably is neutral or acidic in water.
- a product is provided.
- the product is a stable lyophilized formulation of methylnaltrexone, wherein the formulation upon reconstitution and water at a concentration of 20 mg/ml has a pH of between 2 and 6.
- the formulation upon reconstitution has a pH of about 2, about 3, about 4, about 5, or about 6.
- the formulation can include a cryoprotecting agent present in amounts sufficient to render the formulation stable.
- the cryoprotecting agent in important embodiments are polymerized carbohydrates.
- a preferred cryoprotecting agent is mannitol. Any one of the foregoing solutions described above can be lyophilized. It therefore is an aspect of the invention that such materials include one or any combination of a buffering agent, a chelating agent, an antioxidant, and an isotonicity agent. Preferred materials are as described above.
- a product that includes methylnaltrexone and the degradation inhibiting agent selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, and combinations thereof, wherein the degradation inhibiting agent is present in an amount sufficient to render stable the solution of the product containing a concentration of 20 mg/ml methylnaltrexone in water.
- the product when in solution at a concentration of 20 mg/ml methylnaltrexone yields a pH of between 2 and 6.
- a pharmaceutical preparation contains methylnaltrexone, sodium chloride, citric acid, trisodium citrate, and disodium edetate.
- the methylnaltrexone is present between 20 and 40 mg/ml
- the sodium chloride is present between 2 and 6 mg/ml
- the citric acid is present between 0.05 and 0.1 mg/ml
- the trisodium citrate is present between 0.025 and 0.075 mg/ml
- the disodium edetate is present between 0.5 and 1.0 mg/ml.
- the buffering agent may be any pharmaceutically acceptable buffering agent.
- Common buffering agents include citric acid, sodium citrate, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartaric acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazole, sodium bicarbonate and carbonic acid, sodium succinate and succinic acid, histidine, and sodium benzoate and benzoic acid.
- the preferred buffering agent is a citrate buffering agent.
- the chelating agent may be any pharmaceutically acceptable chelating agent.
- Common chelating agents include ethylenediaminetetraacetic acid (EDTA) and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, and sodium desoxycholate and derivatives thereof.
- EDTA ethylenediaminetetraacetic acid
- the preferred chelating agent is disodium edetate.
- the antioxidant may be any pharmaceutically acceptable antioxidant.
- Common antioxidants include those selected from the group consisting of an ascorbic acid derivative, butylated hydroxy anisole, butylated hydroxy toluene, alkyl gallate, sodium meta-bisulfite, sodium bisulfite, sodium dithionite, sodium thioglycollic acid, sodium formaldehyde sulfoxylate, tocopherol and derivatives thereof, monothioglycerol, and sodium sulfite.
- the preferred antioxidant is monothioglycerol.
- the cryoprotecting agent may be any pharmaceutically acceptable cryoprotecting agent.
- Common cryoprotecting agents include histidine, polyethylene qlycol, polyvinyl pyrrolidine, lactose, sucrose, and mannitol.
- Improtant cryoprotecting agents are polyols.
- the preferred cryoprotecting agent of the invention is mannitol.
- the opioid can be any pharmaceutically acceptable opioid.
- Common opioids are those selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol.
- the isotonicity agent can be any pharmaceutically acceptable isotonicity agent.
- Common isotonicity agents include those selected from the group consisting of sodium chloride, mannitol, lactose, dextrose, glycerol, and sorbitol.
- the preferred isotonicity agent is mannitol.
- the pharmaceutical preparation may optionally comprise a preservative.
- preservatives include those selected from the group consisting of chlorobutanol, parabens, thimerosol, benzyl alcohol, and phenol.
- a method for preparing an autoclaved preparation of a solution of methylnaltrexone or salts thereof, whereby the autoclaved preparation has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone or salt thereof in the preparation.
- the method involves providing a solution, having a pH of 4.25 or less, of methylnaltrexone or a salt thereof, and being substantially free of methylnaltrexone degradation products, and autoclaving the solution.
- the solution can contain, optionally, any one of, any combination of, or all of a chelating agent, an isotonicity agent, a buffering agent, an antioxidant, a cryoprotecting agent, and an opioid.
- a chelating agent an isotonicity agent
- a buffering agent an antioxidant
- a cryoprotecting agent an opioid
- the pH of the solution ranges from 2.0 to 4.0. More preferably, from 3.0 to 4.0, and most preferably from 3.0 to 3.5.
- Preferred chelating agents, isotonicity agents, buffering agents, antioxidants, cryoprotecting agents, and opioids are as described above.
- Preferred concentrations of methylnaltrexone likewise, are as described above.
- a method for preparing an autoclaved preparation.
- the preparation has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone or salt thereof in the preparation.
- the method involves providing a solution containing methylnaltrexone or salt thereof and a chelating agent, the solution being substantially free of methylnaltrexone degradation products, and then autoclaving the solution.
- the chelating agent is present in an amount sufficient to protect the preparation against substantial unwanted degradation of methylnaltrexone or its salt, and maintain the solution to be substantially free of methylnaltrexone degradation products.
- Preferred chelating agents and concentrations thereof are as described above.
- the preparation may include, optionally, any one of, any combination of, or all of a buffering agent, an isotonicity agent, an antioxidant, a cryoprotecting agent, and an opioid.
- a buffering agent an isotonicity agent, an antioxidant, a cryoprotecting agent, and an opioid.
- Preferred buffering agents, isotonicity agents, antioxidants and opioids, as well as concentrations, are as described above.
- Preferred pHs of the solution likewise are as described above.
- the degradation products after autoclaving do not exceed 1.5%, 1%, 0.5%, 0.25% or even 0.125%.
- a method for inhibiting the formation of methylnaltrexone degradation products in a preparation that is a solution of methylnaltrexone or salts thereof.
- the method involves preparing an aqueous solution containing at least one methylnaltrexone degradation inhibiting agent selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, a cryoprotecting agent, and combinations thereof.
- a powdered source of methylnaltrexone or salt thereof is dissolved into the solution to form the preparation.
- the preparation has or is adjusted without addition of a pH-adjusting base to have a pH of between 2 and 6.
- the pharmaceutical preparation is adjusted to have a pH ranging from 3 to 5, more preferably, 3 to 4, and most preferably, 3.0 to 3.5.
- An isotonicity agent may be added to the solution.
- an opioid may be added to the solution.
- the preparation can be a pharmaceutical preparation.
- a method for preparing a stable pharmaceutical preparation that is an aqueous solution of methylnaltrexone or salts thereof to inhibit formation of methylnaltrexone degradation products.
- a solution is provided containing methylnaltrexone or salts thereof and at least one methylnaltrexone degradation inhibiting agent.
- the solution is processed under at least one sterilization technique prior to and/or after terminal filling the solution in a sealable container to form the stable pharmaceutical preparation, wherein the method is carried out without the addition of pH-adjusting base to the solution.
- the methylnaltrexone degradation inhibiting agent can be selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, and combinations thereof.
- An isotonicity agent can be added.
- a cryoprotecting agent can also be added.
- an opioid can be added.
- Preferred chelating agents, buffering agents, antioxidants, isotonicity agents, cryoprotecting agents, and opioids are as described above. Preferred concentrations are as described above.
- the solution may be processed to adjust the pH. This is preferably done using an acid. Most preferably, the solution is adjusted to a range between a pH of 2 and 6, more preferably, between 3 and 5, 3 and 4, and most preferably between 3.0 and 3.5.
- the material can be contained in a sealed container. The container can be purged with nitrogen and/or sparged to eliminate oxygen.
- parenteral formulations are provided.
- the formulation made by dissolving methylnaltrexone diluted in water, to which mannitol is added. The solution is then filter sterilized followed by lyophilization. Therefore, the product may be provided in lyophilized form, and in combination with certain cryoprotectants such as mannitol or lactose.
- a reconstituting diluent is provided, such as a physiological saline diluent.
- a kit is provided.
- the kit is a package containing a sealed container comprising any one of the preparations described above, together with instructions for use.
- the kit can also include a diluent container containing a pharmaceutically acceptable diluent.
- the kit can further comprise instructions for mixing the preparation and the diluent.
- the diluent can be any pharmaceutically acceptable diluent.
- Well known diluents include 5% dextrose solution and physiological saline solution.
- the container can be an infusion bag, a sealed bottle, a vial, a vial with a septum, an ampoule, an ampoule with a septum, an infusion bag or a syringe.
- the kit further can contain an opioid container containing an opioid.
- the containers can optionally include indicia indicating that the containers have been autoclaved or otherwise subjected to sterilization techniques.
- the kit can include instructions for administering the various solutions contained in the
- the invention also involves methods of treatment.
- a method for treating a subject in need of such treatment with an effective amount of methylnaltrexone or a salt thereof.
- the method involves administering to the subject an effective amount of methylnaltrexone or salt thereof in any one of the pharmaceutical preparations described above, detailed herein, and/or set forth in the claims.
- the method is a method for inhibiting a peripheral opioid receptor in a human subject.
- the method is for reducing a side-effect of opioid treatment.
- the method is for treating any one of a condition selected from the group consisting of nausea, emesis, dysphoria, pruritus, urinary retention, ileus, post-operative ileus, post-partumileus, parallytic ileus, bowel hypomotility, constipation, gastric hypomotility, delayed gastric emptying, decreased biliary secretion, decreased pancreatic secretion, biliary spasm, increased sphincter tone, cutaneous flushing, impaction, sweating, inhibition of gastrointestinal motility, inhibition of gastric emptying, gastrointestinal dysfunction, incomplete evacuation, bloating, abdominal distention, increased gastroesophageal reflux, hypotension, bradycardia, irritable bowel syndrome, or immunosuppression.
- a condition selected from the group consisting of nausea, emesis, dysphoria, pruritus, urinary retention, ileus, post-operative ileus, post-partumileus, parallytic ileus, bowel hypomotility,
- the methylnaltrexone can be present in an amount sufficient to accelerate discharge from hospital post-surgery, accelerate bowel sounds after surgery, or induce laxation.
- the subject can be any subject in need of such treatment.
- Important subjects include those receiving opioids including opioids for pain, cancer or surgical patients, or immunosuppressed or immunocompromised patients (including HIV infected patients), patients with advanced medical illness, terminally ill patients, patients with neuropathies, patients with rheumatoid arthritis, patients with osteoarthritis, patients with chronic pack pain, patients with spinal cord injury, patients with chronic abdominal pain, patients with chronic pancreatic pain, patients with pelvic/perineal pain, patients with fibromyalgia, patients with chronic fatigue syndrome, patients with migraine or tension headaches, patients on hemodialysis, and patients with sickle cell anemia.
- opioids including opioids for pain, cancer or surgical patients, or immunosuppressed or immunocompromised patients (including HIV infected patients), patients with advanced medical illness, terminally ill patients, patients with neuropathies, patients with rheumatoid arthritis, patients with osteoarthritis, patients with chronic pack pain, patients with spinal cord injury, patients with chronic abdominal pain, patients
- methylnaltrexone or salts thereof.
- Such salts include, but are not limited to, bromide salts, chloride salts, iodide salts, carbonate salts, and sulfate salts.
- methylnaltrexone is a member of a class of compounds known as quaternary derivatives of noroxymorphone, as disclosed in U.S. Pat. No. 4,176,186, the entire disclosure of which is incorporated herein by reference. It is believed that the invention extends to any such quaternary derivative of noroxymorphone, and the invention is intended to embrace pharmaceutical preparations, methods and kits containing such derivatives.
- Another aspect of the invention then embraces the foregoing summary but read in each aspect as if any such derivative is substituted wherever “methylnaltrexone” appears.
- the invention also embraces each and every claim read as if the term “quaternary derivative of noroxymorphone” were substituted whenever “methylnaltrexone” appears.
- FIG. 1 is a graph depicting methylnaltrexone degradation products eluting from a column at time zero (peak Nos. 1, 2 and 4 are degradation products; peak No 4 is methylnaltrexone; peak no 5. O-methylnaltrexone bromide).
- FIG. 2 is a graph depicting methylnaltrexone degradation products eluting from a column at 12 months (peak Nos. 1, 2 and 4 are degradation products; peak No 4 is methylnaltrexone; peak no 5. O-methylnaltrexone bromide).
- FIG. 3 is a schematic representation of a kit according to the invention containing the formulations described herein.
- Applicants have discovered that during the autoclaving process, methylnaltrexone in aqueous solution tends to degrade to a surprising extent.
- the amount of degradation resulting from simple autoclaving (122° C., 15 lbs. pressure for 20 min.) can be as high as 10%.
- the degradation products are depicted in FIG. 1, and appear to include at least two predominant degradants having relative retention times (RRT) of 0.72 (2.828 minutes) and 0.89 (3.435 minutes) and, with other minor forms as can be observed.
- RRT relative retention times
- the degradant identified by the 0.72 RRT peak appears in small amounts, 0.074, immediately upon dissolving the methylnaltrexone into solution and increases overtime with storage or autoclaving 0.25%.
- methylnaltrexone is unstable in aqueous solutions when stored at room temperature or even at 4° C. for significant (but commercially necessary) periods of time such as 6 months, 12 months or even two years. Degradation occurs without regard to whether the aqueous solution was previously autoclaved or filter sterilized. It would be desirable to stabilize formulations of methylnaltrexone such that following the autoclaving process or following storage (or both autoclaving and storage), the amount of the total degradation products would be less than 2.0%, 1.5%, 1.0%, 0.5%, 0.25%, and even 0.125%.
- the invention provides stable formulations of methylnaltrexone.
- stable solutions of methylnaltrexone it is meant that following autoclaving at 122° C., 15 lbs. pressure for 20 minutes, the methylnaltrexone degradation products resulting from such conditions are not more than 2% of the total methylnaltrexone present in a given solution.
- stable solution of methylnaltrexone it also is meant that following storage of an unautoclaved solution at room temperature for twelve months, the methylnaltrexone degradation products resulting from such conditions are not more than 2% of the total methylnaltrexone present in a given solution.
- stable solutions of methylnaltrexone it is also meant that following storage of an unautoclaved solution at room temperature for two months, the methylnaltrexone degradation products resulting from such conditions are not more than 1.0% of the total methylnaltrexone present in a given solution.
- stable lyophilized formulations of methylnaltrexone it is meant that following lyophilization and storage at room temperature of methylnaltrexone for two months, and their reconstitution in water the methylnaltrexone degradation products resulting from such conditions are not more than 1.0% of the total methylnaltrexone present in a given solution.
- the invention in one aspect provides stable formulations of methylnaltrexone in solution, wherein the pH is below 4.25, preferably between 3.0 and 4.0, and most preferably between 3.0 and 3.5.
- Applicants also noted that despite setting the pH of a methylnaltrexone solution at points between 3.0 and 6.0 using a pH-adjusting acid or pH-adjusting base prior to autoclaving and despite the benefits obtained from lower pH, the pH of the autoclaved sample drifted almost immediately to about 7.0. It was therefore tested, in particular, whether buffering agents could eliminate the pH drift that resulted from autoclaving without negatively affecting the ability to protect against heat degradation resulting from autoclaving. Applicants discovered that buffering agents indeed could be employed to stabilize the pH of methylnaltrexone solutions throughout the autoclaving process without permitting degradation products to exceed acceptable minimums. Buffers were used in concentrations ranging from 0.25 mM to 25 mM.
- citrate buffer had properties more desirable than those of acetate buffer.
- the addition of citrate buffer did not seem to alter in any material respects the amount of degradation products resulting from autoclaving the methylnaltrexone solution, resulting in less than 0.23% of degradation products at pH of 3.5.
- the addition of acetate buffer appeared to increase somewhat the amount of methylnaltrexone degradation products, although not to unacceptable levels, resulting in less than 1.39% of degradation products at pH of 3.6. Nonetheless, citrate buffer surprisingly is preferable to acetate buffer.
- the preferred citrate buffer range is between about 2 and 5 mM.
- Buffers in general are well known to those of ordinary skill in the art.
- Buffer systems include citrate buffers, acetate buffers, borate buffers, and phosphate buffers.
- buffers include citric acid, sodium citrate, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartartic acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazole, sodium bicarbonate and carbonic acid, sodium succinate and succinic acid, histidine, and sodium benzoate and benzoic acid.
- a chelating agent alone was capable of reducing the amount of degradation products to acceptable levels.
- pH was not adjusted and disodium edetate was added at concentrations of 0.01, 0.1, 0.25, 0.5, 0.75, and 1.0 mg/mL.
- the disodium edetate stabilized methylnaltrexone against heat degradation in a concentration-dependent manner.
- As little as 0.01 mg/mL had a substantial effect on the amount of degradants, yielding approximately 2.3% total degradants.
- a concentration of 0.1 mg/mL resulted in under 1.5% total degradants.
- Chelating agents are chemicals which form water soluble coordination compounds with metal ions in order to trap or remove the metal irons from solution, thereby avoiding the degradative effects of the metal ions.
- Chelating agents include ethylenediaminetetraacetic acid (also synonymous with EDTA, edetic acid, versene acid, and sequestrene), and EDTA derivatives, such as dipotassium edetate, disodium edetate, edetate calcium disodium, sodium edetate, trisodium edetate, and potassium edetate.
- chelating agents include citric acid and derivatives thereof.
- Citric acid also is known as citric acid monohydrate.
- Derivatives of citric acid include anhydrous citric acid and trisodiumcitrate-dihydrate.
- Still other chelating agents include niacinamide and derivatives thereof and sodium desoxycholate and derivatives thereof.
- a synergistic effect of pH and disodium edetate was also observed. At pH 3-3.5, in the presence of citrate buffer (25 mM), and 0.01 mg/mL disodium edetate, the total degradants after autoclaving amounted to less than 0.4%. Under the same conditions, except increasing the concentration of disodium edetate to 1 mg/mL, there was no detectable difference.
- the degradants were on the order of approximately 0.4% after autoclaving.
- the circumstance differed when pH was adjusted upwardly to between 6.0 and 7.0 in an unbuffered system.
- the total degradants were above 3-6% at a concentration of 0.01 mg/mL disodium edetate and approximately 2.8% at 1.0 mg/mL disodium edetate. This at first glance appears anomalous with the results described above, where disodium edetate alone was sufficient to bring total degradants under 0.5% at concentrations above approximately 0.3 disodium edetate mg/mL.
- citrate buffer also is a chelating agent, which might contribute to its apparent superior properties. However, there was no concentration-dependent stabilization due to citrate buffer and it would appear that the chelating effect of citrate is not wholly responsible for the differential effects observed between citrate buffer and acetate buffer.
- Antioxidants are substances capable of inhibiting oxidation by removing free radicals from solution.
- Antioxidants are well known to those of ordinary skill in the art and include materials such as ascorbic acid, ascorbic acid derivatives (e.g., ascorbylpalmitate, ascorbylstearate, sodium ascorbate, calcium ascorbate, etc.), butylated hydroxy anisole, buylated hydroxy toluene, alkylgallate, sodium meta-bisulfite, sodium bisulfite, sodium dithionite, sodium thioglycollic acid, sodium formaldehyde sulfoxylate, tocopherol and derivatives thereof, (d-alpha tocopherol, d-alpha tocopherol acetate, dl-alpha tocopherol acetate, d-alpha tocopherol succinate, beta tocopherol, delta tocopherol, gamma tocopherol,
- the pharmaceutical preparations of the invention also may include isotonicity agents.
- This term is used in the art interchangeably with iso-osmotic agent, and is known as a compound which is added to the pharmaceutical preparation to increase the osmotic pressure to that of 0.9% sodium chloride solution, which is iso-osmotic with human extracellular fluids, such as plasma.
- Preferred isotonicity agents are sodium chloride, mannitol, sorbitol, lactose, dextrose and glycerol.
- the pharmaceutical preparations of the invention may further comprise a preservative.
- Suitable preservatives include but are not limited to: chlorobutanol (0.3-0.9% W/V), parabens (0.01-5.0%), thimerosal (0.004-0.2%), benzyl alcohol (0.5-5%), phenol (0.1-1.0%), and the like.
- stable pharmaceutical preparations containing methylnaltrexone in solution are permitted, wherein the solution further includes an agent selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, and combinations thereof, provided that the solution has a pH ranging from between 2 to 6.
- the stable pharmaceutical preparations of the invention are stable not only to heat degradation resulting from autoclaving, but also to other sterilization processes used during manufacturing.
- Sterilization processes or techniques as used herein include aseptic techniques such as one or more filtration (0.45 or 0.22 micron filters) steps, autoclaving, and a combination of filtration and autoclaving. They also are stable to long term storage.
- the stable formulations of the invention are stable for at least six months at temperatures of 30° C. or less, preferably a range from 5° C. to 30° C., and, more preferably, they are stable at a temperature above 15° C. for at least six months.
- the stable pharmaceutical preparations are stable for periods of at least six months, at least twelve months, and even at least twenty-four months at about room temperature or 25° C.
- Such preparations remain substantially free of methylnaltrexone degradation products, that is, such solutions contain less than 2% methylnaltrexone degradation products compared to the total amount of methylnaltrexone in the solution.
- cryoprotective agents which protect methylnaltrexone from the harmful effects of freezing. Such agents also can prevent caking and flaking, which can be problematic in reconstituting a solution and in manufacturing processing.
- cryoprotecting agents are mannitol, lactose, sucrose, polyethylene qlycol and polyvinyl pyrrolidine. Most preferred is mannitol. It is believed that cryoprotecting agents which result in a reconstitution pH of 6.0 and higher or which are basic will contribute also to degradation of methylnaltrexone due to pH effects discussed above. Thus, preferred cryoprotecting agents are those which, together with the other components of the formulation, result in a pH in the preferred ranges described above.
- the cryoprotecting agent is neutral or acidic.
- the amount of methylnaltrexone in the solution is effective to treat completely, ameliorate, or even prevent conditions associated with activation of endogenous opioid receptors, in particular, peripheral opioid receptors such as mu opioid receptors.
- Such conditions include nausea, emesis, dysphoria, pruritus, urinary retention, ileus, post-operative ileus, post-partumileus, parallytic ileus, bowel hypomotility, constipation, gastric hypomotility, delayed gastric emptying, decreased biliary secretion, decreased pancreatic secretion, biliary spasm, increased sphincter tone, cutaneous flushing, impaction, sweating, inhibition of gastrointestinal motility, inhibition of gastric emptying, gastrointestinal dysfunction, incomplete evacuation, bloating, abdominal distention, increased gastroesophageal reflux, hypotension, bradycardia, irritable bowel syndrome, or immunosuppression.
- One important use is in the treatment of constipation, i.e., less than one bowel
- the methylnaltrexone can be present in an amount sufficient to accelerate discharge from hospital post-surgery, accelerate bowel sounds after surgery, or induce laxation. Such amounts are well known to those of ordinary skill in the art and are described in the literature, including the patents listed in the background of the invention.
- the methylnaltrexone may also be in a salt form, including the bromide, chloride, iodide, carbonate, and sulfate salts of methylnaltrexone.
- Patients treatable with the formulations of the invention include those receiving opioids including opioids for pain, cancer or surgical patients, immunosuppressed or immunocompromised patients (including HIV infected patients), patients with advanced medical illness, terminally ill patients, patients with neuropathies, patients with rheumatoid arthritis, patients with osteoarthritis, patients with chronic pack pain, patients with spinal cord injury, patients with chronic abdominal pain, patients with chronic pancreatic pain, patients with pelvic perineal pain, patients with fibromyalgia, patients with chronic fatigue syndrome, patients with migraine or tension headaches, patients on hemodialysis, and patients with sickle cell anemia.
- opioids including opioids for pain, cancer or surgical patients, immunosuppressed or immunocompromised patients (including HIV infected patients), patients with advanced medical illness, terminally ill patients, patients with neuropathies, patients with rheumatoid arthritis, patients with osteoarthritis, patients with chronic pack pain, patients with spinal cord injury, patients with chronic abdominal pain, patients with chronic pancreatic pain, patients with
- the pharmaceutical preparations of the invention also can include an opioid.
- opioids include alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trim
- the pharmaceutical preparations of the invention will typically be held in bottles, vials, ampoules, infusion bags, and the like, any one of which may be sparged to eliminate oxygen or purged with nitrogen.
- the bottles vials and ampoules are opaque, such as when amber in color.
- Such sparging and purging protocols are well known to those of ordinary skill in the art and should contribute to maintaining the stability of the pharmaceutical preparations.
- the pharmaceutical preparations also, in certain embodiments, are expected to be contained within syringes.
- kits also are provided.
- the kit 10 includes a pharmaceutical preparation vial 12 , a pharmaceutical preparation diluent vial 14 , an opioid vial 16 , and an opioid diluent vial 18 .
- the kit also includes instructions 20 .
- the vial 14 containing the diluent for the pharmaceutical preparation is optional.
- the vial 14 contains a diluent such as physiological saline for diluting what could be a concentrated solution of methylnaltrexone contained in vial 12 .
