AU2011205217B2 - Oral dosage form comprising a therapeutic agent and an adverse-effect agent - Google Patents
Oral dosage form comprising a therapeutic agent and an adverse-effect agent Download PDFInfo
- Publication number
- AU2011205217B2 AU2011205217B2 AU2011205217A AU2011205217A AU2011205217B2 AU 2011205217 B2 AU2011205217 B2 AU 2011205217B2 AU 2011205217 A AU2011205217 A AU 2011205217A AU 2011205217 A AU2011205217 A AU 2011205217A AU 2011205217 B2 AU2011205217 B2 AU 2011205217B2
- Authority
- AU
- Australia
- Prior art keywords
- dosage form
- oral dosage
- agents
- composition
- adverse
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000003814 drug Substances 0.000 title claims abstract description 141
- 239000006186 oral dosage form Substances 0.000 title claims abstract description 135
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 125
- 229940124597 therapeutic agent Drugs 0.000 title claims abstract description 116
- 239000000203 mixture Substances 0.000 claims abstract description 203
- 238000000576 coating method Methods 0.000 claims abstract description 98
- 239000011248 coating agent Substances 0.000 claims abstract description 92
- 210000001035 gastrointestinal tract Anatomy 0.000 claims abstract description 25
- 239000002552 dosage form Substances 0.000 claims abstract description 15
- -1 anti-diabetics Substances 0.000 claims description 73
- 229920000642 polymer Polymers 0.000 claims description 53
- 229920002678 cellulose Polymers 0.000 claims description 32
- 238000013270 controlled release Methods 0.000 claims description 31
- 239000001913 cellulose Substances 0.000 claims description 29
- 239000008187 granular material Substances 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 27
- 239000011159 matrix material Substances 0.000 claims description 25
- 239000012730 sustained-release form Substances 0.000 claims description 23
- 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 22
- 238000013268 sustained release Methods 0.000 claims description 22
- 239000005557 antagonist Substances 0.000 claims description 21
- 229920001577 copolymer Polymers 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 230000000694 effects Effects 0.000 claims description 19
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 18
- 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 18
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 18
- 229960002085 oxycodone Drugs 0.000 claims description 18
- 229940125717 barbiturate Drugs 0.000 claims description 17
- 229940049706 benzodiazepine Drugs 0.000 claims description 16
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 claims description 15
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 claims description 15
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 claims description 15
- 229940005483 opioid analgesics Drugs 0.000 claims description 15
- 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 claims description 13
- 229960004127 naloxone Drugs 0.000 claims description 13
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 claims description 13
- 229960003086 naltrexone Drugs 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 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 12
- 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 12
- 229960000240 hydrocodone Drugs 0.000 claims description 12
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002775 capsule Substances 0.000 claims description 11
- 229960005181 morphine Drugs 0.000 claims description 11
- 239000003401 opiate antagonist Substances 0.000 claims description 11
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 10
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 10
- 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 9
- 229940025084 amphetamine Drugs 0.000 claims description 9
- 229960003406 levorphanol Drugs 0.000 claims description 9
- 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 8
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 8
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 claims description 8
- 239000000730 antalgic agent Substances 0.000 claims description 8
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 claims description 8
- 229960001344 methylphenidate Drugs 0.000 claims description 8
- 229960004380 tramadol Drugs 0.000 claims description 8
- 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 8
- 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
- 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
- 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
- 229960001797 methadone Drugs 0.000 claims description 7
- 229960005118 oxymorphone Drugs 0.000 claims description 7
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 claims description 6
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims description 6