- the instructions can include instructions for mixing a particular amount of the diluent with a particular amount of the concentrated pharmaceutical preparation, whereby a final formulation for injection or infusion is prepared.
- the instructions may include instructions for use in a patient controlled analgesia (PCA) device.
- the kit optionally contains an opioid in the opioid vial 16 , which also optionally may be in a concentrated form.
- the optional vial 18 contains a diluent for a concentrated opioid.
- the instructions also may include instructions for mixing the opioid with the pharmaceutical preparation and/or diluting the opioid with the opioid diluent contained in the opioid diluent vial 18 .
- the instructions therefore, would take a variety of forms depending on the presence or absence of diluent and opioid.
- the instructions 20 can include instructions for treating a patient with an effective amount of methylnaltrexone.
- the containers containing the pharmaceutical preparation whether the container is a bottle, a vial with a septum, an ampoule with a septum, an infusion bag, and the like, can contain indicia such as conventional markings which change color when the pharmaceutical preparation has been autoclaved or otherwise sterilized.
- the pharmaceutical preparations of the invention when used in alone or in cocktails, are administered in therapeutically effective amounts.
- a therapeutically effective amount will be determined by the parameters discussed below; but, in any event, is that amount which establishes a level of the drug(s) effective for treating a subject, such as a human subject, having one of the conditions described herein.
- An effective amount means that amount alone or with multiple doses, necessary to delay the onset of, inhibit completely or lessen the progression of or halt altogether the onset or progression of the condition being treated.
- effective amounts When administered to a subject, effective amounts will depend, of course, on the particular condition being treated; the severity of the condition; individual patient parameters including age, physical condition, size and weight; concurrent treatment; frequency of treatment; and the mode of administration. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment.
- the pharmaceutical preparations of the present invention may include or be diluted into a pharmaceutically-acceptable carrier.
- pharmaceutically-acceptable carrier means one or more compatible solid, or semi-solid or liquid fillers, diluants or encapsulating substances which are suitable for administration to a human or other mammal such as a dog, cat, horse, cow, sheep, or goat.
- carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
- the carriers are capable of being commingled with the preparations of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy or stability.
- Carriers suitable for oral, subcutaneous, intravenous, intramuscular, etc. formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.
- a variety of administration routes are available. The particular mode selected will depend of course, upon the particular drug selected, the severity of the disease state being treated and the dosage required for therapeutic efficacy.
- the methods of this invention may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects.
- modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes.
- parenteral includes subcutaneous, intravenous, intramuscular, or infusion.
- Dosage may be adjusted appropriately to achieve desired drug levels, locally or systemically.
- daily oral doses of active compounds will be from about 0.1 mg/kg per day to 30 mg/kg per day. It is expected that IV doses in the range of 0.01-1.00 mg/kg will be effective. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous IV dosing over, for example, 24 hours or multiple doses per day also are contemplated to achieve appropriate systemic levels of compounds.
- Preferred subcutaneous doses for chronic opioid users to induce Taxation are 0.1-0.3 mg/kg, and preferred oral doses for the same patient population are 1.0-3.0 mg/kg.
- Preferred IV doses to treat post operative ileus are 0.15 mg/kg.
- the invention also involves methods for preparing autoclaved pharmaceutical preparations that have concentrations of methylnaltrexone degradation products that do not exceed 2% of the methylnaltrexone or salt thereof in the preparation.
- Aqueous solutions of methylnaltrexone are prepared.
- a pH-adjusting acid is added to adjust the pH to 4.25 or less, preferably to a range of between 3.0 and 3.5.
- the solution is then autoclaved according to standard procedures. One such procedure involves autoclaving at 122° C. and 15 pounds of pressure for 20 minutes.
- the pharmaceutical preparation can contain any one, any combination of or all of a chelating agent, an isotonicity agent, a buffering agent, an antioxidant, a cryoprotective agent, and an opioid.
- a pharmaceutical preparation containing methylnaltrexone in a aqueous solution is prepared by combining a chelating agent with the methylnaltrexone solution and then autoclaving the solution.
- the aqueous solution of methylnaltrexone may contain any one of, any combination of or all of a buffering agent, an antioxidant, an isotonicity agent and an opioid.
- a pharmaceutical preparation containing methylnaltrexone in a lyophilized formulation is prepared by combining a cryoprotective agent, such as mannitol, with the methylnaltrexone formulation.
- the lyophilized preparation may also contain any one of, any combination of, or all of a buffering agent, an antioxidant, an isotonicity agent and an opioid.
- the invention also involves methods of inhibiting the formation of methylnaltrexone degradation products in a solution containing methylnaltrexone by combining any one of, any combination of or all of a chelating agent, a buffering agent and an antioxidant with methylnaltrexone or salt thereof in solution.
- a chelating agent any combination of or all of a chelating agent, a buffering agent and an antioxidant
- the aqueous solution containing the chelating agent, buffering agent and/or antioxidant is first prepared, then a powdered source of methylnaltrexone or salt thereof is dissolved into the aqueous solution.
- the invention also involves methods of inhibiting the formation of methylnaltrexone degradation products in a gel containing methylnaltrexone by combining any one of, any combination of or all of a chelating agent, a buffering agent and an antioxidant with methylnaltrexone or salt thereof in a gel matrix.
- the gel containing the chelating agent, buffering agent and/or antioxidant is first prepared, then a powdered source of methylnaltrexone or salt thereof is dissolved into the gel.
- solution embraces gels.
- the pharmaceutical preparations of the invention may be provided in particles.
- Particles as used herein means nano or microparticles (or in some instances larger) which can consist in whole or in part of the peripheral opioid antagonists or the other therapeutic agent(s) as described herein.
- the particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating.
- the therapeutic agent(s) also may be dispersed throughout the particles.
- the therapeutic agent(s) also may be adsorbed into the particles.
- the particles may be of any order release kinetics, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, and any combination thereof, etc.
- the particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof.
- the particles may be microcapsules which contain the antagonist in a solution or in a semi-solid state.
- the particles may be of virtually any shape.
- Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s).
- Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired.
- Bioadhesive polymers of particular interest include bioerodible hydrogels described by H. S. Sawhney, C. P. Pathak and J. A. Hubell in Macromolecules , (1993) 26:581-587, the teachings of which are incorporated herein.
- polyhyaluronic acids casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).
- the invention also provides methods for preparing stable pharmaceutical preparations containing aqueous solutions of methylnaltrexone or salts thereof to inhibit formation of methylnaltrexone degradation products.
- a solution is provided that contains methylnaltrexone or salts thereof and at least one methylnaltrexone inhibiting agent.
- the solution is processed under at least one sterilization technique prior to and/or after terminal filing the solution in the sealable container to form a stable pharmaceutical preparation, wherein the method is carried out without the addition of a pH-adjusting base to the solution.
- a manufacturing process can be outlined as follows:
- step 6 pH of the solution is adjusted by addition of acid. If a buffering agent is used in the solution, pH adjustment may not be required.
- the temperature during formulation can be as high as 80° C.
- a preferred manufacturing process is as follows:
- Methylnaltrexone (bromide salt) and its degradation products in an isotonic saline solution were tested upon manufacture of the solution (no added stabilizers, sterile filtered, not autoclaved) and upon storage at room temperature for 12 months using a Hewlett-Packard HP1100 series, HPLC system equipped with quaternary gradient pump, programmable variable wavelength UV detector and a Millennium data acquisition system.
- Two mobile phases were prepared as follows:
- the reagents, standards and media included naltrexone methobromide as a reference standard, trifluoroacetic acid (ACS grade), acetonitrile (HPLC grade), Milli-Q water (or equivalent), and methanol (HPLC grade).
- the solutions were prepared as follows.
- Mobile phase A 85:15:0.1
- water:methanol:trifluoroacetic acid 850 mL of Milli-Q water was added to a suitable container, to which 150 mL of methanol and 1.0 mL of trifluoroacetic acid were added.
- the solution was mixed well and allowed to equilibrate to room temperature.
- the solution was degassed by helium sparge.
- Mobile phase B (methanol): Methanol was added to a suitable container and degassed by helium sparge.
- Mobile phase A mixture of Mobile phase A and B is used as shown in Table I: TABLE I Time (minutes) % A % B 0 100 0 12 65 35 15 35 65 15.1 100 0 20 100 0
- methylnaltrexone is a peak having an RRT of 1.0 (4.364 minutes). An additional peak was identified as O-methyl naltrexone methobromide, RRT about 1.57 (6.868 minutes).
- the O-methyl-naltrexone is not a degradant of methylnaltrexone but a result from the methylnaltrexone (drug substance) manufacturing process.
- the HPLC analysis of the sample stored for 12 months showed methylnaltrexone RRT of 1.00 (3.839 minutes), O-methyl-methylnaltrexone RRT of about 1.53 (5.866 minutes).
- HPLC analysis revealed that the methylnaltrexone saline formulation which was stored for 12 months had at least three degradation products formed during the manufacturing or during storage of the finished drug product.
- the degradant peak RRT's were approximately 0.74 (2.828 minutes), 0.89 (3.435 minutes) and 1.40(5.326 minutes).
- HPLC analysis was also conducted, prior to storage, on a methylnaltrexone solution manufactured using an isotonic saline solution (no added stabilizers), sterile filtered, and autoclaved.
- This saline, autoclaved solution contained the degradation products formed during manufacturing or storage, as described above (data not shown).
- the pH of this solution is 3.5 and can withstand autoclaving process.
- lyophilization cycle listed below is standard procude well known to one of ordinary skill in the art. This cycle was used for the preparation of lyophilized preparation of methylnaltrexone analyzed in Examples 6 and 7.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Virology (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Inorganic Chemistry (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Gastroenterology & Hepatology (AREA)
- Nutrition Science (AREA)
- Otolaryngology (AREA)
Abstract
Stable pharmaceutical compositions useful for administering methylnaltrexone are described, as are methods for making the same. Kits, including these pharmaceutical compositions, also are provided.
Description
- This invention relates to methylnaltrexone pharmaceutical preparations, methylnaltrexone formulations, methylnaltrexone kits, and methods of making the same.
- Quaternary amine opioid antagonist derivatives have been shown to have utility in a number of contexts. They are considered peripherally acting only, and, therefore, find particular utility in reducing the side-effects of opioids without reducing the analgesic effect of opioids. Such side effects include nausea, emesis, dysphoria, pruritis, urinary retention, bowel hypomotility, constipation, gastric hypomotility, delayed gastric emptying and immune suppression. The utility of these peripherally acting opioid antagonists is not limited to reducing side-effects stemming from opioid analgesic treatment. Instead, these derivatives also have utility in circumstances where endogenous opioids alone (or in conjunction with exogenous opioid treatment) cause undesirable conditions such as ileus and other such conditions including, but not limited to, those mentioned above.
- Methylnaltrexone is a quaternary amine opioid antagonist derivative, discovered in the mid-70s. Methylnaltrexone and some of its uses are described in U.S. Pat. Nos. 4,176,186, 4,719,215, 4,861,781, 5,102,887, 5,972,954, and 6,274,591. Stable formulations of methylnaltrexone, however, have heretofore not existed. Methylnaltrexone apparently was assumed to have a structure that was inherently stable. The stability of a pharmaceutical composition in solution, however, is not necessarily predictable either over time when stored at room temperature or when autoclaved.
- Naloxone is an opioid antagonist that acts both centrally and peripherally. It differs structurally from methylnaltrexone and would be expected to have a different stability in solution. An allegedly stable formulation of naloxone is described in U.S. Pat. No. 5,866,154.
- Surprisingly, it has been discovered that methylnaltrexone is unusually unstable. It further has been discovered that methylnaltrexone has certain degradation products different from those of naloxone. It also has been discovered that critical parameters and conditions are required for stable formulations of methylnaltrexone.
- In one aspect, the invention provides a composition or preparation that is a solution of methylnaltrexone or a salt thereof, wherein the preparation after autoclaving has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone or salt thereof in the preparation. Preferably, the concentration of such degradation products does not exceed 1.5%, 1%, 0.5%, 0.25%, or even 0.125% of the methylnaltrexone or salt thereof in the preparation. The composition or preparation can contain one of, any combination of, or all of a chelating agent, a buffering agent, an anti-oxidant, a cryoprotecting agent, an isotonicity agent and an opioid. The preferred chelating agent is disodium edetate or a derivative thereof. The disodium edetate preferably is at a concentration ranging from between 0.001 and 100 mg/ml, more preferably 0.05 to 25.0 mg/ml, and even more preferably, 0.1 to 2.5 mg/ml. A preferred buffering agent is citrate buffer. The citrate buffer typically is in a concentration ranging from 0.001 to 100.0 mM, preferably from 0.1 to 10 mM, and more preferably, 0.1 to 5.0 mM. A preferred cryoprotecting agent is mannitol.
- The composition or preparation preferably has a pH that does not exceed 4.25. More preferably, the pH ranges from 2.0 to 4.0, 3.0 to 4.0, and most preferably, from 3.0 to 3.5.
- According to another aspect of the invention, a composition or preparation is provided, which includes a solution of methylnaltrexone or a salt thereof, wherein the preparation after storage at about room temperature for six months has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone in the preparation. The concentration of the methylnaltrexone degradation products preferably does not exceed 1.5%, 1.0%, 0.5%, 0.25%, and even 0.125% of the methylnaltrexone in the preparation. The composition or preparation can contain one of, any combination of, or all of a chelating agent, a buffering agent, an anti-oxidant, a cryoprotecting agent, an isotonicity agent and an opioid. The preferred chelating agent and concentrations are as described above. The preferred buffering agent and concentrations are as described above. Preferably, the composition or preparation has a pH that does not exceed 4.25. The preferred pHs and ranges are as described above.
- According to another aspect of the invention, a stable composition or preparation is provided. The composition or preparation is a solution of methylnaltrexone or a salt thereof wherein the pH is below 4.25. Preferably, the pH is between 2.75 and 4.25, more preferably, between 3.0 and 4.0, and most preferably, between 3.0 and 3.5. According to conventional procedures, pH can be adjusted with an acid. Examples of acids useful for this purpose include hydrochloric acid, citric acid, sulfuric acid, acetic acid, and phosphoric acid. The stable composition or preparation can also include any one of, any combination of, or all of a chelating agent, a buffering agent, an isotonicity agent, an antioxidant, a cryogenic agent, and an opioid.
- According to another aspect of the invention, a stable composition or preparation is provided. The composition or preparation is a solution of methylnaltrexone or salt thereof, wherein the solution further comprises a chelating agent in an amount sufficient to inhibit degradation of the methylnaltrexone or salt thereof, whereby the amount is such that the composition or preparation after autoclaving has a concentration of methylnaltrexone degradation products that does not exceed 0.5%, 0.25% or even 0. 125% of the methylnaltrexone or salt thereof in the composition or preparation. The composition or preparation can further include any one of, any combination of, or all of a buffering agent, an isotonicity agent, an antioxidant and an opioid. Preferred chelating agents, buffering agents and pHs are as described above.
- According to another aspect of the invention, a composition or preparation is provided. The composition or preparation is a solution of methylnaltrexone or salt thereof in at least one methylnaltrexone degradation inhibiting agent. The agent can be any one of, any combination of, or all of a chelating agent, a buffering agent, and an antioxidant, provided that the solution has a pH ranging from 2.0 to 6.0. The degradation inhibiting agent is present in an amount sufficient to render the composition or preparation stable, wherein the composition or preparation is processed under at least one sterilization technique, and wherein the composition or preparation is substantially free of methylnaltrexone degradation products. The composition or preparation can be stable to storage for at least six months, at least twelve months, or at least twenty-four months, at about room temperature. Preferably, the composition or preparation is stable after autoclaving. The composition or preparation further may include either or both of an isotonicity agent and an opioid. Preferably, the pH of the solution is between 2.75 and 4.25, more preferably, between 3.0 and 4.0, and most preferably, between 3.0 and 3.5.
- In any one of the foregoing aspects of the invention, the composition or preparation can be a pharmaceutical composition.
- In any one of the foregoing aspects of the invention, the methylnaltrexone can be present in a therapeutically effective amount. In some embodiments, the concentration of methylnaltrexone ranges from 0.01 to 100 mg/ml. In other embodiments, the methylnaltrexone concentration ranges between 0.1 and 100.0 mg/ml. In other embodiments, the methylnaltrexone ranges between 1.0 and 50.0 mg/ml.
- In any one of the foregoing embodiments, the methylnaltrexone can be present in an amount sufficient to treat nausea, emesis, dysphoria, pruritus, urinary retention, ileus, post-operative ileus, post-partum ileus, paralytic ileus, bowel hypomotility, constipation, gastric hypomotility, delayed gastric emptying, decreased biliary secretion, decreased pancreatic secretion, biliary spasm, increased sphincter tone, cutaneous flushing, impaction, sweating, inhibition of gastrointestinal motility, inhibition of gastric emptying, gastrointestinal dysfunction, incomplete evacuation, bloating, abdominal distention, increased gastroesophageal reflux, hypotension, bradycardia, irritable bowel syndrome, or immunosuppression.
- In any of the foregoing embodiments, the methylnaltrexone can be present in an amount sufficient to accelerate discharge from hospital post-surgery (including abdominal surgeries such as rectal resection, colectomy, stomach, esophageal, duodenal, appendectomy, hysterectomy, or non-abdominal surgeries such as orthopedic, trauma injuries, thoracic or transplantation), for example, by accelerating bowel sounds after surgery, or speeding the time to first food intake or first bowel movement. In other important embodiments, the amount is sufficient to induce laxation. This has particular application where the subject is a chronic opioid user.
- In any one of the foregoing embodiments, the solution of methylnaltrexone or salt thereof may be contained in a sealed container such as a bottle, an infusion bag, a syringe, a vial, a vial with a septum, an ampoule, an ampoule with a septum, or a syringe. The container may include indicia indicating that the solution has been autoclaved or otherwise subjected to a sterilization technique.
- According to another aspect of the invention, any of the foregoing embodiments is lyophilized, preferably in the presence of a cryoprotecting agent. The invention therefore provides a lyophilized preparation of methylnaltrexone. Preferably, the lyophilized preparation is a stable preparation, containing less than 1%, less than 0.5%, less than 0.25% and even less than 0.125% methylnaltrexone degradation product. The preparation can contain a cryoprotecting agent, which preferably is neutral or acidic in water.
- According to another aspect of the invention, a product is provided. The product is a stable lyophilized formulation of methylnaltrexone, wherein the formulation upon reconstitution and water at a concentration of 20 mg/ml has a pH of between 2 and 6. In some embodiments, the formulation upon reconstitution has a pH of about 2, about 3, about 4, about 5, or about 6. The formulation can include a cryoprotecting agent present in amounts sufficient to render the formulation stable. The cryoprotecting agent in important embodiments are polymerized carbohydrates. A preferred cryoprotecting agent is mannitol. Any one of the foregoing solutions described above can be lyophilized. It therefore is an aspect of the invention that such materials include one or any combination of a buffering agent, a chelating agent, an antioxidant, and an isotonicity agent. Preferred materials are as described above.
- According to still another aspect of the invention, a product is provided that includes methylnaltrexone and the degradation inhibiting agent selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, and combinations thereof, wherein the degradation inhibiting agent is present in an amount sufficient to render stable the solution of the product containing a concentration of 20 mg/ml methylnaltrexone in water. Preferably, the product when in solution at a concentration of 20 mg/ml methylnaltrexone yields a pH of between 2 and 6.
- According to another aspect of the invention, a pharmaceutical preparation is provided. The pharmaceutical preparation contains methylnaltrexone, sodium chloride, citric acid, trisodium citrate, and disodium edetate. In one important embodiment, the methylnaltrexone is present between 20 and 40 mg/ml, the sodium chloride is present between 2 and 6 mg/ml, the citric acid is present between 0.05 and 0.1 mg/ml, the trisodium citrate is present between 0.025 and 0.075 mg/ml, and the disodium edetate is present between 0.5 and 1.0 mg/ml.
- The buffering agent may be any pharmaceutically acceptable buffering agent. Common buffering agents include citric acid, sodium citrate, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartaric acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazole, sodium bicarbonate and carbonic acid, sodium succinate and succinic acid, histidine, and sodium benzoate and benzoic acid. The preferred buffering agent is a citrate buffering agent.
- The chelating agent may be any pharmaceutically acceptable chelating agent. Common chelating agents include ethylenediaminetetraacetic acid (EDTA) and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, and sodium desoxycholate and derivatives thereof. The preferred chelating agent is disodium edetate.
- The antioxidant may be any pharmaceutically acceptable antioxidant. Common antioxidants include those selected from the group consisting of an ascorbic acid derivative, butylated hydroxy anisole, butylated hydroxy toluene, alkyl gallate, sodium meta-bisulfite, sodium bisulfite, sodium dithionite, sodium thioglycollic acid, sodium formaldehyde sulfoxylate, tocopherol and derivatives thereof, monothioglycerol, and sodium sulfite. The preferred antioxidant is monothioglycerol.
- The cryoprotecting agent may be any pharmaceutically acceptable cryoprotecting agent. Common cryoprotecting agents include histidine, polyethylene qlycol, polyvinyl pyrrolidine, lactose, sucrose, and mannitol. Improtant cryoprotecting agents are polyols. The preferred cryoprotecting agent of the invention is mannitol.
- The opioid can be any pharmaceutically acceptable opioid. Common opioids are those selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol.
- The isotonicity agent can be any pharmaceutically acceptable isotonicity agent. Common isotonicity agents include those selected from the group consisting of sodium chloride, mannitol, lactose, dextrose, glycerol, and sorbitol. The preferred isotonicity agent is mannitol.
- The pharmaceutical preparation may optionally comprise a preservative. Common preservatives include those selected from the group consisting of chlorobutanol, parabens, thimerosol, benzyl alcohol, and phenol.
- According to another aspect of the invention, a method is provided for preparing an autoclaved preparation of a solution of methylnaltrexone or salts thereof, whereby the autoclaved preparation has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone or salt thereof in the preparation. The method involves providing a solution, having a pH of 4.25 or less, of methylnaltrexone or a salt thereof, and being substantially free of methylnaltrexone degradation products, and autoclaving the solution. The solution can contain, optionally, any one of, any combination of, or all of a chelating agent, an isotonicity agent, a buffering agent, an antioxidant, a cryoprotecting agent, and an opioid. Preferably, the pH of the solution ranges from 2.0 to 4.0. More preferably, from 3.0 to 4.0, and most preferably from 3.0 to 3.5. Preferred chelating agents, isotonicity agents, buffering agents, antioxidants, cryoprotecting agents, and opioids are as described above. Preferred concentrations of methylnaltrexone, likewise, are as described above.
- According to another aspect of the invention, a method is provided for preparing an autoclaved preparation. The preparation has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone or salt thereof in the preparation. The method involves providing a solution containing methylnaltrexone or salt thereof and a chelating agent, the solution being substantially free of methylnaltrexone degradation products, and then autoclaving the solution. The chelating agent is present in an amount sufficient to protect the preparation against substantial unwanted degradation of methylnaltrexone or its salt, and maintain the solution to be substantially free of methylnaltrexone degradation products. Preferred chelating agents and concentrations thereof are as described above. The preparation may include, optionally, any one of, any combination of, or all of a buffering agent, an isotonicity agent, an antioxidant, a cryoprotecting agent, and an opioid. Preferred buffering agents, isotonicity agents, antioxidants and opioids, as well as concentrations, are as described above. Preferred pHs of the solution likewise are as described above. Preferably, the degradation products after autoclaving do not exceed 1.5%, 1%, 0.5%, 0.25% or even 0.125%.
- According to another aspect of the invention, a method is provided for inhibiting the formation of methylnaltrexone degradation products in a preparation that is a solution of methylnaltrexone or salts thereof. The method involves preparing an aqueous solution containing at least one methylnaltrexone degradation inhibiting agent selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, a cryoprotecting agent, and combinations thereof. A powdered source of methylnaltrexone or salt thereof is dissolved into the solution to form the preparation. The preparation has or is adjusted without addition of a pH-adjusting base to have a pH of between 2 and 6. More preferably, the pharmaceutical preparation is adjusted to have a pH ranging from 3 to 5, more preferably, 3 to 4, and most preferably, 3.0 to 3.5. An isotonicity agent may be added to the solution. Likewise, an opioid may be added to the solution.
- In any one of the foregoing aspects of the invention, the preparation can be a pharmaceutical preparation.
- According to another aspect of the invention, a method is provided for preparing a stable pharmaceutical preparation that is an aqueous solution of methylnaltrexone or salts thereof to inhibit formation of methylnaltrexone degradation products. A solution is provided containing methylnaltrexone or salts thereof and at least one methylnaltrexone degradation inhibiting agent. The solution is processed under at least one sterilization technique prior to and/or after terminal filling the solution in a sealable container to form the stable pharmaceutical preparation, wherein the method is carried out without the addition of pH-adjusting base to the solution. The methylnaltrexone degradation inhibiting agent can be selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, and combinations thereof. An isotonicity agent can be added. A cryoprotecting agent can also be added. Likewise, an opioid can be added. Preferred chelating agents, buffering agents, antioxidants, isotonicity agents, cryoprotecting agents, and opioids are as described above. Preferred concentrations are as described above. The solution may be processed to adjust the pH. This is preferably done using an acid. Most preferably, the solution is adjusted to a range between a pH of 2 and 6, more preferably, between 3 and 5, 3 and 4, and most preferably between 3.0 and 3.5. The material can be contained in a sealed container. The container can be purged with nitrogen and/or sparged to eliminate oxygen.
- In some embodiments of the invention, parenteral formulations are provided. In one embodiment, the formulation made by dissolving methylnaltrexone diluted in water, to which mannitol is added. The solution is then filter sterilized followed by lyophilization. Therefore, the product may be provided in lyophilized form, and in combination with certain cryoprotectants such as mannitol or lactose. Optionally, a reconstituting diluent is provided, such as a physiological saline diluent.
- According to another aspect of the invention, a kit is provided. The kit is a package containing a sealed container comprising any one of the preparations described above, together with instructions for use. The kit can also include a diluent container containing a pharmaceutically acceptable diluent. The kit can further comprise instructions for mixing the preparation and the diluent. The diluent can be any pharmaceutically acceptable diluent. Well known diluents include 5% dextrose solution and physiological saline solution. The container can be an infusion bag, a sealed bottle, a vial, a vial with a septum, an ampoule, an ampoule with a septum, an infusion bag or a syringe. The kit further can contain an opioid container containing an opioid. The containers can optionally include indicia indicating that the containers have been autoclaved or otherwise subjected to sterilization techniques. The kit can include instructions for administering the various solutions contained in the containers to subjects.
- The invention also involves methods of treatment. According to another aspect of the invention, a method is provided for treating a subject in need of such treatment with an effective amount of methylnaltrexone or a salt thereof. The method involves administering to the subject an effective amount of methylnaltrexone or salt thereof in any one of the pharmaceutical preparations described above, detailed herein, and/or set forth in the claims. In one aspect, the method is a method for inhibiting a peripheral opioid receptor in a human subject. In another aspect, the method is for reducing a side-effect of opioid treatment. In another aspect, the method is for treating any one of a condition selected from the group consisting of nausea, emesis, dysphoria, pruritus, urinary retention, ileus, post-operative ileus, post-partumileus, parallytic ileus, bowel hypomotility, constipation, gastric hypomotility, delayed gastric emptying, decreased biliary secretion, decreased pancreatic secretion, biliary spasm, increased sphincter tone, cutaneous flushing, impaction, sweating, inhibition of gastrointestinal motility, inhibition of gastric emptying, gastrointestinal dysfunction, incomplete evacuation, bloating, abdominal distention, increased gastroesophageal reflux, hypotension, bradycardia, irritable bowel syndrome, or immunosuppression.
- In any of the foregoing embodiments, the methylnaltrexone can be present in an amount sufficient to accelerate discharge from hospital post-surgery, accelerate bowel sounds after surgery, or induce laxation.
- The subject can be any subject in need of such treatment. Important subjects include those receiving opioids including opioids for pain, cancer or surgical patients, or immunosuppressed or immunocompromised patients (including HIV infected patients), patients with advanced medical illness, terminally ill patients, patients with neuropathies, patients with rheumatoid arthritis, patients with osteoarthritis, patients with chronic pack pain, patients with spinal cord injury, patients with chronic abdominal pain, patients with chronic pancreatic pain, patients with pelvic/perineal pain, patients with fibromyalgia, patients with chronic fatigue syndrome, patients with migraine or tension headaches, patients on hemodialysis, and patients with sickle cell anemia.
- In the foregoing description, applicants have described the invention in connection with methylnaltrexone or salts thereof. Such salts include, but are not limited to, bromide salts, chloride salts, iodide salts, carbonate salts, and sulfate salts. It should be understood, however, that methylnaltrexone is a member of a class of compounds known as quaternary derivatives of noroxymorphone, as disclosed in U.S. Pat. No. 4,176,186, the entire disclosure of which is incorporated herein by reference. It is believed that the invention extends to any such quaternary derivative of noroxymorphone, and the invention is intended to embrace pharmaceutical preparations, methods and kits containing such derivatives. Another aspect of the invention then embraces the foregoing summary but read in each aspect as if any such derivative is substituted wherever “methylnaltrexone” appears. Likewise, the invention also embraces each and every claim read as if the term “quaternary derivative of noroxymorphone” were substituted whenever “methylnaltrexone” appears.
- FIG. 1 is a graph depicting methylnaltrexone degradation products eluting from a column at time zero (peak Nos. 1, 2 and 4 are degradation products;
peak No 4 is methylnaltrexone; peak no 5. O-methylnaltrexone bromide). - FIG. 2 is a graph depicting methylnaltrexone degradation products eluting from a column at 12 months (peak Nos. 1, 2 and 4 are degradation products;
peak No 4 is methylnaltrexone; peak no 5. O-methylnaltrexone bromide). - FIG. 3 is a schematic representation of a kit according to the invention containing the formulations described herein.
- Applicants have discovered that during the autoclaving process, methylnaltrexone in aqueous solution tends to degrade to a surprising extent. The amount of degradation resulting from simple autoclaving (122° C., 15 lbs. pressure for 20 min.) can be as high as 10%. The degradation products are depicted in FIG. 1, and appear to include at least two predominant degradants having relative retention times (RRT) of 0.72 (2.828 minutes) and 0.89 (3.435 minutes) and, with other minor forms as can be observed. The degradant identified by the 0.72 RRT peak appears in small amounts, 0.074, immediately upon dissolving the methylnaltrexone into solution and increases overtime with storage or autoclaving 0.25%. The degradant identified by the 0.89 RRT peak appears only after storage over time or after autoclaving (<0.05% and 0.724%, respectively). Applicants also have discovered that methylnaltrexone is unstable in aqueous solutions when stored at room temperature or even at 4° C. for significant (but commercially necessary) periods of time such as 6 months, 12 months or even two years. Degradation occurs without regard to whether the aqueous solution was previously autoclaved or filter sterilized. It would be desirable to stabilize formulations of methylnaltrexone such that following the autoclaving process or following storage (or both autoclaving and storage), the amount of the total degradation products would be less than 2.0%, 1.5%, 1.0%, 0.5%, 0.25%, and even 0.125%.
- The invention provides stable formulations of methylnaltrexone. By stable solutions of methylnaltrexone, it is meant that following autoclaving at 122° C., 15 lbs. pressure for 20 minutes, the methylnaltrexone degradation products resulting from such conditions are not more than 2% of the total methylnaltrexone present in a given solution. By stable solution of methylnaltrexone, it also is meant that following storage of an unautoclaved solution at room temperature for twelve months, the methylnaltrexone degradation products resulting from such conditions are not more than 2% of the total methylnaltrexone present in a given solution. By stable solutions of methylnaltrexone, it is also meant that following storage of an unautoclaved solution at room temperature for two months, the methylnaltrexone degradation products resulting from such conditions are not more than 1.0% of the total methylnaltrexone present in a given solution. By stable lyophilized formulations of methylnaltrexone, it is meant that following lyophilization and storage at room temperature of methylnaltrexone for two months, and their reconstitution in water the methylnaltrexone degradation products resulting from such conditions are not more than 1.0% of the total methylnaltrexone present in a given solution.
- It was surprisingly discovered that pH alone can solve the problem of excessive methylnaltrexone degradation products. In particular, it was discovered that when the pH of a methylnaltrexone solution containing 2 mg/mL of methylnaltrexone was at about 4.25 pH or less, there was a steep drop-off in the amount of methylnaltrexone degradation products following autoclaving. When the pH of the solution containing methylnaltrexone was adjusted to between 3.5 and 4.0, then the total percentage of degradants fell below 2%, and in certain instances even below 1.39%. When the pH was adjusted to between 3.0 and 3.5, the percentage of total degradants dropped to about 0.23% after autoclaving. It was also noted that there was a significant drop, before a plateau, when the pH of the methylnaltrexone solution was brought to below 6.0 prior to autoclaving. Adjusting pHs to between 4.25 and 6 was not sufficient to produce stable formulations of methylnaltrexone (through the adjustment of pH alone). As will be seen below, however, manipulating other parameters in concert with pH resulted in stable formulations of methylnaltrexone anywhere in a range from a pH of 2.0 to 6.0. The benefits of a low pH on the stability of methylnaltrexone formulations persisted in the presence of chelating agents, isotonicity agents, buffering agents, and antioxidants. Thus, the invention in one aspect provides stable formulations of methylnaltrexone in solution, wherein the pH is below 4.25, preferably between 3.0 and 4.0, and most preferably between 3.0 and 3.5.
- Applicants also noted that despite setting the pH of a methylnaltrexone solution at points between 3.0 and 6.0 using a pH-adjusting acid or pH-adjusting base prior to autoclaving and despite the benefits obtained from lower pH, the pH of the autoclaved sample drifted almost immediately to about 7.0. It was therefore tested, in particular, whether buffering agents could eliminate the pH drift that resulted from autoclaving without negatively affecting the ability to protect against heat degradation resulting from autoclaving. Applicants discovered that buffering agents indeed could be employed to stabilize the pH of methylnaltrexone solutions throughout the autoclaving process without permitting degradation products to exceed acceptable minimums. Buffers were used in concentrations ranging from 0.25 mM to 25 mM. Acceptable levels of degradation products were obtained at all buffer concentrations tested. It was noted, however, that citrate buffer had properties more desirable than those of acetate buffer. In particular, the addition of citrate buffer did not seem to alter in any material respects the amount of degradation products resulting from autoclaving the methylnaltrexone solution, resulting in less than 0.23% of degradation products at pH of 3.5. The addition of acetate buffer, however, appeared to increase somewhat the amount of methylnaltrexone degradation products, although not to unacceptable levels, resulting in less than 1.39% of degradation products at pH of 3.6. Nonetheless, citrate buffer surprisingly is preferable to acetate buffer. The preferred citrate buffer range is between about 2 and 5 mM.
- Buffers in general are well known to those of ordinary skill in the art. Buffer systems include citrate buffers, acetate buffers, borate buffers, and phosphate buffers. Examples of buffers include citric acid, sodium citrate, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartartic acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazole, sodium bicarbonate and carbonic acid, sodium succinate and succinic acid, histidine, and sodium benzoate and benzoic acid.
- Applicants also discovered, surprisingly, that a chelating agent alone was capable of reducing the amount of degradation products to acceptable levels. In particular, pH was not adjusted and disodium edetate was added at concentrations of 0.01, 0.1, 0.25, 0.5, 0.75, and 1.0 mg/mL. The disodium edetate stabilized methylnaltrexone against heat degradation in a concentration-dependent manner. As little as 0.01 mg/mL had a substantial effect on the amount of degradants, yielding approximately 2.3% total degradants. A concentration of 0.1 mg/mL resulted in under 1.5% total degradants. There was a critical point at approximately 0.3-0.4 mg/mL where the total degradants became slightly under 0.5% and leveled off with increasing amounts of disodium edetate. Thus, disodium edetate alone was sufficient to render stable an unbuffered solution of methylnaltrexone with no adjustment to pH. This was a surprising result.
- Applicants believe that the result is not limited to disodium edetate. Instead, other chelating agents well known to those of ordinary skill in the art will be useful according to the invention. Chelating agents are chemicals which form water soluble coordination compounds with metal ions in order to trap or remove the metal irons from solution, thereby avoiding the degradative effects of the metal ions. Chelating agents include ethylenediaminetetraacetic acid (also synonymous with EDTA, edetic acid, versene acid, and sequestrene), and EDTA derivatives, such as dipotassium edetate, disodium edetate, edetate calcium disodium, sodium edetate, trisodium edetate, and potassium edetate. Other chelating agents include citric acid and derivatives thereof. Citric acid also is known as citric acid monohydrate. Derivatives of citric acid include anhydrous citric acid and trisodiumcitrate-dihydrate. Still other chelating agents include niacinamide and derivatives thereof and sodium desoxycholate and derivatives thereof. A synergistic effect of pH and disodium edetate was also observed. At pH 3-3.5, in the presence of citrate buffer (25 mM), and 0.01 mg/mL disodium edetate, the total degradants after autoclaving amounted to less than 0.4%. Under the same conditions, except increasing the concentration of disodium edetate to 1 mg/mL, there was no detectable difference. That is, the degradants were on the order of approximately 0.4% after autoclaving. The circumstance, however, differed when pH was adjusted upwardly to between 6.0 and 7.0 in an unbuffered system. In particular, at a pH adjusted upwardly to between 6.0 and 7.0, the total degradants were above 3-6% at a concentration of 0.01 mg/mL disodium edetate and approximately 2.8% at 1.0 mg/mL disodium edetate. This at first glance appears anomalous with the results described above, where disodium edetate alone was sufficient to bring total degradants under 0.5% at concentrations above approximately 0.3 disodium edetate mg/mL. It was discovered, however, that the increase in degradation was due to the addition of a pH-adjusting base to the solution containing methylnaltrexone to upwardly adjust the pH to 6.0-7.0. Therefore, it was discovered unexpectedly that the addition of a pH-adjusting base, such as sodium hydroxide, to a solution containing methylnaltrexone should be avoided in order to minimize the presence of degradants.
- The same results were achieved through a combination of acetate buffer and disodium edetate at 0.01 mg/mL and 1.0 mg/mL, although, once again, citrate buffer seemed to work surprisingly better than acetate buffer in protecting methylnaltrexone from heat degradation. Higher levels of disodium edetate in the presence of acetate buffer could compensate, however, for the differential effect that was observed when using citrate buffer versus acetate buffer. It is to be noted that citrate buffer also is a chelating agent, which might contribute to its apparent superior properties. However, there was no concentration-dependent stabilization due to citrate buffer and it would appear that the chelating effect of citrate is not wholly responsible for the differential effects observed between citrate buffer and acetate buffer.
- Applicants also believe that antioxidants will be useful according to the invention. Antioxidants are substances capable of inhibiting oxidation by removing free radicals from solution. Antioxidants are well known to those of ordinary skill in the art and include materials such as ascorbic acid, ascorbic acid derivatives (e.g., ascorbylpalmitate, ascorbylstearate, sodium ascorbate, calcium ascorbate, etc.), butylated hydroxy anisole, buylated hydroxy toluene, alkylgallate, sodium meta-bisulfite, sodium bisulfite, sodium dithionite, sodium thioglycollic acid, sodium formaldehyde sulfoxylate, tocopherol and derivatives thereof, (d-alpha tocopherol, d-alpha tocopherol acetate, dl-alpha tocopherol acetate, d-alpha tocopherol succinate, beta tocopherol, delta tocopherol, gamma tocopherol, and d-alpha tocopherol polyoxyethylene glycol 1000 succinate) monothioglycerol, and sodium sulfite. Such materials are typically added in ranges from 0.01 to 2.0%.
- The pharmaceutical preparations of the invention also may include isotonicity agents. This term is used in the art interchangeably with iso-osmotic agent, and is known as a compound which is added to the pharmaceutical preparation to increase the osmotic pressure to that of 0.9% sodium chloride solution, which is iso-osmotic with human extracellular fluids, such as plasma. Preferred isotonicity agents are sodium chloride, mannitol, sorbitol, lactose, dextrose and glycerol.
- Optionally, the pharmaceutical preparations of the invention may further comprise a preservative. Suitable preservatives include but are not limited to: chlorobutanol (0.3-0.9% W/V), parabens (0.01-5.0%), thimerosal (0.004-0.2%), benzyl alcohol (0.5-5%), phenol (0.1-1.0%), and the like.
- In view of the success achieved with disodium edetate alone in an unbuffered system, it would have been expected that stable formulations could be prepared at virtually any pH simply by optimizing the various potential methylnaltrexone degradation inhibiting agents. Such agents include those as described above, that is, chelating agents, buffering agents, antioxidants, and the like. It was discovered, however, that stable formulations of methylnaltrexone in solution could not be obtained with such degradation inhibiting agents at pHs above 6. Thus, in one aspect of the invention, stable pharmaceutical preparations containing methylnaltrexone in solution are permitted, wherein the solution further includes an agent selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, and combinations thereof, provided that the solution has a pH ranging from between 2 to 6.
- The stable pharmaceutical preparations of the invention are stable not only to heat degradation resulting from autoclaving, but also to other sterilization processes used during manufacturing. Sterilization processes or techniques as used herein include aseptic techniques such as one or more filtration (0.45 or 0.22 micron filters) steps, autoclaving, and a combination of filtration and autoclaving. They also are stable to long term storage. The stable formulations of the invention are stable for at least six months at temperatures of 30° C. or less, preferably a range from 5° C. to 30° C., and, more preferably, they are stable at a temperature above 15° C. for at least six months. More particularly, the stable pharmaceutical preparations are stable for periods of at least six months, at least twelve months, and even at least twenty-four months at about room temperature or 25° C. Such preparations remain substantially free of methylnaltrexone degradation products, that is, such solutions contain less than 2% methylnaltrexone degradation products compared to the total amount of methylnaltrexone in the solution.
- Applicants also discovered, surprisingly, that lyophilizing conditions could dramatically affect the amount of methylnaltrexone degradation products. The pharmaceutical preparations of the invention therefore may advantageously include cryoprotective agents, which protect methylnaltrexone from the harmful effects of freezing. Such agents also can prevent caking and flaking, which can be problematic in reconstituting a solution and in manufacturing processing. Important cryoprotecting agents are mannitol, lactose, sucrose, polyethylene qlycol and polyvinyl pyrrolidine. Most preferred is mannitol. It is believed that cryoprotecting agents which result in a reconstitution pH of 6.0 and higher or which are basic will contribute also to degradation of methylnaltrexone due to pH effects discussed above. Thus, preferred cryoprotecting agents are those which, together with the other components of the formulation, result in a pH in the preferred ranges described above. Preferably, the cryoprotecting agent is neutral or acidic.
- The amount of methylnaltrexone in the solution is effective to treat completely, ameliorate, or even prevent conditions associated with activation of endogenous opioid receptors, in particular, peripheral opioid receptors such as mu opioid receptors. Such conditions include nausea, emesis, dysphoria, pruritus, urinary retention, ileus, post-operative ileus, post-partumileus, parallytic ileus, bowel hypomotility, constipation, gastric hypomotility, delayed gastric emptying, decreased biliary secretion, decreased pancreatic secretion, biliary spasm, increased sphincter tone, cutaneous flushing, impaction, sweating, inhibition of gastrointestinal motility, inhibition of gastric emptying, gastrointestinal dysfunction, incomplete evacuation, bloating, abdominal distention, increased gastroesophageal reflux, hypotension, bradycardia, irritable bowel syndrome, or immunosuppression. One important use is in the treatment of constipation, i.e., less than one bowel movement in 3 days or less than 3 bowel movements in a week.
- In any of the foregoing embodiments, the methylnaltrexone can be present in an amount sufficient to accelerate discharge from hospital post-surgery, accelerate bowel sounds after surgery, or induce laxation. Such amounts are well known to those of ordinary skill in the art and are described in the literature, including the patents listed in the background of the invention. The methylnaltrexone may also be in a salt form, including the bromide, chloride, iodide, carbonate, and sulfate salts of methylnaltrexone.
- Patients treatable with the formulations of the invention include those receiving opioids including opioids for pain, cancer or surgical patients, immunosuppressed or immunocompromised patients (including HIV infected patients), patients with advanced medical illness, terminally ill patients, patients with neuropathies, patients with rheumatoid arthritis, patients with osteoarthritis, patients with chronic pack pain, patients with spinal cord injury, patients with chronic abdominal pain, patients with chronic pancreatic pain, patients with pelvic perineal pain, patients with fibromyalgia, patients with chronic fatigue syndrome, patients with migraine or tension headaches, patients on hemodialysis, and patients with sickle cell anemia.
- The pharmaceutical preparations of the invention also can include an opioid. The therapeutic use of opioids is well known and, again, is described in both the literature and the patents mentioned above. Opioids include alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol.
- It should be understood that the pharmaceutical preparations of the invention will typically be held in bottles, vials, ampoules, infusion bags, and the like, any one of which may be sparged to eliminate oxygen or purged with nitrogen. In some embodiments, the bottles vials and ampoules are opaque, such as when amber in color. Such sparging and purging protocols are well known to those of ordinary skill in the art and should contribute to maintaining the stability of the pharmaceutical preparations. The pharmaceutical preparations also, in certain embodiments, are expected to be contained within syringes.
- According to another aspect of the invention, kits also are provided. Referring to FIG. 3, a
kit 10 is depicted. Thekit 10 includes apharmaceutical preparation vial 12, a pharmaceuticalpreparation diluent vial 14, anopioid vial 16, and an opioiddiluent vial 18. The kit also includesinstructions 20. Thevial 14 containing the diluent for the pharmaceutical preparation is optional. Thevial 14 contains a diluent such as physiological saline for diluting what could be a concentrated solution of methylnaltrexone contained invial 12. The instructions can include instructions for mixing a particular amount of the diluent with a particular amount of the concentrated pharmaceutical preparation, whereby a final formulation for injection or infusion is prepared. The instructions may include instructions for use in a patient controlled analgesia (PCA) device. Likewise, the kit optionally contains an opioid in theopioid vial 16, which also optionally may be in a concentrated form. Theoptional vial 18 contains a diluent for a concentrated opioid. The instructions also may include instructions for mixing the opioid with the pharmaceutical preparation and/or diluting the opioid with the opioid diluent contained in the opioiddiluent vial 18. The instructions, therefore, would take a variety of forms depending on the presence or absence of diluent and opioid. Theinstructions 20 can include instructions for treating a patient with an effective amount of methylnaltrexone. It also will be understood that the containers containing the pharmaceutical preparation, whether the container is a bottle, a vial with a septum, an ampoule with a septum, an infusion bag, and the like, can contain indicia such as conventional markings which change color when the pharmaceutical preparation has been autoclaved or otherwise sterilized. - The pharmaceutical preparations of the invention, when used in alone or in cocktails, are administered in therapeutically effective amounts. A therapeutically effective amount will be determined by the parameters discussed below; but, in any event, is that amount which establishes a level of the drug(s) effective for treating a subject, such as a human subject, having one of the conditions described herein. An effective amount means that amount alone or with multiple doses, necessary to delay the onset of, inhibit completely or lessen the progression of or halt altogether the onset or progression of the condition being treated. When administered to a subject, effective amounts will depend, of course, on the particular condition being treated; the severity of the condition; individual patient parameters including age, physical condition, size and weight; concurrent treatment; frequency of treatment; and the mode of administration. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment.
- The pharmaceutical preparations of the present invention may include or be diluted into a pharmaceutically-acceptable carrier. The term “pharmaceutically-acceptable carrier” as used herein means one or more compatible solid, or semi-solid or liquid fillers, diluants or encapsulating substances which are suitable for administration to a human or other mammal such as a dog, cat, horse, cow, sheep, or goat. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The carriers are capable of being commingled with the preparations of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy or stability. Carriers suitable for oral, subcutaneous, intravenous, intramuscular, etc. formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.
- A variety of administration routes are available. The particular mode selected will depend of course, upon the particular drug selected, the severity of the disease state being treated and the dosage required for therapeutic efficacy. The methods of this invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes. The term “parenteral” includes subcutaneous, intravenous, intramuscular, or infusion.
- Dosage may be adjusted appropriately to achieve desired drug levels, locally or systemically. Generally, daily oral doses of active compounds will be from about 0.1 mg/kg per day to 30 mg/kg per day. It is expected that IV doses in the range of 0.01-1.00 mg/kg will be effective. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous IV dosing over, for example, 24 hours or multiple doses per day also are contemplated to achieve appropriate systemic levels of compounds. Preferred subcutaneous doses for chronic opioid users to induce Taxation are 0.1-0.3 mg/kg, and preferred oral doses for the same patient population are 1.0-3.0 mg/kg. Preferred IV doses to treat post operative ileus are 0.15 mg/kg.
- The invention also involves methods for preparing autoclaved pharmaceutical preparations that have concentrations of methylnaltrexone degradation products that do not exceed 2% of the methylnaltrexone or salt thereof in the preparation. Aqueous solutions of methylnaltrexone are prepared. A pH-adjusting acid is added to adjust the pH to 4.25 or less, preferably to a range of between 3.0 and 3.5. The solution is then autoclaved according to standard procedures. One such procedure involves autoclaving at 122° C. and 15 pounds of pressure for 20 minutes. The pharmaceutical preparation can contain any one, any combination of or all of a chelating agent, an isotonicity agent, a buffering agent, an antioxidant, a cryoprotective agent, and an opioid. According to another aspect of the invention, a pharmaceutical preparation containing methylnaltrexone in a aqueous solution is prepared by combining a chelating agent with the methylnaltrexone solution and then autoclaving the solution. The aqueous solution of methylnaltrexone may contain any one of, any combination of or all of a buffering agent, an antioxidant, an isotonicity agent and an opioid.