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 6
- DEXMFYZAHXMZNM-UHFFFAOYSA-N Narceine Chemical compound OC(=O)C1=C(OC)C(OC)=CC=C1C(=O)CC1=C(CCN(C)C)C=C(OCO2)C2=C1OC DEXMFYZAHXMZNM-UHFFFAOYSA-N 0.000 claims description 6
- 208000002193 Pain Diseases 0.000 claims description 6
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 230000002411 adverse Effects 0.000 claims description 6
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 claims description 6
- 229940035676 analgesics Drugs 0.000 claims description 6
- 239000003443 antiviral agent Substances 0.000 claims description 6
- 239000011324 bead Substances 0.000 claims description 6
- 229960001736 buprenorphine Drugs 0.000 claims description 6
- 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 6
- 229960001113 butorphanol Drugs 0.000 claims description 6
- 229960004126 codeine Drugs 0.000 claims description 6
- 210000001072 colon Anatomy 0.000 claims description 6
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 claims description 6
- 229960000632 dexamfetamine Drugs 0.000 claims description 6
- BRTSNYPDACNMIP-FAWZKKEFSA-N dihydroetorphine Chemical compound O([C@H]1[C@@]2(OC)CC[C@@]34C[C@@H]2[C@](C)(O)CCC)C2=C5[C@]41CCN(C)[C@@H]3CC5=CC=C2O BRTSNYPDACNMIP-FAWZKKEFSA-N 0.000 claims description 6
- SVDHSZFEQYXRDC-UHFFFAOYSA-N dipipanone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)CC)CC(C)N1CCCCC1 SVDHSZFEQYXRDC-UHFFFAOYSA-N 0.000 claims description 6
- 229960002500 dipipanone Drugs 0.000 claims description 6
- 229960004242 dronabinol Drugs 0.000 claims description 6
- 235000004626 essential fatty acids Nutrition 0.000 claims description 6
- CAHCBJPUTCKATP-FAWZKKEFSA-N etorphine Chemical compound O([C@H]1[C@@]2(OC)C=C[C@@]34C[C@@H]2[C@](C)(O)CCC)C2=C5[C@]41CCN(C)[C@@H]3CC5=CC=C2O CAHCBJPUTCKATP-FAWZKKEFSA-N 0.000 claims description 6
- 229950004155 etorphine Drugs 0.000 claims description 6
- 229960002428 fentanyl Drugs 0.000 claims description 6
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 claims description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 6
- 229940035363 muscle relaxants Drugs 0.000 claims description 6
- 239000003158 myorelaxant agent Substances 0.000 claims description 6
- GECBBEABIDMGGL-RTBURBONSA-N nabilone Chemical compound C1C(=O)CC[C@H]2C(C)(C)OC3=CC(C(C)(C)CCCCCC)=CC(O)=C3[C@@H]21 GECBBEABIDMGGL-RTBURBONSA-N 0.000 claims description 6
- 229960002967 nabilone Drugs 0.000 claims description 6
- 235000016709 nutrition Nutrition 0.000 claims description 6
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 claims description 6
- 229960000482 pethidine Drugs 0.000 claims description 6
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 claims description 6
- 239000000021 stimulant Substances 0.000 claims description 6
- 210000002784 stomach Anatomy 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- 239000000749 benzodiazepine receptor blocking agent Substances 0.000 claims description 5
- LGFMXOTUSSVQJV-NEYUFSEYSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;(4r,4ar,7s,7ar,12bs)-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol;1-[(3,4-dimethoxyphenyl)methyl]-6 Chemical compound Cl.Cl.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 LGFMXOTUSSVQJV-NEYUFSEYSA-N 0.000 claims description 4
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 claims description 4
- 101800001288 Atrial natriuretic factor Proteins 0.000 claims description 4
- 101800001890 Atrial natriuretic peptide Proteins 0.000 claims description 4
- 102400001282 Atrial natriuretic peptide Human genes 0.000 claims description 4
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 claims description 4
- 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 claims description 4
- 102000003951 Erythropoietin Human genes 0.000 claims description 4
- 108090000394 Erythropoietin Proteins 0.000 claims description 4
- 108010016076 Octreotide Proteins 0.000 claims description 4
- 102000003982 Parathyroid hormone Human genes 0.000 claims description 4
- 108090000445 Parathyroid hormone Proteins 0.000 claims description 4
- 229920001800 Shellac Polymers 0.000 claims description 4
- NSQLIUXCMFBZME-MPVJKSABSA-N carperitide Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 NSQLIUXCMFBZME-MPVJKSABSA-N 0.000 claims description 4
- 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 4
- QIRAYNIFEOXSPW-UHFFFAOYSA-N dimepheptanol Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(O)CC)C1=CC=CC=C1 QIRAYNIFEOXSPW-UHFFFAOYSA-N 0.000 claims description 4
- 229950004655 dimepheptanol Drugs 0.000 claims description 4
- 239000002895 emetic Substances 0.000 claims description 4
- 229940105423 erythropoietin Drugs 0.000 claims description 4
- 150000002191 fatty alcohols Chemical class 0.000 claims description 4