- According to yet another aspect of the invention, a pharmaceutical preparation containing methylnaltrexone in a lyophilized formulation is prepared by combining a cryoprotective agent, such as mannitol, with the methylnaltrexone formulation. The lyophilized preparation may also contain any one of, any combination of, or all of a buffering agent, an antioxidant, an isotonicity agent and an opioid.
- The invention also involves methods of inhibiting the formation of methylnaltrexone degradation products in a solution containing methylnaltrexone by combining any one of, any combination of or all of a chelating agent, a buffering agent and an antioxidant with methylnaltrexone or salt thereof in solution. In one preferred embodiment, the aqueous solution containing the chelating agent, buffering agent and/or antioxidant is first prepared, then a powdered source of methylnaltrexone or salt thereof is dissolved into the aqueous solution.
- The invention also involves methods of inhibiting the formation of methylnaltrexone degradation products in a gel containing methylnaltrexone by combining any one of, any combination of or all of a chelating agent, a buffering agent and an antioxidant with methylnaltrexone or salt thereof in a gel matrix. In one preferred embodiment, the gel containing the chelating agent, buffering agent and/or antioxidant is first prepared, then a powdered source of methylnaltrexone or salt thereof is dissolved into the gel. As used herein, solution embraces gels.
- The pharmaceutical preparations of the invention may be provided in particles. Particles as used herein means nano or microparticles (or in some instances larger) which can consist in whole or in part of the peripheral opioid antagonists or the other therapeutic agent(s) as described herein. The particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic agent(s) also may be dispersed throughout the particles. The therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the antagonist in a solution or in a semi-solid state. The particles may be of virtually any shape.
- Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described by H. S. Sawhney, C. P. Pathak and J. A. Hubell inMacromolecules, (1993) 26:581-587, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).
- The invention also provides methods for preparing stable pharmaceutical preparations containing aqueous solutions of methylnaltrexone or salts thereof to inhibit formation of methylnaltrexone degradation products. A solution is provided that contains methylnaltrexone or salts thereof and at least one methylnaltrexone inhibiting agent. The solution is processed under at least one sterilization technique prior to and/or after terminal filing the solution in the sealable container to form a stable pharmaceutical preparation, wherein the method is carried out without the addition of a pH-adjusting base to the solution.
- A manufacturing process can be outlined as follows:
- 1. Add required amount of water for injection (˜80% or final volume) to a stainless steel tank.
- 2. Add chelating agent to the tank and stir till dissolved.
- 3. Add buffering agent to the tank and stir till dissolved.
- 4. Add methylnaltrexone to the tank and stir till dissolved.
- 5. Add isotonicity agent to the tank and stir till dissolved.
- 6. Adjust the pH of the solution to pH 3.25.
- 7. Add water for injection to increase the volume to the required amount.
- 8. Transfer material to supply pressure vessel.
- 9. Sterile filter into a sterile stainless steel pressure vessel.
- 10. Fill into bottles/vials, purge with nitrogen and then stopper the bottles/vials.
- 11. Sterilize the filled vials by autoclaving.
- Exact amount of excipients to be used:
Disodium edetate = 0.75 mg/ml Added in step 2Sodium Citrate = 0.199 mg/ml Added in step 3Citric acid = 0.35 mg/ml Added in step 3Sodium Chloride = 8.5 mg/ml Added in step 5 - The order of addition of excipients is described above.
Steps 2 to 5 can take place in any order. - When all excipients and drug have been added, step 6, pH of the solution is adjusted by addition of acid. If a buffering agent is used in the solution, pH adjustment may not be required.
- There are no specifics on the temperature or the stirring speed during the formulation. The temperature during formulation can be as high as 80° C.
- A preferred manufacturing process is as follows:
- 100 ml of 20 mg/ml solution of methylnaltrexone solutions
- 1. Add 80 ml of water for injection (˜80% or final volume) to a stainless steel tank.
- 2. Add 75 mg of disodium edetate, a chelating agent, to the tank and stir till dissolved.
- 3. Add 19.9 mg of sodium citrate and 35 mg of citric acid (as buffering agents) to the tank and stir till dissolved.
- 4. Add 2000 mg of methylnaltrexone to the tank and stir till dissolved.
- 5. Add 850 mg of sodium chloride, an isotonicity agent, to the tank and stir till dissolved.
- 6. Adjust the pH of the solution if necessary.
- 7. Add water for injection to increase the volume to 100 ml.
- 8. Transfer the material to supply pressure vessel.
- 9. Sterile filter using a 0.22 micron filter into a sterile stainless steel pressure vessel.
- 10. Fill, purge with nitrogen and then stopper the bottles/vials.
- 11. Sterilize the filled vials by autoclaving.
- Methylnaltrexone (bromide salt) and its degradation products in an isotonic saline solution were tested upon manufacture of the solution (no added stabilizers, sterile filtered, not autoclaved) and upon storage at room temperature for 12 months using a Hewlett-Packard HP1100 series, HPLC system equipped with quaternary gradient pump, programmable variable wavelength UV detector and a Millennium data acquisition system. Two mobile phases were prepared as follows:
- The reagents, standards and media included naltrexone methobromide as a reference standard, trifluoroacetic acid (ACS grade), acetonitrile (HPLC grade), Milli-Q water (or equivalent), and methanol (HPLC grade). The solutions were prepared as follows. Mobile phase A (85:15:0.1) (water:methanol:trifluoroacetic acid): 850 mL of Milli-Q water was added to a suitable container, to which 150 mL of methanol and 1.0 mL of trifluoroacetic acid were added. The solution was mixed well and allowed to equilibrate to room temperature. The solution was degassed by helium sparge. Mobile phase B (methanol): Methanol was added to a suitable container and degassed by helium sparge.
- Instrumental Conditions
- Analytical Column: Metachem Inertsil ODS3, 5 μm, 150×4.6 mm or equivalent
- Mobile phase: A mixture of Mobile phase A and B is used as shown in Table I:
TABLE I Time (minutes) % A % B 0 100 0 12 65 35 15 35 65 15.1 100 0 20 100 0 - Column temperature: 50° C.
- Detection: UV at 280 nm
- Injection volume: 20 μL
- Run time: 20 minutes
- Flow rate: 1.5 mL/minute
- Quantitation: Peak area responses
- Results:
- 20 mg/ml saline drug product lot CTM-02085
Initial 12 months Peak % % No. RRT Degradants RRT Degradants 1 degradation product 0.72 0.07 0.74 0.25 2 degradation product 0.89 <0.05 0.89 0.72 3 methylnaltrexone 1.00 99.7 1.00 98.6 4 degradation product 1.48 0.06 1.40 0.16 5 O-Methylnaltrexone 1.57* 0.17 1.54* 0.17 Bromide (process impurity) - Samples from the methylnaltrexone saline formulation (not autoclaved) were analyzed for methylnaltrexone degradation products before and after storage for 12 months at 25° C.
- The starting material was analyzed by HPLC. As shown in FIG. 1, methylnaltrexone is a peak having an RRT of 1.0 (4.364 minutes). An additional peak was identified as O-methyl naltrexone methobromide, RRT about 1.57 (6.868 minutes). The O-methyl-naltrexone is not a degradant of methylnaltrexone but a result from the methylnaltrexone (drug substance) manufacturing process.
- The material stored for 12 months was similarly analyzed by HPLC. The chromatogram is shown in FIG. 2.
- As in the starting material, the HPLC analysis of the sample stored for 12 months showed methylnaltrexone RRT of 1.00 (3.839 minutes), O-methyl-methylnaltrexone RRT of about 1.53 (5.866 minutes). However, HPLC analysis revealed that the methylnaltrexone saline formulation which was stored for 12 months had at least three degradation products formed during the manufacturing or during storage of the finished drug product. The degradant peak RRT's were approximately 0.74 (2.828 minutes), 0.89 (3.435 minutes) and 1.40(5.326 minutes).
- HPLC analysis was also conducted, prior to storage, on a methylnaltrexone solution manufactured using an isotonic saline solution (no added stabilizers), sterile filtered, and autoclaved. This saline, autoclaved solution contained the degradation products formed during manufacturing or storage, as described above (data not shown).
- The degradation products seen with very low citrate level were the same as those seen with normal saline solution. These low citrate formulas were autoclaved and after three months the amount of degradation products seen were less than 0. 1% for each degradation product. The formula used for the citrate/EDTA formulation is listed below:
mg/mL Methynaltrexone 30 mg Sodium Chloride 4 mg Citric acid 0.0875 mg Trisodium Citrate 0.0496 mg Disodium edetate 0.75 mg Water for injection q.s. to 1 gram - The pH of this solution is 3.5 and can withstand autoclaving process.
- The lyophilization cycle listed below is standard procude well known to one of ordinary skill in the art. This cycle was used for the preparation of lyophilized preparation of methylnaltrexone analyzed in Examples 6 and 7.
- 1. Load chamber at room temperature (20-25 C)
- 2. Lower shelf temp to −45 degrees C. at 1.0 degrees C./min
- 3. Hold shelf temp at −45 for 120 minutes
- 4. When condenser is below −50 degrees C., evacuate the chamber to 100-125 mt.
- 5. Ramp shelf to −20 degrees C. at 0.5 degrees C./min.
- 6. Hold at −20 degrees C. for 16 hours
- 7. Ramp shelf to +27 degrees C. at 0.10 degrees C./min.
- 8. Hold for a minimum of 8 hours. Maintain chamber pressure at 100-125 mt for the entire cycle.
- 9. Restore chamber to 11.0 PSIA + or −1.0 with sterile filtered Nitrogen and then seat the closures (2″ Hg), then bleed to atmospheric pressure with Nitrogen to unload.
- The following data reports the stability of lyophilized formulations of methylnaltrexone using different cryoprotecting agents.
total degradation Cryoprotecting Agent pH products Mannitol 5.0 0.34% Polyvinyl pyrrolidone 4.1 0.37% Polyethylene glycol 5.7 0.44% Histidine 7.4 0.55% - The following data reports the stability of lyophilized formulations of methylnaltrexone in comparison to buffered formulations.
- Amount of total related substances at various stages of manufacturing
1 2 3 4 5 6 Key Monothio- Citrate Citrate Acetate Lyophilized Lyophilized Ingredient glycerol Buffer Buffer Buffer using using pH 3.5 pH 5pH 3.6 Mannitol Lactose Unautoclaved 0.13 0.12 0.16 0.20 0.14 0.12 Autoclaved 0.91 0.23 0.61 1.39 n/a n/a Stability (2 mths 1.10 0.16 0.48 1.26 0.15 0.15 at room temp) - It should be understood that various changes and modifications to the preferred embodiments described herein will be apparent to those of ordinary skill in the art. Such changes and modifications can be made without departing from the spirit and scope of this invention without diminishing its advantages. It is therefore intended that such changes and modifications, including equivalents, be covered by the appended claims. All of the patents, patent applications and references listed herein are incorporated by reference in their entirety.
Claims (210)
1. A pharmaceutical preparation comprising a solution of methylnaltrexone or a salt thereof, wherein the preparation after autoclaving has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone or salt thereof in the preparation.
2-6. (canceled)
7. The pharmaceutical preparation of claim 1 , wherein the pharmaceutical preparation further comprises a chelating agent.
8. The pharmaceutical preparation of claim 7 , wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA) or a derivative thereof.
9. (canceled)
10. The pharmaceutical preparation of claim 8 , wherein the EDTA or derivative thereof is present in a concentration ranging from 0.001 to 100.0 mg/ml.
11-16. (canceled)
17. The pharmaceutical preparation of claim 1 , further comprising a buffering agent.
18. The pharmaceutical preparation of claim 17 , wherein the buffering agent is citrate buffer.
19. The pharmaceutical preparation of claim 18 , wherein the citrate is present in a concentration ranging from 0.01 to 100.0 mM.
20-21. (canceled)
22. The pharmaceutical preparation of claim 1 , wherein the pH of the preparation does not exceed 4.25.
23-25. (canceled)
26. The pharmaceutical preparation of claim 1 , wherein the concentration of methylnaltrexone ranges from 0.01 to 100 mg/ml.
27-32. (canceled)
33. The pharmaceutical preparation of claim 1 , further comprising an anti-oxidant.
34. The pharmaceutical preparation of claim 1 , further comprising an isotonicity agent.
35. The pharmaceutical preparation of claim 1 , further comprising an opioid.
36. The pharmaceutical preparation of claim 1 , further comprising a cryoprotective agent.
37. The pharmaceutical preparation of claim 36 , wherein the cryoprotective agent is a polyol.
38. The pharmaceutical preparation of claim 1 , wherein the solution is provided in a vial or ampoule with a septum.
39. The pharmaceutical preparation of claim 1 , wherein the solution is provided in a syringe, infusion bag or sealable bottle.
40-43. (canceled)
44. The pharmaceutical preparation of claim 1 , wherein the solution is provided in a container including indicia indicating that the pharmaceutical preparation has been autoclaved.
45-49. (canceled)
50. A method for preparing an autoclaved pharmaceutical preparation that has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone or salt thereof in the preparation comprising:
providing a solution having a pH of 4.25 or less comprising methylnaltrexone or salt thereof and being substantially free of methylnaltrexone degradation products; and
autoclaving the solution.
51-53. (canceled)
54. The method of claim 50 , wherein the solution contains a chelating agent.
55. The method of claim 50 , wherein the solution further comprises an isotonicity agent.
56. The method of claim 50 , wherein the solution comprises a buffering agent.
57. (canceled)
58. The method of claim 50 , wherein the solution comprises an anti-oxidant.
59-60. (canceled)
61. The method of claim 54 , wherein the chelating agent is EDTA or derivative thereof.
62. The method of claim 56 , wherein the buffering agent is citrate buffer.
63. The method of claim 50 , further comprising lyophilizing the solution.
64. The method of claim 63 , further comprising adding a cryoprotecting agent to the solution.
65. The method of claim 63 , wherein the cryoprotective agent is a polyol.
66. A method for preparing an autoclaved pharmaceutical preparation that has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone or salt thereof in the preparation comprising:
providing a solution comprising methylnaltrexone or salt thereof and a chelating agent, the solution being substantially free of methylnaltrexone degradation products; and
autoclaving the solution.
67. The method of claim 66 , wherein the chelating agent is EDTA or derivative thereof.
68. The method of claim 67 , wherein the EDTA or derivative thereof is present in a concentration ranging from 0.001 to 100.0 mg/ml.
69-70. (canceled)
71. The method of claim 66 , wherein the solution contains a buffering agent.
72. The method of claim 71 , wherein the buffering agent is citrate buffer.
73. The method of claim 66 , wherein the solution is adjusted to have a pH of 4.25 or less.
74-76. (canceled)
77. The method of claim 66 , wherein the solution contains an anti-oxidant.
78. The method of claim 66 , wherein the solution contains an isotonicity agent.
79-82. (canceled)
83. The method of claim 66 , further comprising lyophilizing the solution.
84. The method of claim 83 , further comprising adding a cryoprotecting agent to the solution.
85. The method of claim 84 , wherein the cryoprotective agent is a polyol.
86. A pharmaceutical preparation comprising a solution of methylnaltrexone or a salt thereof, wherein the preparation after storage at about room temperature for six months has a concentration of methylnaltrexone degradation products that does not exceed 2% of the methylnaltrexone in the preparation.
87-91. (canceled)
92. The pharmaceutical preparation of claim 86 , wherein the pharmaceutical preparation further comprises a chelating agent.
93. The pharmaceutical preparation of claim 92 , wherein the chelating agent is EDTA or derivative thereof.
94. The pharmaceutical preparation of claim 93 , wherein the EDTA or derivative thereof is present in a concentration ranging from 0.001 to 100.0 mg/ml.
95-100. (canceled)
101. The pharmaceutical preparation of claim 86 , wherein the pharmaceutical preparation further comprises a buffering agent.
102. The pharmaceutical preparation of claim 86 , wherein the buffering agent is citrate buffer.
103. The pharmaceutical preparation of claim 102 , wherein the citrate is present in a concentration ranging from 0.01 to 100.0 mM.
104-105. (canceled)
106. The pharmaceutical preparation of claim 86 , wherein the pH does not exceed 4.25.
107-109. (canceled)
110. The pharmaceutical preparation of claim 86 , wherein the concentration of methylnaltrexone ranges from 0.01 to 100 mg/ml.
111-116. (canceled)
117. The pharmaceutical preparation of claim 86 , further comprising an anti-oxidant.
118. The pharmaceutical preparation of claim 86 , further comprising an isotonicity agent.
119. The pharmaceutical preparation claim 86 , further comprising a cryoprotective agent.
120. The pharmaceutical preparation of claim 119 , wherein the cryoprotective agent is a polyol.
121. The pharmaceutical preparation of claim 86 , further comprising an opioid.
122-128. (canceled)
129. The pharmaceutical preparation of claim 86 , wherein the solution is provided in a vial or ampoule with a septum, in a syringe, an infusion bag, or a sealable bottle.
130-132. (canceled)
133. The pharmaceutical preparation of claim 86 , wherein the solution is provided in a container including indicia indicating that the solution has been autoclaved.
134-135. (canceled)
136. A stable pharmaceutical preparation comprising a solution of methylnaltrexone or salt thereof, wherein the pH is below 4.25.
137-139. (canceled)
140. The pharmaceutical preparation of claim 136 , wherein the pH is adjusted with an acid selected from the group consisting of HCI, citric acid, sulfuric acid, acetic acid, or phosphoric acid.
141. The pharmaceutical preparation of claim 136 , wherein the preparation further comprises a buffering agent.
142. The pharmaceutical preparation of claim 141 , wherein the buffering agent is selected from the group consisting of citric acid, sodium citrate, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartartic acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazole, sodium bicarbonate and carbonic acid, sodium succinate and succinic acid, histidine, and sodium benzoate and benzoic acid.
143. The pharmaceutical preparation of claim 141 , wherein the buffering agent is a citrate buffer.
144. The pharmaceutical preparation of claim 143 , wherein the citrate buffer concentration ranges from 0.001 mM to 100 mM.
145-146. (canceled)
147. The pharmaceutical preparation of claim 136 , further comprising a chelating agent.
148. (canceled)
149. The pharmaceutical preparation of claim 147 , wherein the chelating agent is selected from the group consisting of EDTA and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives sodium desoxycholate and derivatives thereof.
150-154. (canceled)
155. The pharmaceutical preparation of claim 136 , wherein the preparation is substantially free of methylnaltrexone degradation products.
156-157. (canceled)
158. The pharmaceutical preparation of claim 136 , wherein the pharmaceutical preparation has been autoclaved and the concentration of methylnaltrexone degradation products is less than 2.0% of the methylnaltrexone in the preparation.
159-162. (canceled)
163. The pharmaceutical preparation of claim 136 , wherein the methylnaltrexone or salt thereof is present in an amount effective to treat a side effect associated with opioid treatment when administered to a human subject.
164. The pharmaceutical preparation of claim 163 , wherein the concentration of methylnaltrexone or salt thereof is sufficient to treat constipation.
165. The pharmaceutical preparation of claim 136 , wherein the concentration of methylnaltrexone or salt thereof ranges from 0.01 to 100 mg/ml.
166-171. (canceled)
172. The pharmaceutical composition of claim 141 , further comprising an isotonicity agent.
173-175. (canceled)
176. The preparation of claim 136 , further comprising an antioxidant.
177-178. (canceled)
179. The preparation of claim 176 , wherein the antioxidant is selected from the group consisting of an ascorbic acid derivative, butylated hydroxy anisole, butylated hydroxy toluene, alkyl gallate, sodium meta-bisulfite, sodium bisulfite, sodium dithionite, sodium thioglycollic acid, sodium formaldehyde sulfoxylate, tocopherol and derivatives thereof, monothioglycerol, and sodium sulfite.
180. The preparation of claim 136 , further comprising a cryoprotective agent.
181-182. (canceled)
183. The preparation of claim 180 wherein the cryoprotective agent is a polyol.
184. The preparation of claim 136 , further comprising an opioid.
185-186. (canceled)
187. The preparation of claim 184 , wherein the opioid is selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol.
188. A stable pharmaceutical preparation comprising a solution of methylnaltrexone or salt thereof, wherein the solution further comprises a chelating agent in an amount sufficient to inhibit degradation of the methylnaltrexone or salt thereof, whereby the amount is such that the preparation after autoclaving has a concentration of methylnaltrexone degradation products that does not exceed 0.5% of the methylnaltrexone or salt thereof in the preparation.
189. The pharmaceutical preparation of claim 188 , wherein the chelating agent is selected from the group consisting of EDTA and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, and sodium desoxycholate and derivatives thereof.
190-194. (canceled)
195. The pharmaceutical preparation of claim 188 , wherein the preparation further comprises a buffering agent.
196. The pharmaceutical preparation of claim 195 , wherein the buffering agent is selected from the group consisting of citric acid, sodium citrate, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartartic acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazole, sodium bicarbonate and carbonic acid, sodium succinate and succinic acid, histidine, and sodium benzoate and benzoic acid.
197-201. (canceled)
202. The pharmaceutical preparation of claim 188 , wherein the preparation is substantially free of methylnaltrexone degradation products.
203-205. (canceled)
206. The pharmaceutical preparation of claim 188 , wherein the methylnaltrexone or salt thereof is present in an amount effective to treat a side effect associated with opioid treatment when administered to a human subject.
207. The pharmaceutical preparation of claim 206 , wherein the concentration of methylnaltrexone or salt thereof is sufficient to treat constipation.
208. The pharmaceutical preparation of claim 188 , wherein the concentration of methylnaltrexone or salt thereof ranges from 0.01 to 100 mg/ml.
209-213. (canceled)
214. The pharmaceutical composition of claim 188 , further comprising an isotonicity agent.
215. (canceled)
216. The composition of claim 214 , wherein the isotonicity agent is selected from the group consisting of sodium chloride, mannitol, lactose, dextrose, glycerol, and sorbitol.
217. (canceled)
218. (canceled)
219. The preparation of claim 188 , further comprising an antioxidant.
220. (canceled)
221. The preparation of claim 219 , wherein the antioxidant is selected from the group consisting of an ascorbic acid derivative, butylated hydroxy anisole, butylated hydroxy toluene, alkyl gallate, sodium meta-bisulfite, sodium bisulfite, sodium dithionite, sodium thioglycollic acid, sodium formaldehyde sulfoxylate, tocopherol and derivatives thereof, monothioglycerol, and sodium sulfite.
222. (canceled)
223. The preparation of claim 188 , further comprising a cryoprotective agent.
224. (canceled)
225. The preparation of claim 188 , further comprising an opioid.
226. (canceled)
227. (canceled)
228. The preparation of claim 225 , wherein the opioid is selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol.
29. (canceled)
230. (canceled)
231. A pharmaceutical preparation comprising a solution of methylnaltrexone or salt thereof and at least one methylnaltrexone degradation inhibiting agent selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, and combinations thereof, wherein the solution has a pH ranging from 2 to 6, wherein the degradation inhibiting agent is present in an amount sufficient to render the preparation stable, wherein the preparation is processed under at least one sterilization technique, and wherein the preparation is substantially free of methylnaltrexone degradation products.
232. The pharmaceutical preparation of claim 231 , wherein the preparation is stable to storage for 6 months at about room temperature.
233. (canceled)
234. (canceled)
235. The pharmaceutical preparation of claim 231 , wherein the preparation is stable to autoclaving.
236. The pharmaceutical preparation of claim 231 , further comprising an isotonicity agent.
237. The preparation of claim 231 , further comprising a cryoprotective agent.
238. The pharmaceutical preparation of claim 231 , further comprising an opioid.
239. The pharmaceutical preparation of claim 238 , wherein the opioid is selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol.
240. The pharmaceutical preparation of claim 231 , wherein the preparation is provided in a vial or an ampoule with a septum.
241. The pharmaceutical preparation of claim 231 , wherein the preparation is provided in an infusion bag.
242. The pharmaceutical preparation of claim 231 , wherein the preparation is provided in a syringe.
243. The pharmaceutical preparation of claim 231 , wherein the preparation is provided in a sealable bottle.
244. The pharmaceutical preparation of claim 231 , wherein the preparation is suitable for parenteral administration.
245. The pharmaceutical preparation of claim 231 , wherein the preparation is suitable for oral imbibing.
246. The pharmaceutical preparation of claim 231 , wherein the solution is provided in a container including indicia indicating the preparation has been processed under at least one sterilization technique.
247. A method of inhibiting formation of methylnaltrexone degradation products in a pharmaceutical preparation comprising methylnaltrexone or salts thereof, the method comprising:
preparing an aqueous solution comprising at least one methylnaltrexone degradation inhibiting agent selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, and combinations thereof, dissolving a powdered source of methylnaltrexone or salt thereof with the solution to form the pharmaceutical preparation.
248-251. (canceled)
252. The method of claim 247 , further comprising adjusting with an acid the pH of the solution or the preparation to a pH ranging from 2 to 6.
253. (canceled)
254. (canceled)
255. The method of claim 247 , further comprising adding an isotonicity agent to the solution.
256. A method of preparing a stable pharmaceutical preparation comprising an aqueous solution of methylnaltrexone or salts thereof to inhibit formation of methylnaltrexone degradation products, comprising:
providing a solution comprising methylnaltrexone or salts thereof and at least one methylnaltrexone degradation inhibiting agent;
processing the solution under at least one sterilization technique prior to and/or after terminal filling the solution in a sealable container to form the stable pharmaceutical preparation, wherein the method is carried out without the addition of a pH-adjusting-base to the solution.
257. The method according to claim 256 , wherein the concentration of methylnaltrexone degradation products is less than 2.0% of the total methylnaltrexone in the preparation.
258-260. (canceled)
261. The method of claim 256 , wherein the methylnaltrexone degradation inhibiting agent is selected from the group consisting of a chelating agent, a buffering agent, an antioxidant, and combinations thereof.
262-266. (canceled)
267. The method of claim 256 , wherein the initial solution is adjusted to a pH ranging from 2 to 6 prior to the processing under the at least one sterilization technique.
268-270. (canceled)
271. The method of claim 256 , wherein the aseptic technique is autoclaving after terminal filling the sealable container.
272. The method of claim 256 , wherein the processing comprises sterile filtration prior to terminal filling followed by autoclaving after terminal filling the sealable container.
273. The method of claim 256 , further comprising sealing the container, wherein the container is purged with nitrogen.
274. The method of claim 256 , further comprising sealing the container, wherein the container is sparged to eliminate oxygen.
275. The method of claim 256 , wherein the initial solution further comprises an isotonicity agent.
276. The method of claim 275 , wherein the isotonicity agent is sodium chloride.
277. The method of claim 256 , wherein the initial solution further comprising a cryoprotective agent.
278. The method of claim 277 wherein the cryoprotective agent is a polyol.
279. The method of claim 256 , further comprising adding at least one opioid to the initial solution.
280. The method of claim 279 , wherein the opioid is selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol.
281. The method of claim 279 , wherein the opioid is solubilized in a nonaqueous solvent prior to addition to the initial solution.
282. The method of claim 281 , wherein the nonaqueous solvent is an oil, wax, or alcohol.
283. A product comprising
a stable lyophilized formulation of methylnaltrexone, wherein the formulation upon reconstitution in water at a concentration of 20 mg/ml has a pH of between 2 and 6.
284. (canceled)
285. The product of claim 283 , wherein the formulation comprises a cryoprotecting agent present in an amount sufficient to render the formulation stable.
286. (canceled)
287. The product of claim 285 , wherein the cryoprotecting agent is a polyol.
288. (canceled)
289. The product of claim 285 , wherein the cryoprotecting agent is mannitol.
290. (canceled)
291. The product of claim 283 , further comprising any one or more of a buffering agent, a chelating agent and an antioxidant.
292. (canceled)
293. A product comprising
a lyophilized formulation of methylnaltrexone prepared from a solution comprising the solution of claim 1 .
294. A product comprising
a lyophilized formulation of methylnaltrexone prepared from a solution comprising the solution of claim 36 .
295. (canceled)
296. A product comprising
a lyophilized formulation of methylnaltrexone prepared from a solution comprising the solution of claims claim 86 .
297. (canceled)
298. (canceled)
299. A product comprising
a lyophilized formulation of methylnaltrexone prepared from a solution comprising the solution of claim 136 .
300. (canceled)
301. (canceled)
302. A product comprising
methylnaltrexone and a degradation inhibiting agent selected from the group consisting of a chelating agent, a buffering agent, an anti-oxidant, and combinations thereof, wherein the degradation inhibiting agent is present in an amount sufficient to render stable a solution of the product containing a concentration of 20 mg/ml methylnaltrexone.
303. The product of claim 302 , wherein the product when in solution at a concentration of 20 mg/ml methylnaltrexone yields a solution with a pH of between 2 and 6.
304. The product of claim 303 , wherein the product has less than 1% methylnaltrexone degradation products when stored at room temperature in the solution for 6 months.
305. (canceled)
306. (canceled)
307. A pharmaceutical preparation comprising methylnaltrexone;
sodium chloride,
citric acid,
trisodium citrate, and
disodium edetate.
308. The pharmaceutical preparation of claim 307 , wherein the preparation is a solution and the methylnaltrexone is present at between 20 and 40 mg/ml, the sodium chloride is present between 2 and 6 mg/ml, the citric acid is present between 0.05 and 0.1 mg/ml, the trisodium citrate is present between 0.025 and 0.075 mg/ml and the disodium edetate is present between 0.5 and 1.0 mg/ml.
309. A kit comprising a package containing a sealed container comprising the pharmaceutical preparation of claim 231 , and instructions for use.
310. The kit of claim 309 , further comprising a diluant container containing a pharmaceutically acceptable diluant.
311. The kit of claim 310 , further comprising instructions for mixing the preparation and diluant.
312. The kit of claim 310 , wherein the diluant is selected from the group consisting of a 5% dextrose solution and a physiological saline solution.
313. The kit of claim 310 , wherein the diluant is contained in a sealable bottle or an infusion bag.
314. The kit of claim 309 , further comprising an opioid container containing an opioid.
315. The kit of claim 314 , wherein the opioid is selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol.
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/821,811 US20040266806A1 (en) | 2003-04-08 | 2004-04-08 | Pharmaceutical formulation |
US12/639,862 US8552025B2 (en) | 2003-04-08 | 2009-12-16 | Stable methylnaltrexone preparation |
US12/639,889 US20100261745A1 (en) | 2003-04-08 | 2009-12-16 | Pharmaceutical formulation |
US12/639,892 US20100261746A1 (en) | 2003-04-08 | 2009-12-16 | Pharmaceutical formulation |
US12/639,880 US20100267758A1 (en) | 2003-04-08 | 2009-12-16 | Pharmaceutical formulation |
US14/039,866 US9669096B2 (en) | 2003-04-08 | 2013-09-27 | Stable pharmaceutical formulations of methylnaltrexone |
US15/474,614 US10376584B2 (en) | 2003-04-08 | 2017-03-30 | Stable pharmaceutical formulations of methylnaltrexone |
US16/440,304 US20190358328A1 (en) | 2003-04-08 | 2019-06-13 | Stable pharmaceutical formulations of methylnaltrexone |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US46161103P | 2003-04-08 | 2003-04-08 | |
US10/821,811 US20040266806A1 (en) | 2003-04-08 | 2004-04-08 | Pharmaceutical formulation |
Related Child Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/639,892 Continuation US20100261746A1 (en) | 2003-04-08 | 2009-12-16 | Pharmaceutical formulation |
US12/639,880 Continuation US20100267758A1 (en) | 2003-04-08 | 2009-12-16 | Pharmaceutical formulation |
US12/639,862 Continuation US8552025B2 (en) | 2003-04-08 | 2009-12-16 | Stable methylnaltrexone preparation |
US12/639,889 Continuation US20100261745A1 (en) | 2003-04-08 | 2009-12-16 | Pharmaceutical formulation |
Publications (1)
Publication Number | Publication Date |
---|---|
US20040266806A1 true US20040266806A1 (en) | 2004-12-30 |
Family
ID=33299842
Family Applications (8)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/821,811 Abandoned US20040266806A1 (en) | 2003-04-08 | 2004-04-08 | Pharmaceutical formulation |
US12/639,889 Abandoned US20100261745A1 (en) | 2003-04-08 | 2009-12-16 | Pharmaceutical formulation |
US12/639,880 Abandoned US20100267758A1 (en) | 2003-04-08 | 2009-12-16 | Pharmaceutical formulation |
US12/639,892 Abandoned US20100261746A1 (en) | 2003-04-08 | 2009-12-16 | Pharmaceutical formulation |
US12/639,862 Expired - Lifetime US8552025B2 (en) | 2003-04-08 | 2009-12-16 | Stable methylnaltrexone preparation |
US14/039,866 Expired - Lifetime US9669096B2 (en) | 2003-04-08 | 2013-09-27 | Stable pharmaceutical formulations of methylnaltrexone |
US15/474,614 Expired - Lifetime US10376584B2 (en) | 2003-04-08 | 2017-03-30 | Stable pharmaceutical formulations of methylnaltrexone |
US16/440,304 Abandoned US20190358328A1 (en) | 2003-04-08 | 2019-06-13 | Stable pharmaceutical formulations of methylnaltrexone |
Family Applications After (7)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/639,889 Abandoned US20100261745A1 (en) | 2003-04-08 | 2009-12-16 | Pharmaceutical formulation |
US12/639,880 Abandoned US20100267758A1 (en) | 2003-04-08 | 2009-12-16 | Pharmaceutical formulation |
US12/639,892 Abandoned US20100261746A1 (en) | 2003-04-08 | 2009-12-16 | Pharmaceutical formulation |
US12/639,862 Expired - Lifetime US8552025B2 (en) | 2003-04-08 | 2009-12-16 | Stable methylnaltrexone preparation |
US14/039,866 Expired - Lifetime US9669096B2 (en) | 2003-04-08 | 2013-09-27 | Stable pharmaceutical formulations of methylnaltrexone |
US15/474,614 Expired - Lifetime US10376584B2 (en) | 2003-04-08 | 2017-03-30 | Stable pharmaceutical formulations of methylnaltrexone |
US16/440,304 Abandoned US20190358328A1 (en) | 2003-04-08 | 2019-06-13 | Stable pharmaceutical formulations of methylnaltrexone |
Country Status (19)
Country | Link |
---|---|
US (8) | US20040266806A1 (en) |
EP (3) | EP1615646B2 (en) |
JP (3) | JP2006522818A (en) |
CN (2) | CN1767831B (en) |
AU (2) | AU2004229463B2 (en) |
BR (1) | BRPI0409133B8 (en) |
CA (2) | CA2521379C (en) |
CY (3) | CY1116373T1 (en) |
DK (3) | DK1615646T4 (en) |
ES (3) | ES2527870T5 (en) |
HK (2) | HK1082181A1 (en) |
HR (3) | HRP20150038T1 (en) |
IL (1) | IL171228A (en) |
MX (1) | MXPA05010817A (en) |
PL (3) | PL2368554T3 (en) |
PT (3) | PT2368553E (en) |
RU (1) | RU2362560C2 (en) |
SI (3) | SI2368554T1 (en) |
WO (1) | WO2004091623A1 (en) |
Cited By (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030065003A1 (en) * | 1997-11-03 | 2003-04-03 | The University Of Chicago | Use of methylnaltrexone and related compounds |
US20040162306A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnal trexone and related compounds to treat constipation in chronic opioid users |
US20040259899A1 (en) * | 2003-04-08 | 2004-12-23 | Sanghvi Suketu P. | Combination therapy for constipation |
US20050004155A1 (en) * | 2003-04-08 | 2005-01-06 | Boyd Thomas A. | Use of methylnaltrexone to treat irritable bowel syndrome |
US20060205753A1 (en) * | 2005-01-20 | 2006-09-14 | Israel Robert J | Use of methylnaltrexone and related compounds to treat post-operative gastrointestinal dysfunction |
WO2006127899A2 (en) | 2005-05-25 | 2006-11-30 | Progenics Pharmaceuticals, Inc. | (r)-n-methylnaltrexone, processes for its synthesis and its pharmaceutical use |
US20070265293A1 (en) * | 2005-05-25 | 2007-11-15 | Boyd Thomas A | (S)-N-methylnaltrexone |
US20080064744A1 (en) * | 2006-08-04 | 2008-03-13 | Wyeth | 6-Carboxy-normorphinan derivatives, synthesis and uses thereof |
US20080070975A1 (en) * | 2006-08-04 | 2008-03-20 | Wyeth | Formulations for parenteral delivery of compounds and uses thereof |
US20080207669A1 (en) * | 2006-11-22 | 2008-08-28 | Progenics Pharmaceuticals, Inc. | (S)-N-Stereoisomers of 7,8-Saturated-4,5-Epoxy-Morphinanium Analogs |
US20080242720A1 (en) * | 2007-03-30 | 2008-10-02 | Mangel Allen | Kappa-opiate agonists for the treatment of diarrhea-predominant and alternating irritable bowel syndrome |
US20110250278A1 (en) * | 2008-07-01 | 2011-10-13 | University Of Chicago | Particles containing an opioid receptor antagonist and methods of use |
US20120059025A1 (en) * | 2006-09-08 | 2012-03-08 | Wyeth | Dry powder compound formulations and uses thereof |
US8182836B2 (en) | 2003-04-08 | 2012-05-22 | Elite Laboratories, Inc. | Abuse-resistant oral dosage forms and method of use thereof |
US8247425B2 (en) | 2008-09-30 | 2012-08-21 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
US8338446B2 (en) | 2007-03-29 | 2012-12-25 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US8471022B2 (en) | 2008-02-06 | 2013-06-25 | Progenics Pharmaceuticals, Inc. | Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone |
US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US8546418B2 (en) | 2007-03-29 | 2013-10-01 | Progenics Pharmaceuticals, Inc. | Peripheral opioid receptor antagonists and uses thereof |
US8552025B2 (en) | 2003-04-08 | 2013-10-08 | Progenics Pharmaceuticals, Inc. | Stable methylnaltrexone preparation |
US8637538B1 (en) | 2012-12-14 | 2014-01-28 | Trevi Therapeutics, Inc. | Methods for treatment of pruritis |
US8685995B2 (en) | 2008-03-21 | 2014-04-01 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
US8940753B1 (en) | 2012-12-14 | 2015-01-27 | Trevi Therapeutics, Inc. | Methods for treating pruritis |
US8987289B2 (en) | 2012-12-14 | 2015-03-24 | Trevi Therapeutics, Inc. | Methods for treating pruritus |
US9102680B2 (en) | 2007-03-29 | 2015-08-11 | Wyeth Llc | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
US9314461B2 (en) | 2010-03-11 | 2016-04-19 | Wyeth, Llc | Oral formulations and lipophilic salts of methylnaltrexone |
US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US9662390B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
WO2018119108A1 (en) * | 2016-12-21 | 2018-06-28 | Tioga Pharmaceuticals Inc. | Splid pharmaceutical formulations of asimadoline |
US10023574B2 (en) | 2002-08-21 | 2018-07-17 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US10022379B2 (en) | 2008-04-03 | 2018-07-17 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US10034877B2 (en) | 2008-08-06 | 2018-07-31 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US10080754B2 (en) | 2006-05-04 | 2018-09-25 | Boehringer Ingelheim International Gmbh | Uses of DPP IV inhibitors |
US10092571B2 (en) | 2009-11-27 | 2018-10-09 | Boehringer Ingelheim International Gmbh | Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin |
US10155000B2 (en) | 2016-06-10 | 2018-12-18 | Boehringer Ingelheim International Gmbh | Medical use of pharmaceutical combination or composition |
US10195203B2 (en) | 2012-05-14 | 2019-02-05 | Boehringr Ingelheim International GmbH | Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome |
US10213424B2 (en) | 2013-03-14 | 2019-02-26 | Fresenius Kabi Deutschland Gmbh | Morphine formulations |
US10214338B2 (en) | 2013-03-14 | 2019-02-26 | Fresenius Kabi Deutschland Gmbh | Packaging system for oxygen-sensitive drugs |
US10301313B2 (en) | 2006-05-04 | 2019-05-28 | Boehringer Ingelheim International Gmbh | Polymorphs |
US11033552B2 (en) | 2006-05-04 | 2021-06-15 | Boehringer Ingelheim International Gmbh | DPP IV inhibitor formulations |
US11660296B2 (en) | 2018-07-23 | 2023-05-30 | Trevi Therapeutics, Inc. | Treatment of chronic cough, breathlessness and dyspnea |
US20240033284A1 (en) * | 2017-09-15 | 2024-02-01 | Dyve Biosciences, Inc. | Method of administration and treatment |
US11911388B2 (en) | 2008-10-16 | 2024-02-27 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug |
US11911387B2 (en) | 2010-11-15 | 2024-02-27 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
Families Citing this family (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6375957B1 (en) | 1997-12-22 | 2002-04-23 | Euro-Celtique, S.A. | Opioid agonist/opioid antagonist/acetaminophen combinations |
PT1041987E (en) | 1997-12-22 | 2006-07-31 | Euro Celtique Sa | PHARMACEUTICAL FORM OF ORAL DOSAGE, UNDERSTANDING A COMBINATION OF AN AGRONIST OF OPIOIDE AND NALTREXONE |
EP1387673B1 (en) | 2001-05-11 | 2010-12-29 | Endo Pharmaceuticals Inc. | Abuse-resistant controlled-release opioid dosage form |
DE60325567D1 (en) | 2002-04-05 | 2009-02-12 | Euro Celtique Sa | MATRIX FOR THE MODIFIED RELEASE OF ACTIVE SUBSTANCES |
EP1604666A1 (en) | 2004-06-08 | 2005-12-14 | Euro-Celtique S.A. | Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD) |
EP1702558A1 (en) | 2005-02-28 | 2006-09-20 | Euro-Celtique S.A. | Method and device for the assessment of bowel function |
PT1962805T (en) | 2005-12-08 | 2016-10-05 | Insmed Inc | Lipid-based compositions of antiinfectives for treating pulmonary infections |
WO2007123800A2 (en) * | 2006-04-03 | 2007-11-01 | Nutramax Laboratories, Inc. | Stabilized pentosan polysulfate (pps) formulations and methods of analyzing them |
AU2013263750C1 (en) * | 2006-08-04 | 2017-01-12 | Wyeth Llc | Formulations for parenteral delivery of compounds and uses thereof |
WO2008075997A1 (en) * | 2006-12-21 | 2008-06-26 | Sergey Konstantinovich Sudakov | Method for treating opioid withdrawal syndrome |
EP2116241B1 (en) | 2007-01-26 | 2016-04-27 | Pola Pharma Inc. | Pharmaceutical composition |
PL2151241T3 (en) | 2007-04-26 | 2012-08-31 | Toray Industries | Stable solid preparation comprising 4,5-epoxymorphinan derivative |
US9119783B2 (en) | 2007-05-07 | 2015-09-01 | Insmed Incorporated | Method of treating pulmonary disorders with liposomal amikacin formulations |
US9365634B2 (en) | 2007-05-29 | 2016-06-14 | Angiochem Inc. | Aprotinin-like polypeptides for delivering agents conjugated thereto to tissues |
US8383649B2 (en) | 2007-07-11 | 2013-02-26 | Mallinckrodt Llc | Crystalline forms of naltrexone methobromide |
WO2009045985A1 (en) * | 2007-10-01 | 2009-04-09 | The University Of Chicago | Treatment of drug-induced nausea with opioid antagonists |
EP2065038A1 (en) * | 2007-11-30 | 2009-06-03 | Pharnext | New therapeutic approaches for treating Charcot-Marie-Tooth disease |
AU2009238187B2 (en) * | 2008-04-18 | 2014-03-06 | Angiochem Inc. | Pharmaceutical compositions of paclitaxel, paclitaxel analogs or paclitaxel conjugates and related methods of preparation and use |
BRPI0920209A2 (en) | 2008-10-15 | 2015-12-22 | Angiochem Inc | conjugates of glp-1 agonists and their uses |
BRPI0920599B1 (en) | 2008-10-24 | 2021-10-19 | Toray Industries, Inc. | STABLE TABLET CONTAINING A 4,5-EPOXYMORPHINE DERIVATIVE |
WO2010063122A1 (en) | 2008-12-05 | 2010-06-10 | Angiochem Inc. | Conjugates of neurotensin or neurotensin analogs and uses thereof |
CN102387802B (en) | 2009-03-10 | 2016-05-04 | 欧洲凯尔特公司 | The release of pharmaceutical compositions immediately that comprises Oxycodone and naloxone |
RU2011146654A (en) | 2009-04-20 | 2013-05-27 | Ангиокем Инк. | METHODS FOR TREATING OVARIAN CANCER USING CONJUGATED PRODUCT |
CN102596993A (en) | 2009-07-02 | 2012-07-18 | 安吉奥开米公司 | Multimeric peptide conjugates and uses thereof |
PL2456424T3 (en) * | 2009-07-22 | 2013-12-31 | Gruenenthal Gmbh | Oxidation-stabilized tamper-resistant dosage form |
BR112012028656A2 (en) | 2010-05-10 | 2016-08-09 | Euro Celtique Sa | combination of active loaded granules with additional assets |
MY157673A (en) | 2010-05-10 | 2016-07-15 | Euro Celtique Sa | Pharmaceutical compositions comprising hydromorphone and naloxone |
NZ603173A (en) | 2010-05-10 | 2014-10-31 | Euro Celtique Sa | Manufacturing of active-free granules and tablets comprising the same |
ES2753981T3 (en) | 2010-10-21 | 2020-04-15 | Rtu Pharmaceuticals Llc | Ready-to-use ketorolac formulations |
CN102525911B (en) * | 2012-03-20 | 2013-09-18 | 南京臣功制药股份有限公司 | Methyhaaltrexone bromide injection and preparation method thereof |
RU2483731C1 (en) * | 2012-04-24 | 2013-06-10 | Федеральное государственное унитарное предприятие "Московский эндокринный завод" | Solution for injections containing nalbuphine |
US10485798B2 (en) | 2012-08-22 | 2019-11-26 | Aptapharma Inc. | Methylnaltrexone nasal formulations, methods of making, and use thereof |
BR112015012351A8 (en) * | 2012-11-29 | 2019-10-01 | Insmed Inc | stabilized lipid glycopeptide antibiotic composition and use of a lipid component, a glycopeptide antibiotic component and an amino acid or derivative thereof |
NZ716267A (en) | 2013-07-23 | 2017-05-26 | Euro Celtique Sa | A combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation |
EP3068397A1 (en) | 2013-11-13 | 2016-09-21 | Euro-Celtique S.A. | Hydromorphone and naloxone for treatment of pain and opioid bowel dysfunction syndrome |
CA2949078C (en) | 2014-05-15 | 2022-09-20 | Insmed Incorporated | Methods for treating pulmonary non-tuberculous mycobacterial infections |
CN104116707B (en) * | 2014-08-03 | 2016-11-23 | 张星一 | A kind of pharmaceutical composition containing methylnaltrexone bromide |
CN104224734A (en) * | 2014-08-15 | 2014-12-24 | 南京优科生物医药有限公司 | Dezocine freeze-dried powder injection and preparation method thereof |
CN107249327A (en) | 2014-10-17 | 2017-10-13 | 萨利克斯药品公司 | Slow down tumour progression using methyl naltrexone |
CN105769755A (en) * | 2014-12-23 | 2016-07-20 | 北大方正集团有限公司 | Methyhaaltrexone bromide injection and preparation method thereof |
JP6823055B2 (en) | 2015-06-15 | 2021-01-27 | アンジオケム インコーポレーテッド | How to treat soft meningeal carcinomatosis |
CN106265493A (en) * | 2016-08-09 | 2017-01-04 | 成都佳迪璐莎生物科技有限公司 | Improve the pharmaceutical composition of Codeine Hydrochloride drug injection preparation stability |
CN106176588A (en) * | 2016-08-09 | 2016-12-07 | 成都佳迪璐莎生物科技有限公司 | Improve the preparation method of composition of Codeine Hydrochloride ejection preparation stability |
US11571386B2 (en) | 2018-03-30 | 2023-02-07 | Insmed Incorporated | Methods for continuous manufacture of liposomal drug products |
WO2020033402A1 (en) * | 2018-08-06 | 2020-02-13 | Summit Biosciences Inc. | Drug products for nasal administration and uses thereof |
WO2021022045A1 (en) | 2019-07-31 | 2021-02-04 | Ecolab Usa Inc. | Personal protective equipment free delimer compositions |
IT202000002860A1 (en) * | 2020-02-13 | 2021-08-13 | Tred S R L | COMPOSITIONS FOR THE DISINFECTANT TREATMENT OF THE RHINOPHARYNGAL CAVITY |
Citations (66)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4176186A (en) * | 1978-07-28 | 1979-11-27 | Boehringer Ingelheim Gmbh | Quaternary derivatives of noroxymorphone which relieve intestinal immobility |
US4311833A (en) * | 1979-03-06 | 1982-01-19 | Daicel Chemical Industries Ltd. | Process for preparing ethylcarboxymethylcellulose |
US4322426A (en) * | 1980-04-28 | 1982-03-30 | E. I. Du Pont De Nemours And Company | 17-Substituted-6-desoxy-7,8-dihydro-6α-methylnoroxymorphone narcotic antagonists |
US4377568A (en) * | 1981-08-12 | 1983-03-22 | Merck Sharp & Dohme (I.A.) Corp. | Preparation of aqueous alcoholic dispersions of pH sensitive polymers and plasticizing agents and a method of enteric coating dosage forms using same |
US4385078A (en) * | 1978-09-04 | 1983-05-24 | Shin-Etsu Chemical Co., Ltd. | Method for providing enteric coating on solid dosage forms and aqueous compositions therefor |
US4457907A (en) * | 1982-08-05 | 1984-07-03 | Clear Lake Development Group | Composition and method for protecting a therapeutic drug |
US4462839A (en) * | 1983-06-16 | 1984-07-31 | Fmc Corporation | Enteric coating for pharmaceutical dosage forms |
US4518433A (en) * | 1982-11-08 | 1985-05-21 | Fmc Corporation | Enteric coating for pharmaceutical dosage forms |
US4556552A (en) * | 1983-09-19 | 1985-12-03 | Colorcon, Inc. | Enteric film-coating compositions |
US4606909A (en) * | 1981-11-20 | 1986-08-19 | A/S Alfred Benzon | Pharmaceutical multiple-units formulation |
US4615885A (en) * | 1983-11-01 | 1986-10-07 | Terumo Kabushiki Kaisha | Pharmaceutical composition containing urokinase |
US4670287A (en) * | 1985-07-30 | 1987-06-02 | Washu Kirai Kogyo Kabushiki Kaisha | Method of film-coating hard capsules |
US4719215A (en) * | 1986-03-07 | 1988-01-12 | University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
US4857833A (en) * | 1987-08-27 | 1989-08-15 | Teradyne, Inc. | Diagnosis of faults on circuit board |
US4861781A (en) * | 1986-03-07 | 1989-08-29 | The University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
US4888346A (en) * | 1986-10-07 | 1989-12-19 | Bernard Bihari | Method for the treatment of persons infected with HTLV-III (AIDS) virus |
US4965269A (en) * | 1989-12-20 | 1990-10-23 | Ab Hassle | Therapeutically active chloro substituted benzimidazoles |
US4987136A (en) * | 1982-03-16 | 1991-01-22 | The Rockefeller University | Method for controlling gastrointestinal dysmotility |
US5102887A (en) * | 1989-02-17 | 1992-04-07 | Arch Development Corporation | Method for reducing emesis and nausea induced by the administration of an emesis causing agent |
US5159081A (en) * | 1991-03-29 | 1992-10-27 | Eli Lilly And Company | Intermediates of peripherally selective n-carbonyl-3,4,4-trisubstituted piperidine opioid antagonists |
US5202159A (en) * | 1990-12-27 | 1993-04-13 | Standard Chemical & Pharmaceutical Corp., Ltd. | Preparation method of microdispersed tablet formulation of spray-dried sodium diclofenac enteric-coated microcapsules |
US5256154A (en) * | 1992-01-31 | 1993-10-26 | Sterling Winthrop, Inc. | Pre-filled plastic syringes and containers and method of terminal sterilization thereof |
US5270328A (en) * | 1991-03-29 | 1993-12-14 | Eli Lilly And Company | Peripherally selective piperidine opioid antagonists |
US5391372A (en) * | 1993-06-28 | 1995-02-21 | Campbell; Elizabeth | Methods of treating colic and founder in horses |
US5426112A (en) * | 1984-04-09 | 1995-06-20 | Scully, Scott, Murphy & Presser, P.C. | Growth regulation and related applications of opioid antagonists |
US5472943A (en) * | 1992-09-21 | 1995-12-05 | Albert Einstein College Of Medicine Of Yeshiva University, | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists |
US5512578A (en) * | 1992-09-21 | 1996-04-30 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists |
US5536507A (en) * | 1994-06-24 | 1996-07-16 | Bristol-Myers Squibb Company | Colonic drug delivery system |
US5567423A (en) * | 1986-08-28 | 1996-10-22 | Enzacor Properties, Ltd. | Animal growth promotant |
US5591433A (en) * | 1991-06-21 | 1997-01-07 | University Of Cincinnati | Oral administration of immunologically active biomolecules and other therapeutic proteins |
US5597564A (en) * | 1986-08-28 | 1997-01-28 | Enzacor Properties Limited | Method of administering a microgranular preparation to the intestinal region of animals |
US5609871A (en) * | 1991-06-21 | 1997-03-11 | Michael; J. Gabriel | Oral administration of therapeutic proteins for treatment of infectious disease |
US5614219A (en) * | 1991-12-05 | 1997-03-25 | Alfatec-Pharma Gmbh | Oral administration form for peptide pharmaceutical substances, in particular insulin |
US5614222A (en) * | 1994-10-25 | 1997-03-25 | Kaplan; Milton R. | Stable aqueous drug suspensions and methods for preparation thereof |
US5626875A (en) * | 1995-02-01 | 1997-05-06 | Esteve Quimica, S.A. | Stabilized galenic formulations comprising an acid labile benzimidazole compound and its preparation |
US5656290A (en) * | 1993-02-26 | 1997-08-12 | The Procter & Gamble Company | Bisacodyl dosage form with multiple enteric polymer coatings for colonic delivery |
US5767125A (en) * | 1992-09-21 | 1998-06-16 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
US5804595A (en) * | 1995-12-05 | 1998-09-08 | Regents Of The University Of Minnesota | Kappa opioid receptor agonists |
US5811451A (en) * | 1994-05-24 | 1998-09-22 | Minoia; Paolo | Pharmaceutical compositions comprising an opiate antagonist and calcium salts, their use for the treatment of endorphin-mediated pathologies |
US5866164A (en) * | 1996-03-12 | 1999-02-02 | Alza Corporation | Composition and dosage form comprising opioid antagonist |
US5866154A (en) * | 1994-10-07 | 1999-02-02 | The Dupont Merck Pharmaceutical Company | Stabilized naloxone formulations |
US5958452A (en) * | 1994-11-04 | 1999-09-28 | Euro-Celtique, S.A. | Extruded orally administrable opioid formulations |
US5972954A (en) * | 1997-11-03 | 1999-10-26 | Arch Development Corporation | Use of methylnaltrexone and related compounds |
US5981185A (en) * | 1994-05-05 | 1999-11-09 | Beckman Coulter, Inc. | Oligonucleotide repeat arrays |
USRE36547E (en) * | 1992-09-21 | 2000-02-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists |
US6025154A (en) * | 1995-06-06 | 2000-02-15 | Human Genome Sciences, Inc. | Polynucleotides encoding human G-protein chemokine receptor HDGNR10 |
US6096756A (en) * | 1992-09-21 | 2000-08-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
US6194382B1 (en) * | 1999-03-03 | 2001-02-27 | Albert Einstein College Of Medicine Of Yeshiva University | Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists |
US6274591B1 (en) * | 1997-11-03 | 2001-08-14 | Joseph F. Foss | Use of methylnaltrexone and related compounds |
US20010036951A1 (en) * | 1999-11-29 | 2001-11-01 | Farrar John J. | Novel methods for the treatment and prevention of ileus |
US20010047005A1 (en) * | 1999-09-29 | 2001-11-29 | Farrar John J. | Novel methods and compositions involving opioids and antagonists thereof |
US6353004B1 (en) * | 1997-07-14 | 2002-03-05 | Adolor Coporation | Peripherally acting anti-pruritic opiates |
US20020064771A1 (en) * | 2000-04-07 | 2002-05-30 | Weidong Zhong | HCV replicase complexes |
US6419959B1 (en) * | 1996-12-11 | 2002-07-16 | Klinge Pharma Gmbh | Galenic composition containing opioid antagonists |
US6455537B1 (en) * | 1999-08-25 | 2002-09-24 | Barrett R. Cooper | Methods for treating opiate intolerance |
US20030022909A1 (en) * | 2001-06-05 | 2003-01-30 | University Of Chicago | Use of methylnaltrexone to treat immune suppression |
US20030026801A1 (en) * | 2000-06-22 | 2003-02-06 | George Weiner | Methods for enhancing antibody-induced cell lysis and treating cancer |
US6559158B1 (en) * | 1997-11-03 | 2003-05-06 | Ur Labs, Inc. | Use of methylnaltrexone and related compounds to treat chronic opioid use side affects |
US20030124086A1 (en) * | 2001-10-18 | 2003-07-03 | Shearwater Corporation | Polymer conjugates of opioid antagonists |
US20030191147A1 (en) * | 2002-04-09 | 2003-10-09 | Barry Sherman | Opioid antagonist compositions and dosage forms |
US20040162307A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnaltrexone and related compounds to induce laxation in chronic opioid users |
US20040259899A1 (en) * | 2003-04-08 | 2004-12-23 | Sanghvi Suketu P. | Combination therapy for constipation |
US20050004155A1 (en) * | 2003-04-08 | 2005-01-06 | Boyd Thomas A. | Use of methylnaltrexone to treat irritable bowel syndrome |
US20050124885A1 (en) * | 2003-10-29 | 2005-06-09 | Vuesonix Sensors, Inc. | Method and apparatus for determining an ultrasound fluid flow centerline |
US6986901B2 (en) * | 2002-07-15 | 2006-01-17 | Warner-Lambert Company Llc | Gastrointestinal compositions |
US20060205753A1 (en) * | 2005-01-20 | 2006-09-14 | Israel Robert J | Use of methylnaltrexone and related compounds to treat post-operative gastrointestinal dysfunction |
Family Cites Families (214)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1420015B1 (en) * | 1959-10-16 | 1971-08-26 | Boehringer Sohn Ingelheim | 2'-Hydroxy-5,9-dimethyl-6,7-benzomorphane |
GB1202148A (en) | 1968-03-06 | 1970-08-12 | Sankyo Co | Pharmaceutical compositions |
US3854480A (en) | 1969-04-01 | 1974-12-17 | Alza Corp | Drug-delivery system |
US3884916A (en) * | 1971-03-30 | 1975-05-20 | Janssen Pharmaceutica Nv | 2,2-Diaryl-4-(4-aryl-4-hydroxy-piperidino)-butyramides |
US3714159A (en) | 1971-03-30 | 1973-01-30 | Janssen Pharmaceutica Nv | 2,2-diaryl-4-(4'-aryl-4'-hydroxy-piper-idino)-butyramides |
US4326074A (en) | 1972-09-22 | 1982-04-20 | William H. Rorer, Inc. | Amidinoureas |
US4025652A (en) | 1975-03-31 | 1977-05-24 | William H. Rorer, Inc. | Amidinoureas |
US3937801A (en) * | 1973-07-10 | 1976-02-10 | American Home Products Corporation | Reducing the incidence of gastrointestinal side effects during the treatment of inflammatory conditions with antiinflammatory drugs |
US4060635A (en) | 1975-03-31 | 1977-11-29 | William H. Rorer, Inc. | Amidinoureas for treating diarrhea |
US4203920A (en) * | 1975-03-31 | 1980-05-20 | William H. Rorer, Inc. | Amidinoureas |
US4072686A (en) * | 1975-04-16 | 1978-02-07 | G. D. Searle & Co. | 1-(3,3,3-Triarylalkyl)-4-phenyl-piperidinealkanols |
US4066654A (en) * | 1975-04-16 | 1978-01-03 | G. D. Searle & Co. | 1-triarylalkyl-4-phenyl-4-piperidine carboxylic acids and derivatives |
US3996214A (en) | 1976-02-23 | 1976-12-07 | G. D. Searle & Co. | 5-(1,1-Diphenyl-4-(cyclic amino) but-2-trans-en-1-yl)-2-alkyl-1,3,4-oxadiazoles and intermediates thereto |
US4013668A (en) * | 1976-03-10 | 1977-03-22 | G. D. Searle & Co. | 5-(1,1-diphenyl-3-(5- or 6-hydroxy-2-azabicyclo(2.2.2)oct-2-yl)propyl)-2-alkyl-1,3,4-oxadiazoles and related compounds |
US4012393A (en) | 1976-03-22 | 1977-03-15 | G. D. Searle & Co. | 2-[5-(CYCLIC AMINO) ETHYL-10,11-DIHYDRO-5H-dibenzo[a,d]-cyclohepten-5- yl]-5 |
US4115400A (en) | 1976-05-27 | 1978-09-19 | Eli Lilly And Company | 1-Azoniabicyclo[3.1.0]hexanes |
GB1593191A (en) | 1977-03-23 | 1981-07-15 | Reckitt & Colmann Prod Ltd | Derivatives of morphine |
US4125531A (en) | 1977-04-18 | 1978-11-14 | G. D. Searle & Co. | 2-Substituted-1-azabicyclo[2.2.2]octanes |
US4069223A (en) * | 1977-05-02 | 1978-01-17 | G. D. Searle & Co. | 4-Aminomethyl-1-(3,3,3-triarylpropyl)-4-arylpiperidine and derivatives thereof |
US4116963A (en) | 1977-05-23 | 1978-09-26 | G.D. Searle & Co. | 3,3,3-triarylalkyl-4-phenylalkyl-4-hydroxy piperidines and related compounds |
US4194045A (en) * | 1977-12-27 | 1980-03-18 | G. D. Searle & Co. | 1-(3,3-Diaryl-3-oxadiazolalkyl)-4-phenyl-4-piperidinomethanols and related compounds |
IT1096665B (en) | 1978-06-14 | 1985-08-26 | Tecnofarmaci Spa | PHARMACEUTICAL COMPOSITION FOR THE THERAPY OF FRIGIDITY AND IMPOTENCE STATES |
US4277605A (en) | 1980-03-07 | 1981-07-07 | Bristol-Myers Company | Chemical compounds |
US4675189A (en) | 1980-11-18 | 1987-06-23 | Syntex (U.S.A.) Inc. | Microencapsulation of water soluble active polypeptides |
US4466968A (en) | 1980-11-24 | 1984-08-21 | Dermall, Ltd. | Method for prophylaxis or treatment of emesis and nausea |
US4427676A (en) * | 1980-12-19 | 1984-01-24 | John Wyeth & Brother Ltd. | Thiomorpholine derivatives |
US4870084A (en) | 1982-03-16 | 1989-09-26 | Pfizer Inc. | Bicyclic benzo fused pyran compounds used for nausea treatment and prevention |
EP0103636B1 (en) | 1982-03-16 | 1990-09-12 | Rockefeller University | Use of opium antagonists for the manufacture of medicaments for controlling gastrointestinal dysmotility |
US4430327A (en) * | 1982-05-18 | 1984-02-07 | Eli Lilly And Company | Method for treating pregnant females for pain and anxiety |
US4533739A (en) | 1982-10-12 | 1985-08-06 | G. D. Searle & Co. | 2-[(Aminophenyl and amidophenyl)amino]-1-azacycloalkanes having antidiarrheal activity |
US4452775A (en) | 1982-12-03 | 1984-06-05 | Syntex (U.S.A.) Inc. | Cholesterol matrix delivery system for sustained release of macromolecules |
US4689332A (en) | 1984-04-09 | 1987-08-25 | Research Corporation | Growth regulation and related applications of opioid antagonists |
US4666716A (en) | 1984-09-04 | 1987-05-19 | Richardson-Vicks Inc. | Antidiarrheal compositions and use thereof |
JPH0676314B2 (en) | 1985-09-30 | 1994-09-28 | 花王株式会社 | Suppository base and suppository |
US4824853A (en) * | 1985-10-11 | 1989-04-25 | Janssen Pharmaceutica N.V. | α,α-diaryl-4-aryl-4-hydroxy-1-piperidinebutanamide, N-oxides and method of treating diarrhea |
US4806556A (en) | 1985-12-12 | 1989-02-21 | Regents Of The University Of Minnesota | Gut-selective opiates |
US4730048A (en) * | 1985-12-12 | 1988-03-08 | Regents Of The University Of Minnesota | Gut-selective opiates |
DE3609073C2 (en) | 1986-03-18 | 1995-08-10 | Hans J Prof Dr Rer Nat Schmitt | Measuring device for non-invasive detection of peripheral drainage and flow disorders in human extremities |
US4990521A (en) * | 1986-07-03 | 1991-02-05 | Janssen Pharmaceutica | 4-(aroylamino)piperidine-butanimide derivatives |
US4765978A (en) | 1986-12-16 | 1988-08-23 | Schering Corporation | Novel vaginal suppository |
FR2609632B1 (en) | 1987-01-21 | 1991-03-29 | Shelly Marc | NOVEL THERAPEUTIC APPLICATION OF 17- (CYCLOPROPYLMETHYL) -4,5-EPOXY-3,14-DIHYDROXYMORPHINON-6-ONE AND PHARMACEUTICAL COMPOSITIONS FOR THIS USE |
NL8700842A (en) | 1987-04-10 | 1988-11-01 | Duphar Int Res | |
US4891379A (en) * | 1987-04-16 | 1990-01-02 | Kabushiki Kaisha Kobe Seikosho | Piperidine opioid antagonists |
IL83086A (en) | 1987-07-06 | 1991-03-10 | Teva Pharma | Stable,injectable solutions of vincristine salts |
CA1315689C (en) | 1987-09-03 | 1993-04-06 | Leon I. Goldberg | Quarternary derivatives of noroxymorphone which relieve nausea and emesis |
ES2051742T3 (en) | 1987-09-10 | 1994-07-01 | Univ Chicago | QUARTERLY DERIVATIVES OF NOROXI-MORPHINE THAT MITIGATE NAUSEA AND EMESIS. |
US4912114A (en) * | 1988-03-18 | 1990-03-27 | Sandoz Ltd. | Morphinan derivatives |
DE68926269T2 (en) * | 1988-06-30 | 1996-08-14 | Astra Ab | Dermorphin analogs, their manufacturing process, pharmaceutical compositions and method of therapeutic treatment using the analogs |
JPH0653683B2 (en) | 1988-07-14 | 1994-07-20 | ザ ロックフェラー ユニバーシティ | Oral composition for treating chronic pain or cough |
EP0352361A1 (en) | 1988-07-29 | 1990-01-31 | The Rockefeller University | Method of treating patients suffering from chronic pain or chronic cough |
US4999342A (en) * | 1988-08-16 | 1991-03-12 | Ortho Pharmaceutical Corporation | Long lasting contraceptive suppository composition and methods of use |
US4857533A (en) | 1988-12-15 | 1989-08-15 | Baker Cummins Pharmaceuticals, Inc. | Method of treatment for autoimmune diseases |
US4863928A (en) | 1989-01-04 | 1989-09-05 | Baker Cummins Pharmaceuticals, Inc. | Method of treatment for arthritic and inflammatory diseases |
US5116868A (en) * | 1989-05-03 | 1992-05-26 | The Johns Hopkins University | Effective ophthalmic irrigation solution |
US5133974A (en) | 1989-05-05 | 1992-07-28 | Kv Pharmaceutical Company | Extended release pharmaceutical formulations |
US5236947A (en) | 1990-02-28 | 1993-08-17 | Jouveinal S.A. | Propanamines, their pharmacological properties and their application as an antidiarrheal |
JPH0813748B2 (en) | 1990-04-23 | 1996-02-14 | 帝國製薬株式会社 | Colon disintegrating polypeptide oral preparation |
EP0527879B1 (en) | 1990-05-11 | 1997-02-05 | Pfizer Inc. | Synergistic therapeutic compositions and methods |
US5780012A (en) | 1990-06-21 | 1998-07-14 | Huland; Edith | Method for reducing lung afflictions by inhalation of cytokine solutions |
JP3160862B2 (en) | 1990-11-15 | 2001-04-25 | 雪印乳業株式会社 | Bone-fortified foods, feeds and pharmaceuticals |
ES2148174T3 (en) | 1991-02-25 | 2000-10-16 | Univ Boston | OPIACEAN RECEPTOR ANTAGONIST THAT MODULATES HYPERCINETIC MOVEMENT DISORDERS. |
JP2916290B2 (en) | 1991-03-22 | 1999-07-05 | 帝國製薬株式会社 | Colon-disintegrating oral preparation containing bioactive polypeptide |
CA2064373C (en) | 1991-03-29 | 2005-08-23 | Buddy Eugene Cantrell | Piperidine derivatives |
US5250542A (en) | 1991-03-29 | 1993-10-05 | Eli Lilly And Company | Peripherally selective piperidine carboxylate opioid antagonists |
US5220017A (en) | 1991-04-10 | 1993-06-15 | Merck & Co., Inc. | Cholecystokinin antagonists |
US5407686A (en) * | 1991-11-27 | 1995-04-18 | Sidmak Laboratories, Inc. | Sustained release composition for oral administration of active ingredient |
JPH05213763A (en) | 1992-02-10 | 1993-08-24 | Sanwa Kagaku Kenkyusho Co Ltd | Readily absorbable activated calcium preparation |
WO1993020826A1 (en) | 1992-04-10 | 1993-10-28 | Vsesojuzny Nauchno-Issledovatelsky Institut Meditsinskikh Polimerov | Pharmaceutical composition |
US5686072A (en) | 1992-06-17 | 1997-11-11 | Board Of Regents, The University Of Texas | Epitope-specific monoclonal antibodies and immunotoxins and uses thereof |
DE69233739D1 (en) | 1992-10-28 | 2008-08-07 | Genentech Inc | Use of Antagonists of Cell Growth Factor VEGF |
DE4303214A1 (en) | 1993-02-04 | 1994-08-11 | Wolfgang Marks | Treatment of diseases of viral, viroidal or oncogenic origin by steroid saponins or their aglycones |
US5585348A (en) | 1993-02-10 | 1996-12-17 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Use of excitatory opioid receptor antagonists to prevent growth factor-induced hyperalgesia |
NZ268969A (en) | 1993-07-23 | 1997-06-24 | Toray Industries | Morphinan derivatives and pharmaceutical compositions |
US5358970A (en) | 1993-08-12 | 1994-10-25 | Burroughs Wellcome Co. | Pharmaceutical composition containing bupropion hydrochloride and a stabilizer |
GB2281205A (en) | 1993-08-24 | 1995-03-01 | Euro Celtique Sa | Oral opioid analgesic |
SE9303744D0 (en) | 1993-11-12 | 1993-11-12 | Astra Ab | Pharmaceutical emulsion |
US5434171A (en) | 1993-12-08 | 1995-07-18 | Eli Lilly And Company | Preparation of 3,4,4-trisubstituted-piperidinyl-N-alkylcarboxylates and intermediates |
US6190691B1 (en) * | 1994-04-12 | 2001-02-20 | Adolor Corporation | Methods for treating inflammatory conditions |
US5578725A (en) | 1995-01-30 | 1996-11-26 | Regents Of The University Of Minnesota | Delta opioid receptor antagonists |
US6096763A (en) | 1995-02-23 | 2000-08-01 | Merck & Co., Inc. | α1a adrenergic receptor antagonists |
US5714586A (en) * | 1995-06-07 | 1998-02-03 | American Cyanamid Company | Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates |
US5821219A (en) | 1995-08-11 | 1998-10-13 | Oregon Health Sciences University | Opioid antagonists and methods of their use |
GB9517001D0 (en) | 1995-08-18 | 1995-10-18 | Denny William | Enediyne compounds |
EP0780372B3 (en) | 1995-12-21 | 2013-05-22 | Syngenta Participations AG | 3-Amino-2-mercaptobenzoic acid derivatives and processes for their preparation |
DE69725345T2 (en) | 1996-02-15 | 2004-08-19 | Janssen Pharmaceutica N.V. | USE OF 5-HT4 ANTAGONISTS TO OVERCOME THE GASTROINTESTINAL DAMAGE CAUSED BY SEROTONIN REINVISION INHIBITORS |
US6136780A (en) | 1996-03-29 | 2000-10-24 | The Penn State Research Foundation | Control of cancer growth through the interaction of [Met5 ]-enkephalin and the zeta (ζ) receptor |
US20040024006A1 (en) * | 1996-05-06 | 2004-02-05 | Simon David Lew | Opioid pharmaceutical compositions |
US20010036469A1 (en) | 1997-01-13 | 2001-11-01 | Gooberman Lance L. | Opiate antagonist implant and process for preparation therefor |
SK282549B6 (en) † | 1997-02-14 | 2002-10-08 | G�decke Aktiengesellschaft | Stabilization method of naloxone hydrochloride |
US6884879B1 (en) | 1997-04-07 | 2005-04-26 | Genentech, Inc. | Anti-VEGF antibodies |
US6329516B1 (en) | 1997-04-28 | 2001-12-11 | Fmc Corporation | Lepidopteran GABA-gated chloride channels |
GB9801231D0 (en) * | 1997-06-05 | 1998-03-18 | Merck & Co Inc | A method of treating cancer |
HU9701081D0 (en) * | 1997-06-23 | 1997-08-28 | Gene Research Lab Inc N | Pharmaceutical composition of antitumoral activity |
US6525038B1 (en) * | 1997-06-24 | 2003-02-25 | Werner Kreutz | Synergistic compositions for the selective control of tumor tissue |
US6096764A (en) | 1997-08-21 | 2000-08-01 | Eli Lilly And Company | Methods for inhibiting detrimental side-effects due to GnRH of GnRH agonist administration |
US6099853A (en) | 1997-09-04 | 2000-08-08 | Protein Express | Vaginal suppository vaccine for urogenital infections |
AU2003204844B2 (en) | 1997-11-03 | 2007-06-07 | Arch Development Corporation | Use of methylnaltrexone and related compounds |
ATE210983T1 (en) † | 1997-11-03 | 2002-01-15 | Stada Arzneimittel Ag | STABILIZED COMBINATION MEDICINAL PRODUCT CONTAINING NALOXONE AND AN OPIATE ANALGESIC |
US6777534B1 (en) | 1997-12-09 | 2004-08-17 | Children's Medical Center Corporation | Peptide antagonists of vascular endothelial growth factor |
PT1041987E (en) | 1997-12-22 | 2006-07-31 | Euro Celtique Sa | PHARMACEUTICAL FORM OF ORAL DOSAGE, UNDERSTANDING A COMBINATION OF AN AGRONIST OF OPIOIDE AND NALTREXONE |
EP0930334A1 (en) | 1998-01-16 | 1999-07-21 | Quest International B.V. | Polysaccharide conjugate capable of binding cellulose |
AU3596599A (en) | 1998-01-26 | 1999-08-09 | Unilever Plc | Method for producing antibody fragments |
GB9802251D0 (en) | 1998-02-03 | 1998-04-01 | Ciba Geigy Ag | Organic compounds |
ATE328599T1 (en) * | 1998-04-03 | 2006-06-15 | Ajinomoto Kk | ANTITUMORAL AGENTS |
DE19818802A1 (en) | 1998-04-27 | 1999-10-28 | Dresden Arzneimittel | Stable mitoxantron solutions useful for cancer therapy |
US6359111B1 (en) | 1998-05-28 | 2002-03-19 | Neorx Corporation | Opioid receptor targeting |
HN1999000149A (en) * | 1998-09-09 | 2000-01-12 | Pfizer Prod Inc | DERIVATIVES OF 4,4-BIARILPIPERIDINA |
US20010010919A1 (en) | 1998-10-13 | 2001-08-02 | David K. Grandy | Opioid antagonists and methods of their use |
BR9916765A (en) | 1999-01-05 | 2001-09-25 | Unilever Nv | Process for producing an immunoadsorbent material, use of a protein that is linked via a covalent bond to an antibody fragment, immunosorbent material, use of a material, and, diagnostic test kit |
DE60013767T3 (en) | 1999-01-19 | 2009-07-09 | Unilever N.V. | PROCESS FOR THE PRODUCTION OF ANTIBODY FRAGMENTS |
CA2293008A1 (en) | 1999-01-28 | 2000-07-28 | Hong Qi | Premixed alatrofloxacin injectable compositions |
JP2002535993A (en) | 1999-02-05 | 2002-10-29 | リイクスニフェルシタイト ライデン | Methods for modulating biosynthesis of metabolites in recombinant cells |
JP4049477B2 (en) | 1999-03-23 | 2008-02-20 | 大鵬薬品工業株式会社 | Side effect reducing agent |
BR0009866A (en) | 1999-04-22 | 2002-01-08 | Unilever Nv | Viral infection inhibition method, use of a monovalent antigen binding protein, food product, pharmaceutical or cosmetic composition, monovalent antigen binding protein, nucleotide sequence, expression vector, host cell, and selection and selection methods. identification of an antigen binding protein |
US7129265B2 (en) | 1999-04-23 | 2006-10-31 | Mason R Preston | Synergistic effects of amlodipine and atorvastatin metabolite as a basis for combination therapy |
US6171620B1 (en) | 1999-04-27 | 2001-01-09 | Health Research, Inc. | Method of enhancing the efficacy of anti-tumor agents |
AU4564200A (en) | 1999-04-29 | 2000-11-17 | Aventis Pharma S.A. | Method for treating cancer using camptothecin derivatives and 5-fluorouracil |
US6833349B2 (en) | 1999-06-08 | 2004-12-21 | Regeneron Pharmaceuticals, Inc. | Methods of treating inflammatory skin diseases |
US20020068712A1 (en) | 1999-07-23 | 2002-06-06 | Troy Stevens | Use of decreasing levels of functional transient receptor potential gene product |
US20030105121A1 (en) | 1999-07-27 | 2003-06-05 | Bernard Bihari | Method of preventing lipodystrophy syndrome or reversing a pre-existing syndrome in HIV-infected patients being treated with antiretroviral agents |
IL147920A0 (en) | 1999-08-02 | 2002-08-14 | Keygene Nv | Method for generating cgmmv resistant plants, genetic constructs, and the obtained cgmmv-resistant plants |
BR0013825A (en) | 1999-08-31 | 2002-07-23 | Gruenenthal Chemie | Forms of presentation of tramadol |
ATE275402T1 (en) | 1999-11-01 | 2004-09-15 | John Rhodes | MEDICINAL PRODUCTS FOR THE TREATMENT OF INTESTINAL CONSTITUTION AND irritable colon |
EP1097720B1 (en) * | 1999-11-04 | 2005-10-12 | Institut Gustave Roussy | Antiviral agent in combination with radiation therapy for use in treatment of cancer |
US6384044B1 (en) | 1999-11-29 | 2002-05-07 | Bernard Bihari | Method of treating cancer of the prostate |
AU4136901A (en) * | 1999-11-29 | 2001-06-18 | Adolor Corporation | Novel methods for the treatment and prevention of dizziness and pruritus |
DE60042282D1 (en) | 1999-11-29 | 2009-07-09 | Adolor Corp | NEW METHODS AND METHODS FOR TREATING AND AVOIDING ILEUS |
MXPA02005335A (en) | 1999-11-29 | 2003-01-28 | Adolor Corp | Novel methods and compositions involving opioids and antagonists thereof. |
US6911455B2 (en) * | 1999-12-22 | 2005-06-28 | Smithkline Beecham Corporation | Methods for preparing pharmaceutical formulations |
US6545010B2 (en) | 2000-03-17 | 2003-04-08 | Aventis Pharma S.A. | Composition comprising camptothecin or a camptothecin derivative and a platin derivative for the treatment of cancer |
US20010046968A1 (en) | 2000-03-23 | 2001-11-29 | Zagon Ian S. | Opioid growth factor modulates angiogenesis |
AU5945801A (en) | 2000-05-05 | 2001-11-20 | Pain Therapeutics Inc | Opoid antagonist compositions and dosage forms |
EP1175905A1 (en) | 2000-07-24 | 2002-01-30 | Societe Des Produits Nestle S.A. | Nutritional Composition |
FI116089B (en) * | 2000-07-27 | 2005-09-15 | Johan Tore Karlstroem | Device and procedures for controls |
JP4265911B2 (en) | 2000-07-28 | 2009-05-20 | エフ.ホフマン−ラ ロシュ アーゲー | New pharmaceutical composition |
JP4183371B2 (en) | 2000-08-31 | 2008-11-19 | 日本・バイオ株式会社 | Manufacturing method of fermented turmeric |
NZ507152A (en) * | 2000-09-27 | 2001-06-29 | Hiltive Pty Ltd | Wall cladding assembly with cladding having recesses along opposite sides to engage with flanges of support members |
AU2002249885A1 (en) | 2000-11-17 | 2002-08-12 | Adolor Corporation | Delta agonist analgesics |
JP2002229183A (en) * | 2000-12-01 | 2002-08-14 | Hoya Corp | Lithography mask blank and method for manufacturing the same |
IL156286A0 (en) | 2000-12-04 | 2004-01-04 | Primagen Holding Bv | Testing endosymbiont cellular organelles and compounds identifiable therewith |
UA73619C2 (en) | 2000-12-13 | 2005-08-15 | Pfizer Prod Inc | Stable pharmaceutical compositions of nmda receptor agonist (variants) and method of treatment |
AU2002239384B2 (en) | 2000-12-13 | 2007-01-11 | Eli Lilly And Company | Chronic treatment regimen using glucagon-like insulinotropic peptides |
KR100405161B1 (en) | 2000-12-14 | 2003-11-12 | 신풍제약주식회사 | Pharmaceutical composition for intramuscular injection containing loxoprofen |
GB0100115D0 (en) | 2001-01-04 | 2001-02-14 | Alchemia Pty Ltd | Delivery systems |
US6693125B2 (en) | 2001-01-24 | 2004-02-17 | Combinatorx Incorporated | Combinations of drugs (e.g., a benzimidazole and pentamidine) for the treatment of neoplastic disorders |
PL365285A1 (en) | 2001-03-23 | 2004-12-27 | Shire Biochem Inc. | Pharmaceutical combinations for the treatment of cancer comprising dioxolane nucleoside analogs |
US20040242523A1 (en) | 2003-03-06 | 2004-12-02 | Ana-Farber Cancer Institue And The Univiersity Of Chicago | Chemo-inducible cancer gene therapy |
JP2004527528A (en) | 2001-04-09 | 2004-09-09 | プロジェニクス・ファーマスーティカルズ・インコーポレイテッド | Anti-CD19 immunotoxin |
NZ528994A (en) * | 2001-04-26 | 2006-02-24 | Control Delivery Sys Inc | Sustained release drug delivery system containing codrugs |
CA2463733C (en) | 2001-08-31 | 2011-03-22 | Eugene A. Woltering | Inhibition of angiogenesis and destruction of angiogenic vessels with extracts of noni juice (morinda citrifolia) |
US20030144312A1 (en) | 2001-10-30 | 2003-07-31 | Schoenhard Grant L. | Inhibitors of ABC drug transporters in multidrug resistant cancer cells |
WO2003037365A1 (en) | 2001-11-01 | 2003-05-08 | The Johns Hopkins University | Methods and compositions for treating vascular leak using hepatocyte growth factor |
AU2002364906B2 (en) | 2001-12-21 | 2007-08-16 | Merck & Co., Inc. | Heteroaryl substituted pyrrole modulators of metabotropic glutamate receptor-5 |
US20050011468A1 (en) * | 2002-02-04 | 2005-01-20 | Jonathan Moss | Use of methylnaltrexone in treating gastrointestinal dysfunction in equines |
CA2475305A1 (en) | 2002-02-04 | 2004-02-19 | Jonathan Moss | Use of methylnaltrexone in treating gastrointestinal dysfunction in equines |
US7074825B2 (en) | 2002-03-07 | 2006-07-11 | Huanbiao Mo | Composition and method for treating cancer |
US20030229111A1 (en) † | 2002-03-14 | 2003-12-11 | Benjamin Oshlack | Naltrexone hydrochloride compositions |
US7355081B2 (en) | 2002-04-17 | 2008-04-08 | The University Of North Carolina At Chapel Hill | Curcumin analogues and uses thereof |
ATE510553T1 (en) | 2002-05-17 | 2011-06-15 | Univ Texas | BETA-2-GLYCOPROTEIN 1 AS ANGIOGENESIS INHIBITOR |
US7012100B1 (en) * | 2002-06-04 | 2006-03-14 | Avolix Pharmaceuticals, Inc. | Cell migration inhibiting compositions and methods and compositions for treating cancer |
US20040010997A1 (en) | 2002-07-17 | 2004-01-22 | Oren Close | Guides to align masonry walls defining apertures, and methods of use |
US7160913B2 (en) * | 2002-09-13 | 2007-01-09 | Thomas Jefferson University | Methods and kit for treating Parkinson's disease |
US7691374B2 (en) * | 2002-10-23 | 2010-04-06 | Health Research, Inc. | Method for increasing the efficacy of anti-tumor agents by anti-endoglin antibody |
ATE444295T1 (en) | 2002-11-08 | 2009-10-15 | Mallinckrodt Inc | METHOD FOR PRODUCING QUATERNARY N-ALKYL MORPHINANE ALKALOID SALTS |
WO2004054511A2 (en) | 2002-12-13 | 2004-07-01 | The Regents Of The University Of California | Analgesic combination comprising nalbuphine |
WO2004054569A1 (en) | 2002-12-16 | 2004-07-01 | Council Of Scientific And Industrial Research | Pharmaceutical composition containing brevifoliol for use in chemotherapeutic treatment of human beings |
TW200500067A (en) * | 2003-01-21 | 2005-01-01 | Control Delivery Sys Inc | Salts of codrugs and uses related thereto |
US7396943B2 (en) | 2003-03-07 | 2008-07-08 | Eli Lilly And Company | Opioid receptor antagonists |
AU2004229463B2 (en) † | 2003-04-08 | 2010-07-22 | Progenics Pharmaceuticals. Inc. | Pharmaceutical formulations containing methylnaltrexone |
JP4343948B2 (en) | 2003-04-29 | 2009-10-14 | オレキシジェン・セラピューティクス・インコーポレーテッド | Composition for affecting weight loss |
US6992193B2 (en) | 2003-06-10 | 2006-01-31 | Adolor Corporation | Sulfonylamino phenylacetamide derivatives and methods of their use |
CA2529307C (en) * | 2003-06-13 | 2013-12-24 | Microbia, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
US7494979B2 (en) | 2003-06-13 | 2009-02-24 | Ironwood Pharmaceuticals, Inc. | Method for treating congestive heart failure and other disorders |
AU2003903387A0 (en) | 2003-07-02 | 2003-07-17 | Sirtex Medical Limited | Combination therapy for treatment of neoplasia |
US8946262B2 (en) | 2003-12-04 | 2015-02-03 | Adolor Corporation | Methods of preventing and treating gastrointestinal dysfunction |
US6984403B2 (en) * | 2003-12-04 | 2006-01-10 | Pfizer Inc. | Azithromycin dosage forms with reduced side effects |
CA2550071A1 (en) | 2003-12-19 | 2005-07-07 | Schering Corporation | Pharmaceutical compositions |
JP4225922B2 (en) | 2004-01-15 | 2009-02-18 | アキレス株式会社 | Polyolefin resin foam sheet |
WO2005087208A2 (en) | 2004-03-10 | 2005-09-22 | Trustees Of Tufts College | Synergistic effect of compositions comprising carotenoids selected from lutein, beta-carotene and lycopene |
TW200533339A (en) | 2004-03-16 | 2005-10-16 | Bristol Myers Squibb Co | Therapeutic synergy of anti-cancer compounds |
US6946556B1 (en) | 2004-05-21 | 2005-09-20 | Acura Pharmaceuticals, Inc. | Preparation of opioid analgesics by a one-pot process |
US7094775B2 (en) | 2004-06-30 | 2006-08-22 | Bone Care International, Llc | Method of treating breast cancer using a combination of vitamin D analogues and other agents |
US7388008B2 (en) * | 2004-08-02 | 2008-06-17 | Ambrilia Biopharma Inc. | Lysine based compounds |
US20060063792A1 (en) | 2004-09-17 | 2006-03-23 | Adolor Corporation | Substituted morphinans and methods of their use |
JP5219513B2 (en) | 2004-09-23 | 2013-06-26 | バスジーン セラピューティクス,インコーポレイテッド | Polypeptide compounds for angiogenesis and tumor growth inhibition |
US20080103438A1 (en) | 2004-09-30 | 2008-05-01 | Prais Alfred W | Method For Reducing Or Eliminating Residue In A Glass Container And A Glass Container Made In Accordance Therewith |
WO2006096626A2 (en) | 2005-03-07 | 2006-09-14 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
AR057325A1 (en) | 2005-05-25 | 2007-11-28 | Progenics Pharm Inc | SYNTHESIS OF (S) -N-METHYLNTREXONE, PHARMACEUTICAL COMPOSITIONS AND USES |
AR057035A1 (en) | 2005-05-25 | 2007-11-14 | Progenics Pharm Inc | SYNTHESIS OF (R) -N-METHYLNTREXONE, PHARMACEUTICAL COMPOSITIONS AND USES |
EP1906838A4 (en) | 2005-06-03 | 2008-10-08 | Univ Chicago | Modulation of microbial pathogen-host cell interactions |
CA2609985A1 (en) | 2005-06-03 | 2007-05-10 | The University Of Chicago | Modulation of cell barrier dysfunction |
US20080194611A1 (en) | 2005-06-03 | 2008-08-14 | Alverdy John C | Modulation of Cell Barrier Dysfunction |
US7935821B2 (en) | 2005-06-09 | 2011-05-03 | Mallinckrodt Inc. | Method for separation and purification of naltrexone by preparative chromatography |
PE20070207A1 (en) * | 2005-07-22 | 2007-03-09 | Genentech Inc | COMBINED TREATMENT OF TUMORS THAT EXPRESS HER |
CA2627158A1 (en) * | 2005-08-30 | 2007-03-08 | Queen's University At Kingston | Potentiation of the therapeutic action of an opioid receptor agonist and/or inhibition or reversal of tolerance to an opioid receptoi agonists using an ultralow dose of an alpha-2receptor antagonist |
PL116330U1 (en) | 2005-10-31 | 2007-04-02 | Alza Corp | Method for the reduction of alcohol provoked rapid increase in the released dose of the orally administered opioide with prolonged liberation |
US20070259939A1 (en) | 2006-05-04 | 2007-11-08 | Accelerated Technologies | Using naltrexone as a multi-purpose health supplement to improve the human condition and preventing multiple diseases and infirmities by stimulating immune system vitality and robustness |
US20080020032A1 (en) * | 2006-07-21 | 2008-01-24 | Michael Crowley | Hydrophobic abuse deterrent delivery system for hydromorphone |
TW200815451A (en) * | 2006-08-04 | 2008-04-01 | Wyeth Corp | 6-carboxy-normorphinan derivatives, synthesis and uses thereof |
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 |
TW200817048A (en) | 2006-09-08 | 2008-04-16 | Wyeth Corp | Dry powder compound formulations and uses thereof |
US20090047279A1 (en) | 2006-11-22 | 2009-02-19 | Progenics Pharmaceuticals, Inc. | (R)-N-Stereoisomers of 7,8-Saturated-4,5-Epoxy-Morphinanium Analogs |
CA2670386A1 (en) | 2006-11-22 | 2008-05-29 | Progenics Pharmaceuticals, Inc. | Processes for synthesizing quaternary 4,5-epoxy-morphinan analogs and isolating their n-stereoisomers |
CN101678016A (en) | 2006-11-22 | 2010-03-24 | 普罗基因制药公司 | 4, the N-oxide of 5-epoxy-morphinanium analogs |
TW200843802A (en) | 2007-02-09 | 2008-11-16 | Drugtech Corp | Compositions for improving gastrointestinal nutrient and drug absorption |
SI2565195T1 (en) * | 2007-03-29 | 2015-09-30 | Wyeth Llc | Peripheral opioid receptor and antagonists and uses thereof |
EP3263571B2 (en) | 2007-03-29 | 2023-08-23 | Progenics Pharmaceuticals, Inc. | Crystal form of (r)-n-methylnaltrexone bromide and uses thereof |
PA8774201A1 (en) | 2007-03-29 | 2009-06-23 | Progenics Pharm Inc | RECEIVER ANTAGONIST |
EA201001643A1 (en) | 2008-05-07 | 2011-06-30 | Нектар Терапеутикс | ORAL ADMINISTRATION OF PERIPHERICALLY ACTING OPIOID ANTAGONISTS |
CA2676881C (en) † | 2008-09-30 | 2017-04-25 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
JP5213763B2 (en) | 2009-03-03 | 2013-06-19 | キヤノン株式会社 | Lens barrel and optical apparatus having the same |
NZ702826A (en) | 2010-03-11 | 2016-08-26 | Wyeth Llc | Oral formulations and lipophilic salts of methylnaltrexone |
-
2004
- 2004-04-08 AU AU2004229463A patent/AU2004229463B2/en not_active Expired
- 2004-04-08 JP JP2006509865A patent/JP2006522818A/en active Pending
- 2004-04-08 PL PL10184684T patent/PL2368554T3/en unknown
- 2004-04-08 SI SI200432214T patent/SI2368554T1/en unknown
- 2004-04-08 PL PL04759349.6T patent/PL1615646T5/en unknown
- 2004-04-08 EP EP04759349.6A patent/EP1615646B2/en not_active Expired - Lifetime
- 2004-04-08 PT PT10184575T patent/PT2368553E/en unknown
- 2004-04-08 ES ES04759349T patent/ES2527870T5/en not_active Expired - Lifetime
- 2004-04-08 DK DK04759349.6T patent/DK1615646T4/en active
- 2004-04-08 PT PT47593496T patent/PT1615646E/en unknown
- 2004-04-08 PL PL10184575T patent/PL2368553T3/en unknown
- 2004-04-08 SI SI200432216T patent/SI2368553T1/en unknown
- 2004-04-08 CN CN200480009192.7A patent/CN1767831B/en not_active Expired - Lifetime
- 2004-04-08 EP EP10184575.8A patent/EP2368553B1/en not_active Revoked
- 2004-04-08 ES ES10184684.8T patent/ES2528631T3/en not_active Expired - Lifetime
- 2004-04-08 DK DK10184575.8T patent/DK2368553T3/en active
- 2004-04-08 US US10/821,811 patent/US20040266806A1/en not_active Abandoned
- 2004-04-08 MX MXPA05010817A patent/MXPA05010817A/en active IP Right Grant
- 2004-04-08 WO PCT/US2004/010997 patent/WO2004091623A1/en active Application Filing
- 2004-04-08 BR BRPI0409133A patent/BRPI0409133B8/en active IP Right Grant
- 2004-04-08 ES ES10184575.8T patent/ES2528669T3/en not_active Expired - Lifetime
- 2004-04-08 EP EP10184684.8A patent/EP2368554B1/en not_active Revoked
- 2004-04-08 CA CA2521379A patent/CA2521379C/en not_active Expired - Lifetime
- 2004-04-08 RU RU2005134361/15A patent/RU2362560C2/en active
- 2004-04-08 SI SI200432215T patent/SI1615646T2/en unknown
- 2004-04-08 CN CN201410683081.XA patent/CN104383542B/en not_active Expired - Lifetime
- 2004-04-08 PT PT101846848T patent/PT2368554E/en unknown
- 2004-04-08 CA CA2811272A patent/CA2811272C/en not_active Expired - Lifetime
- 2004-04-08 DK DK10184684.8T patent/DK2368554T3/en active
-
2005
- 2005-10-02 IL IL171228A patent/IL171228A/en active IP Right Grant
-
2006
- 2006-02-07 HK HK06101582.6A patent/HK1082181A1/en not_active IP Right Cessation
-
2009
- 2009-12-16 US US12/639,889 patent/US20100261745A1/en not_active Abandoned
- 2009-12-16 US US12/639,880 patent/US20100267758A1/en not_active Abandoned
- 2009-12-16 US US12/639,892 patent/US20100261746A1/en not_active Abandoned
- 2009-12-16 US US12/639,862 patent/US8552025B2/en not_active Expired - Lifetime
-
2010
- 2010-07-05 AU AU2010202824A patent/AU2010202824B2/en not_active Expired
-
2012
- 2012-04-27 JP JP2012103554A patent/JP5847643B2/en not_active Expired - Lifetime
-
2013
- 2013-09-27 US US14/039,866 patent/US9669096B2/en not_active Expired - Lifetime
-
2015
- 2015-01-12 HR HRP20150038TT patent/HRP20150038T1/en unknown
- 2015-01-12 HR HRP20150037TT patent/HRP20150037T4/en unknown
- 2015-01-12 HR HRP20150039TT patent/HRP20150039T1/en unknown
- 2015-01-28 CY CY20151100090T patent/CY1116373T1/en unknown
- 2015-01-28 CY CY20151100091T patent/CY1116372T1/en unknown
- 2015-01-28 CY CY20151100089T patent/CY1116272T1/en unknown
- 2015-03-24 JP JP2015061493A patent/JP6262169B2/en not_active Expired - Lifetime
- 2015-09-02 HK HK15108569.7A patent/HK1207965A1/en unknown
-
2017
- 2017-03-30 US US15/474,614 patent/US10376584B2/en not_active Expired - Lifetime
-
2019
- 2019-06-13 US US16/440,304 patent/US20190358328A1/en not_active Abandoned
Patent Citations (84)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4176186A (en) * | 1978-07-28 | 1979-11-27 | Boehringer Ingelheim Gmbh | Quaternary derivatives of noroxymorphone which relieve intestinal immobility |
US4385078A (en) * | 1978-09-04 | 1983-05-24 | Shin-Etsu Chemical Co., Ltd. | Method for providing enteric coating on solid dosage forms and aqueous compositions therefor |
US4311833A (en) * | 1979-03-06 | 1982-01-19 | Daicel Chemical Industries Ltd. | Process for preparing ethylcarboxymethylcellulose |
US4322426A (en) * | 1980-04-28 | 1982-03-30 | E. I. Du Pont De Nemours And Company | 17-Substituted-6-desoxy-7,8-dihydro-6α-methylnoroxymorphone narcotic antagonists |
US4377568A (en) * | 1981-08-12 | 1983-03-22 | Merck Sharp & Dohme (I.A.) Corp. | Preparation of aqueous alcoholic dispersions of pH sensitive polymers and plasticizing agents and a method of enteric coating dosage forms using same |
US4606909A (en) * | 1981-11-20 | 1986-08-19 | A/S Alfred Benzon | Pharmaceutical multiple-units formulation |
US4987136A (en) * | 1982-03-16 | 1991-01-22 | The Rockefeller University | Method for controlling gastrointestinal dysmotility |
US4457907A (en) * | 1982-08-05 | 1984-07-03 | Clear Lake Development Group | Composition and method for protecting a therapeutic drug |
US4518433A (en) * | 1982-11-08 | 1985-05-21 | Fmc Corporation | Enteric coating for pharmaceutical dosage forms |
US4462839A (en) * | 1983-06-16 | 1984-07-31 | Fmc Corporation | Enteric coating for pharmaceutical dosage forms |
US4556552A (en) * | 1983-09-19 | 1985-12-03 | Colorcon, Inc. | Enteric film-coating compositions |
US4615885A (en) * | 1983-11-01 | 1986-10-07 | Terumo Kabushiki Kaisha | Pharmaceutical composition containing urokinase |
US5426112A (en) * | 1984-04-09 | 1995-06-20 | Scully, Scott, Murphy & Presser, P.C. | Growth regulation and related applications of opioid antagonists |
US4670287A (en) * | 1985-07-30 | 1987-06-02 | Washu Kirai Kogyo Kabushiki Kaisha | Method of film-coating hard capsules |
US4719215A (en) * | 1986-03-07 | 1988-01-12 | University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
US4861781A (en) * | 1986-03-07 | 1989-08-29 | The University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
US5597564A (en) * | 1986-08-28 | 1997-01-28 | Enzacor Properties Limited | Method of administering a microgranular preparation to the intestinal region of animals |
US5567423A (en) * | 1986-08-28 | 1996-10-22 | Enzacor Properties, Ltd. | Animal growth promotant |
US4888346A (en) * | 1986-10-07 | 1989-12-19 | Bernard Bihari | Method for the treatment of persons infected with HTLV-III (AIDS) virus |
US4857833A (en) * | 1987-08-27 | 1989-08-15 | Teradyne, Inc. | Diagnosis of faults on circuit board |
US5102887A (en) * | 1989-02-17 | 1992-04-07 | Arch Development Corporation | Method for reducing emesis and nausea induced by the administration of an emesis causing agent |
US4965269A (en) * | 1989-12-20 | 1990-10-23 | Ab Hassle | Therapeutically active chloro substituted benzimidazoles |
US5202159A (en) * | 1990-12-27 | 1993-04-13 | Standard Chemical & Pharmaceutical Corp., Ltd. | Preparation method of microdispersed tablet formulation of spray-dried sodium diclofenac enteric-coated microcapsules |
US5159081A (en) * | 1991-03-29 | 1992-10-27 | Eli Lilly And Company | Intermediates of peripherally selective n-carbonyl-3,4,4-trisubstituted piperidine opioid antagonists |
US5270328A (en) * | 1991-03-29 | 1993-12-14 | Eli Lilly And Company | Peripherally selective piperidine opioid antagonists |
US5629001A (en) * | 1991-06-21 | 1997-05-13 | University Of Cincinnati | Oral administration of therapeutic proteins for treatment of infectious disease |
US5609871A (en) * | 1991-06-21 | 1997-03-11 | Michael; J. Gabriel | Oral administration of therapeutic proteins for treatment of infectious disease |
US5591433A (en) * | 1991-06-21 | 1997-01-07 | University Of Cincinnati | Oral administration of immunologically active biomolecules and other therapeutic proteins |
US5614219A (en) * | 1991-12-05 | 1997-03-25 | Alfatec-Pharma Gmbh | Oral administration form for peptide pharmaceutical substances, in particular insulin |
US5256154A (en) * | 1992-01-31 | 1993-10-26 | Sterling Winthrop, Inc. | Pre-filled plastic syringes and containers and method of terminal sterilization thereof |
USRE36547E (en) * | 1992-09-21 | 2000-02-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists |
US5472943A (en) * | 1992-09-21 | 1995-12-05 | Albert Einstein College Of Medicine Of Yeshiva University, | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists |
US6096756A (en) * | 1992-09-21 | 2000-08-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
US5767125A (en) * | 1992-09-21 | 1998-06-16 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists |
US5512578A (en) * | 1992-09-21 | 1996-04-30 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists |
US5656290A (en) * | 1993-02-26 | 1997-08-12 | The Procter & Gamble Company | Bisacodyl dosage form with multiple enteric polymer coatings for colonic delivery |
US5391372A (en) * | 1993-06-28 | 1995-02-21 | Campbell; Elizabeth | Methods of treating colic and founder in horses |
US5981185A (en) * | 1994-05-05 | 1999-11-09 | Beckman Coulter, Inc. | Oligonucleotide repeat arrays |
US5811451A (en) * | 1994-05-24 | 1998-09-22 | Minoia; Paolo | Pharmaceutical compositions comprising an opiate antagonist and calcium salts, their use for the treatment of endorphin-mediated pathologies |
US5536507A (en) * | 1994-06-24 | 1996-07-16 | Bristol-Myers Squibb Company | Colonic drug delivery system |
US5866154A (en) * | 1994-10-07 | 1999-02-02 | The Dupont Merck Pharmaceutical Company | Stabilized naloxone formulations |
US5614222A (en) * | 1994-10-25 | 1997-03-25 | Kaplan; Milton R. | Stable aqueous drug suspensions and methods for preparation thereof |
US5958452A (en) * | 1994-11-04 | 1999-09-28 | Euro-Celtique, S.A. | Extruded orally administrable opioid formulations |
US20010033865A1 (en) * | 1994-11-04 | 2001-10-25 | Benjamin Oshlack | Melt-extrusion multiparticulates |
US6261599B1 (en) * | 1994-11-04 | 2001-07-17 | Euro-Celtique, S.A. | Melt-extruded orally administrable opioid formulations |
US20010036476A1 (en) * | 1994-11-04 | 2001-11-01 | Euro-Celtique S.A. | Melt-extruded orally administrable opioid formulations |
US5626875A (en) * | 1995-02-01 | 1997-05-06 | Esteve Quimica, S.A. | Stabilized galenic formulations comprising an acid labile benzimidazole compound and its preparation |
US6025154A (en) * | 1995-06-06 | 2000-02-15 | Human Genome Sciences, Inc. | Polynucleotides encoding human G-protein chemokine receptor HDGNR10 |
US5804595A (en) * | 1995-12-05 | 1998-09-08 | Regents Of The University Of Minnesota | Kappa opioid receptor agonists |
US5866164A (en) * | 1996-03-12 | 1999-02-02 | Alza Corporation | Composition and dosage form comprising opioid antagonist |
US6419959B1 (en) * | 1996-12-11 | 2002-07-16 | Klinge Pharma Gmbh | Galenic composition containing opioid antagonists |
US6353004B1 (en) * | 1997-07-14 | 2002-03-05 | Adolor Coporation | Peripherally acting anti-pruritic opiates |
US20020028825A1 (en) * | 1997-11-03 | 2002-03-07 | Foss Joseph F. | Use of methylnaltrexone and related compounds |
US20040162306A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnal trexone and related compounds to treat constipation in chronic opioid users |
US6608075B2 (en) * | 1997-11-03 | 2003-08-19 | The University Of Chicago | Use of methylnaltrexone and related compounds |
US20040162307A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnaltrexone and related compounds to induce laxation in chronic opioid users |
US6274591B1 (en) * | 1997-11-03 | 2001-08-14 | Joseph F. Foss | Use of methylnaltrexone and related compounds |
US20030187010A1 (en) * | 1997-11-03 | 2003-10-02 | Foss Joseph F. | Use of methylnaltrexone and related compounds to treat chronic opioid use side effects |
US6559158B1 (en) * | 1997-11-03 | 2003-05-06 | Ur Labs, Inc. | Use of methylnaltrexone and related compounds to treat chronic opioid use side affects |
US20050048117A1 (en) * | 1997-11-03 | 2005-03-03 | Foss Joseph F. | Use of methylnaltrexone and related compounds |
US20030065003A1 (en) * | 1997-11-03 | 2003-04-03 | The University Of Chicago | Use of methylnaltrexone and related compounds |
US20040162308A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids |
US5972954A (en) * | 1997-11-03 | 1999-10-26 | Arch Development Corporation | Use of methylnaltrexone and related compounds |
US20040167147A1 (en) * | 1997-11-03 | 2004-08-26 | Foss Joseph F. | Oral use of methylnaltrexone and related compounds to induce laxation in chronic opioid users |
US20040167148A1 (en) * | 1997-11-03 | 2004-08-26 | Foss Joseph F. | Oral use of methylnaltrexone and related compounds to treat constipation in chronic opioid users |
US6194382B1 (en) * | 1999-03-03 | 2001-02-27 | Albert Einstein College Of Medicine Of Yeshiva University | Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists |
US6395705B2 (en) * | 1999-03-03 | 2002-05-28 | Albert Einstein College Of Medicine Of Yeshiva University | Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists |
US20010018413A1 (en) * | 1999-03-03 | 2001-08-30 | Crain Stanley M. | Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists |
US6455537B1 (en) * | 1999-08-25 | 2002-09-24 | Barrett R. Cooper | Methods for treating opiate intolerance |
US6451806B2 (en) * | 1999-09-29 | 2002-09-17 | Adolor Corporation | Methods and compositions involving opioids and antagonists thereof |
US20010047005A1 (en) * | 1999-09-29 | 2001-11-29 | Farrar John J. | Novel methods and compositions involving opioids and antagonists thereof |
US20010036951A1 (en) * | 1999-11-29 | 2001-11-01 | Farrar John J. | Novel methods for the treatment and prevention of ileus |
US6469030B2 (en) * | 1999-11-29 | 2002-10-22 | Adolor Corporation | Methods for the treatment and prevention of ileus |
US20020064771A1 (en) * | 2000-04-07 | 2002-05-30 | Weidong Zhong | HCV replicase complexes |
US20020188005A1 (en) * | 2000-04-27 | 2002-12-12 | Adolor Corporation | Novel methods for the treatment and prevention of ileus |
US20030026801A1 (en) * | 2000-06-22 | 2003-02-06 | George Weiner | Methods for enhancing antibody-induced cell lysis and treating cancer |
US20030022909A1 (en) * | 2001-06-05 | 2003-01-30 | University Of Chicago | Use of methylnaltrexone to treat immune suppression |
US20030124086A1 (en) * | 2001-10-18 | 2003-07-03 | Shearwater Corporation | Polymer conjugates of opioid antagonists |
US20030191147A1 (en) * | 2002-04-09 | 2003-10-09 | Barry Sherman | Opioid antagonist compositions and dosage forms |
US6986901B2 (en) * | 2002-07-15 | 2006-01-17 | Warner-Lambert Company Llc | Gastrointestinal compositions |
US20040259899A1 (en) * | 2003-04-08 | 2004-12-23 | Sanghvi Suketu P. | Combination therapy for constipation |
US20050004155A1 (en) * | 2003-04-08 | 2005-01-06 | Boyd Thomas A. | Use of methylnaltrexone to treat irritable bowel syndrome |
US20050124885A1 (en) * | 2003-10-29 | 2005-06-09 | Vuesonix Sensors, Inc. | Method and apparatus for determining an ultrasound fluid flow centerline |
US20060205753A1 (en) * | 2005-01-20 | 2006-09-14 | Israel Robert J | Use of methylnaltrexone and related compounds to treat post-operative gastrointestinal dysfunction |
Cited By (98)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030065003A1 (en) * | 1997-11-03 | 2003-04-03 | The University Of Chicago | Use of methylnaltrexone and related compounds |
US20040162308A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids |
US20040162306A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnal trexone and related compounds to treat constipation in chronic opioid users |
US20040162307A1 (en) * | 1997-11-03 | 2004-08-19 | Foss Joseph F. | Use of methylnaltrexone and related compounds to induce laxation in chronic opioid users |
US20040167148A1 (en) * | 1997-11-03 | 2004-08-26 | Foss Joseph F. | Oral use of methylnaltrexone and related compounds to treat constipation in chronic opioid users |
US10202383B2 (en) | 2002-08-21 | 2019-02-12 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US10023574B2 (en) | 2002-08-21 | 2018-07-17 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US20040259899A1 (en) * | 2003-04-08 | 2004-12-23 | Sanghvi Suketu P. | Combination therapy for constipation |
US8552025B2 (en) | 2003-04-08 | 2013-10-08 | Progenics Pharmaceuticals, Inc. | Stable methylnaltrexone preparation |
US10376584B2 (en) | 2003-04-08 | 2019-08-13 | Progenics Pharmaceuticals, Inc. | Stable pharmaceutical formulations of methylnaltrexone |
US9669096B2 (en) | 2003-04-08 | 2017-06-06 | Progenics Pharmaceuticals, Inc. | Stable pharmaceutical formulations of methylnaltrexone |
US8425933B2 (en) | 2003-04-08 | 2013-04-23 | Elite Laboratories, Inc. | Abuse-resistant oral dosage forms and method of use thereof |
US8182836B2 (en) | 2003-04-08 | 2012-05-22 | Elite Laboratories, Inc. | Abuse-resistant oral dosage forms and method of use thereof |
US8703186B2 (en) | 2003-04-08 | 2014-04-22 | Elite Laboratories, Inc. | Abuse-resistant oral dosage forms and method of use thereof |
US20050004155A1 (en) * | 2003-04-08 | 2005-01-06 | Boyd Thomas A. | Use of methylnaltrexone to treat irritable bowel syndrome |
US20060205753A1 (en) * | 2005-01-20 | 2006-09-14 | Israel Robert J | Use of methylnaltrexone and related compounds to treat post-operative gastrointestinal dysfunction |
US9675602B2 (en) | 2005-03-07 | 2017-06-13 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
US9717725B2 (en) | 2005-03-07 | 2017-08-01 | The University Of Chicago | Use of opioid antagonists |
US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US9662390B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
EP2450359A2 (en) | 2005-05-25 | 2012-05-09 | Progenics Pharmaceuticals, Inc. | (R)-N-Methylnaltrexone |
US8916581B2 (en) | 2005-05-25 | 2014-12-23 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone |
WO2006127899A2 (en) | 2005-05-25 | 2006-11-30 | Progenics Pharmaceuticals, Inc. | (r)-n-methylnaltrexone, processes for its synthesis and its pharmaceutical use |
US9597327B2 (en) | 2005-05-25 | 2017-03-21 | Progenics Pharmaceuticals, Inc. | Synthesis of (R)-N-methylnaltrexone |
EP2450360A2 (en) | 2005-05-25 | 2012-05-09 | Progenics Pharmaceuticals, Inc. | (S)-N-Methylnaltrexone |
US8003794B2 (en) | 2005-05-25 | 2011-08-23 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone |
EP3219717A1 (en) | 2005-05-25 | 2017-09-20 | Progenics Pharmaceuticals, Inc. | Pharmaceutical compositions comprising (r)-n-methylnaltrexone |
US20070099946A1 (en) * | 2005-05-25 | 2007-05-03 | Doshan Harold D | Synthesis of R-N-methylnaltrexone |
US8343992B2 (en) | 2005-05-25 | 2013-01-01 | Progenics Pharmaceuticals, Inc. | Synthesis of R-N-methylnaltrexone |
US20070265293A1 (en) * | 2005-05-25 | 2007-11-15 | Boyd Thomas A | (S)-N-methylnaltrexone |
US7563899B2 (en) | 2005-05-25 | 2009-07-21 | Progenics Pharmaceuticals, Inc. | (S)-N-methylnaltrexone |
US7674904B2 (en) | 2005-05-25 | 2010-03-09 | Progenics Pharmaceuticals, Inc. | Synthesis of R-N-methylnaltrexone |
US10080754B2 (en) | 2006-05-04 | 2018-09-25 | Boehringer Ingelheim International Gmbh | Uses of DPP IV inhibitors |
US11291668B2 (en) | 2006-05-04 | 2022-04-05 | Boehringer Ingelheim International Gmbh | Uses of DPP IV inhibitors |
US10301313B2 (en) | 2006-05-04 | 2019-05-28 | Boehringer Ingelheim International Gmbh | Polymorphs |
US11033552B2 (en) | 2006-05-04 | 2021-06-15 | Boehringer Ingelheim International Gmbh | DPP IV inhibitor formulations |
US11919903B2 (en) | 2006-05-04 | 2024-03-05 | Boehringer Ingelheim International Gmbh | Polymorphs |
US11084819B2 (en) | 2006-05-04 | 2021-08-10 | Boehringer Ingelheim International Gmbh | Polymorphs |
US7501434B2 (en) | 2006-08-04 | 2009-03-10 | Wyeth | 6-carboxy-normorphinan derivatives, synthesis and uses thereof |
US20080064744A1 (en) * | 2006-08-04 | 2008-03-13 | Wyeth | 6-Carboxy-normorphinan derivatives, synthesis and uses thereof |
US20080070975A1 (en) * | 2006-08-04 | 2008-03-20 | Wyeth | Formulations for parenteral delivery of compounds and uses thereof |
US20140228389A1 (en) * | 2006-09-08 | 2014-08-14 | Wyeth, Llc | Dry powder compound formulations and uses thereof |
US20120059025A1 (en) * | 2006-09-08 | 2012-03-08 | Wyeth | Dry powder compound formulations and uses thereof |
US20080207669A1 (en) * | 2006-11-22 | 2008-08-28 | Progenics Pharmaceuticals, Inc. | (S)-N-Stereoisomers of 7,8-Saturated-4,5-Epoxy-Morphinanium Analogs |
WO2008136865A2 (en) * | 2006-11-22 | 2008-11-13 | Progenics Pharmaceuticals, Inc. | (s)-n-stereoisomers of 7,8-saturated-4,5-epoxy-morphinanium analogs |
WO2008136865A3 (en) * | 2006-11-22 | 2009-02-26 | Progenics Pharm Inc | (s)-n-stereoisomers of 7,8-saturated-4,5-epoxy-morphinanium analogs |
US8772310B2 (en) | 2007-03-29 | 2014-07-08 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US8853232B2 (en) | 2007-03-29 | 2014-10-07 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US9879024B2 (en) | 2007-03-29 | 2018-01-30 | Progenics Pharmaceuticals., Inc. | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
US8546418B2 (en) | 2007-03-29 | 2013-10-01 | Progenics Pharmaceuticals, Inc. | Peripheral opioid receptor antagonists and uses thereof |
US8338446B2 (en) | 2007-03-29 | 2012-12-25 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US9102680B2 (en) | 2007-03-29 | 2015-08-11 | Wyeth Llc | Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof |
US8877800B2 (en) | 2007-03-30 | 2014-11-04 | Tioga Pharmaceuticals, Inc. | Kappa-opiate agonists for the treatment of diarrhea-predominant irritable bowel syndrome |
US20080242720A1 (en) * | 2007-03-30 | 2008-10-02 | Mangel Allen | Kappa-opiate agonists for the treatment of diarrhea-predominant and alternating irritable bowel syndrome |
US20110046174A1 (en) * | 2007-03-30 | 2011-02-24 | Tioga Pharmaceuticals, Inc. | Kappa-opiate agonists for the treatment of diarrhea-predominant irritable bowel syndrome |
US7960429B2 (en) | 2007-03-30 | 2011-06-14 | Tioga Pharmaceuticals, Inc | Kappa-opiate agonists for the treatment of diarrhea-predominant irritable bowel syndrome |
US8916706B2 (en) | 2008-02-06 | 2014-12-23 | Progenics Pharmaceuticals, Inc. | Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone |
US8471022B2 (en) | 2008-02-06 | 2013-06-25 | Progenics Pharmaceuticals, Inc. | Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone |
EP2730578A1 (en) | 2008-02-06 | 2014-05-14 | Progenics Pharmaceuticals, Inc. | Preparation and use of (r),(r)-2,2'-bis-methylnal trexone |
US8685995B2 (en) | 2008-03-21 | 2014-04-01 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
US9526723B2 (en) | 2008-03-21 | 2016-12-27 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
US10383869B2 (en) | 2008-03-21 | 2019-08-20 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
US10973827B2 (en) | 2008-04-03 | 2021-04-13 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US10022379B2 (en) | 2008-04-03 | 2018-07-17 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US10507188B2 (en) | 2008-07-01 | 2019-12-17 | The University Of Chicago | Particles containing an opioid receptor antagonist and methods of use |
US20110250278A1 (en) * | 2008-07-01 | 2011-10-13 | University Of Chicago | Particles containing an opioid receptor antagonist and methods of use |
AU2009265034B2 (en) * | 2008-07-01 | 2015-09-03 | University Of Chicago | Particles containing an opioid receptor antagonist and methods of use |
US10034877B2 (en) | 2008-08-06 | 2018-07-31 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US8455644B2 (en) | 2008-09-30 | 2013-06-04 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
US9492445B2 (en) | 2008-09-30 | 2016-11-15 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
EP3608322A1 (en) | 2008-09-30 | 2020-02-12 | Wyeth LLC | Syringe containing nmtx bromide |
US8247425B2 (en) | 2008-09-30 | 2012-08-21 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
US8822490B2 (en) | 2008-09-30 | 2014-09-02 | Wyeth Llc | Peripheral opioid receptor antagonists and uses thereof |
US8420663B2 (en) | 2008-09-30 | 2013-04-16 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
US9180125B2 (en) | 2008-09-30 | 2015-11-10 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
US9724343B2 (en) | 2008-09-30 | 2017-08-08 | Wyeth, Llc | Peripheral opioid receptor antagonists and uses thereof |
US11911388B2 (en) | 2008-10-16 | 2024-02-27 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug |
US10092571B2 (en) | 2009-11-27 | 2018-10-09 | Boehringer Ingelheim International Gmbh | Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin |
US9314461B2 (en) | 2010-03-11 | 2016-04-19 | Wyeth, Llc | Oral formulations and lipophilic salts of methylnaltrexone |
US10307417B2 (en) | 2010-03-11 | 2019-06-04 | Wyeth, Llc | Oral formulations and lipophilic salts of methylnaltrexone |
US10376505B2 (en) | 2010-03-11 | 2019-08-13 | Wyeth, Llc | Oral formulations and lipophilic salts of methylnaltrexone |
US10507206B2 (en) | 2010-03-11 | 2019-12-17 | Wyeth, Llc | Oral formulations and lipophilic salts of methylnaltrexone |
US11911387B2 (en) | 2010-11-15 | 2024-02-27 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
US10195203B2 (en) | 2012-05-14 | 2019-02-05 | Boehringr Ingelheim International GmbH | Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome |
US8940753B1 (en) | 2012-12-14 | 2015-01-27 | Trevi Therapeutics, Inc. | Methods for treating pruritis |
US8987289B2 (en) | 2012-12-14 | 2015-03-24 | Trevi Therapeutics, Inc. | Methods for treating pruritus |
US10238646B2 (en) | 2012-12-14 | 2019-03-26 | Trevi Therapeutics Inc. | Methods for treating pruritus |
US8637538B1 (en) | 2012-12-14 | 2014-01-28 | Trevi Therapeutics, Inc. | Methods for treatment of pruritis |
US10781027B2 (en) | 2013-03-14 | 2020-09-22 | Fresenius Kabi Deutschland Gmbh | Packaging system for oxygen-sensitive drugs |
US10214338B2 (en) | 2013-03-14 | 2019-02-26 | Fresenius Kabi Deutschland Gmbh | Packaging system for oxygen-sensitive drugs |
US11214426B2 (en) | 2013-03-14 | 2022-01-04 | Fresenius Kabi Deutschland Gmbh | Packaging system for oxygen-sensitive drugs |
US10213424B2 (en) | 2013-03-14 | 2019-02-26 | Fresenius Kabi Deutschland Gmbh | Morphine formulations |
US10155000B2 (en) | 2016-06-10 | 2018-12-18 | Boehringer Ingelheim International Gmbh | Medical use of pharmaceutical combination or composition |
WO2018119108A1 (en) * | 2016-12-21 | 2018-06-28 | Tioga Pharmaceuticals Inc. | Splid pharmaceutical formulations of asimadoline |
US20240033284A1 (en) * | 2017-09-15 | 2024-02-01 | Dyve Biosciences, Inc. | Method of administration and treatment |
US11660296B2 (en) | 2018-07-23 | 2023-05-30 | Trevi Therapeutics, Inc. | Treatment of chronic cough, breathlessness and dyspnea |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10376584B2 (en) | Stable pharmaceutical formulations of methylnaltrexone | |
AU2007281984B2 (en) | Formulations for parenteral delivery of compounds and uses thereof | |
AU2013203378B2 (en) | Pharmaceutical formulations containing methylnaltrexone | |
AU2013263750C1 (en) | Formulations for parenteral delivery of compounds and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: PROGENICS PHARMACEUTICALS, INC., NEW YORK Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SANGHVI, SUKETU P.;BOYD, THOMAS A.;REEL/FRAME:015281/0912;SIGNING DATES FROM 20040426 TO 20040427 |
|
STCB | Information on status: application discontinuation |
Free format text: EXPRESSLY ABANDONED -- DURING EXAMINATION |