- 229940088597 hormone Drugs 0.000 claims description 4
- 239000005556 hormone Substances 0.000 claims description 4
- 239000008141 laxative Substances 0.000 claims description 4
- 229960002700 octreotide Drugs 0.000 claims description 4
- 239000003921 oil Substances 0.000 claims description 4
- 235000019198 oils Nutrition 0.000 claims description 4
- 239000000014 opioid analgesic Substances 0.000 claims description 4
- 239000000199 parathyroid hormone Substances 0.000 claims description 4
- 229960001319 parathyroid hormone Drugs 0.000 claims description 4
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 4
- 239000004208 shellac Substances 0.000 claims description 4
- 229940113147 shellac Drugs 0.000 claims description 4
- 235000013874 shellac Nutrition 0.000 claims description 4
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 claims description 4
- 150000003431 steroids Chemical class 0.000 claims description 4
- 229960001402 tilidine Drugs 0.000 claims description 4
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 claims description 3
- UVITTYOJFDLOGI-UHFFFAOYSA-N (1,2,5-trimethyl-4-phenylpiperidin-4-yl) propanoate Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CC(C)N(C)CC1C UVITTYOJFDLOGI-UHFFFAOYSA-N 0.000 claims description 3
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 claims description 3
- ZEHYJZXQEQOSON-AATRIKPKSA-N (e)-1-chloro-3-ethylpent-1-en-4-yn-3-ol Chemical compound CCC(O)(C#C)\C=C\Cl ZEHYJZXQEQOSON-AATRIKPKSA-N 0.000 claims description 3
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 claims description 3
- IYNWSQDZXMGGGI-NUEKZKHPSA-N 3-hydroxymorphinan Chemical compound C1CCC[C@H]2[C@H]3CC4=CC=C(O)C=C4[C@]21CCN3 IYNWSQDZXMGGGI-NUEKZKHPSA-N 0.000 claims description 3
- 241000894006 Bacteria Species 0.000 claims description 3
- VMIYHDSEFNYJSL-UHFFFAOYSA-N Bromazepam Chemical compound C12=CC(Br)=CC=C2NC(=O)CN=C1C1=CC=CC=N1 VMIYHDSEFNYJSL-UHFFFAOYSA-N 0.000 claims description 3
- QORQZMBCPRBCAB-UHFFFAOYSA-M Butabarbital sodium Chemical compound [Na+].CCC(C)C1(CC)C(=O)NC([O-])=NC1=O QORQZMBCPRBCAB-UHFFFAOYSA-M 0.000 claims description 3
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 3
- ZCKAMNXUHHNZLN-UHFFFAOYSA-N Chlorphentermine Chemical compound CC(C)(N)CC1=CC=C(Cl)C=C1 ZCKAMNXUHHNZLN-UHFFFAOYSA-N 0.000 claims description 3
- 108010000437 Deamino Arginine Vasopressin Proteins 0.000 claims description 3
- IJVCSMSMFSCRME-KBQPJGBKSA-N Dihydromorphine Chemical compound O([C@H]1[C@H](CC[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O IJVCSMSMFSCRME-KBQPJGBKSA-N 0.000 claims description 3
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 3
- OGDVEMNWJVYAJL-LEPYJNQMSA-N Ethyl morphine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OCC OGDVEMNWJVYAJL-LEPYJNQMSA-N 0.000 claims description 3
- OGDVEMNWJVYAJL-UHFFFAOYSA-N Ethylmorphine Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OCC OGDVEMNWJVYAJL-UHFFFAOYSA-N 0.000 claims description 3
- JMBQKKAJIKAWKF-UHFFFAOYSA-N Glutethimide Chemical compound C=1C=CC=CC=1C1(CC)CCC(=O)NC1=O JMBQKKAJIKAWKF-UHFFFAOYSA-N 0.000 claims description 3
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims description 3
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims description 3
- 102000038461 Growth Hormone-Releasing Hormone Human genes 0.000 claims description 3
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 claims description 3
- WYCLKVQLVUQKNZ-UHFFFAOYSA-N Halazepam Chemical compound N=1CC(=O)N(CC(F)(F)F)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 WYCLKVQLVUQKNZ-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- 229940122236 Histamine receptor antagonist Drugs 0.000 claims description 3
- 102000002265 Human Growth Hormone Human genes 0.000 claims description 3
- 108010000521 Human Growth Hormone Proteins 0.000 claims description 3
- 239000000854 Human Growth Hormone Substances 0.000 claims description 3
- 206010020880 Hypertrophy Diseases 0.000 claims description 3
- 102000004877 Insulin Human genes 0.000 claims description 3
- 108090001061 Insulin Proteins 0.000 claims description 3
- 102000014150 Interferons Human genes 0.000 claims description 3
- 108010050904 Interferons Proteins 0.000 claims description 3
- 229940124091 Keratolytic Drugs 0.000 claims description 3
- ALFGKMXHOUSVAD-UHFFFAOYSA-N Ketobemidone Chemical compound C=1C=CC(O)=CC=1C1(C(=O)CC)CCN(C)CC1 ALFGKMXHOUSVAD-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- LEROTMJVBFSIMP-UHFFFAOYSA-N Mebutamate Chemical compound NC(=O)OCC(C)(C(C)CC)COC(N)=O LEROTMJVBFSIMP-UHFFFAOYSA-N 0.000 claims description 3
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 claims description 3
- FWJKNZONDWOGMI-UHFFFAOYSA-N Metharbital Chemical compound CCC1(CC)C(=O)NC(=O)N(C)C1=O FWJKNZONDWOGMI-UHFFFAOYSA-N 0.000 claims description 3
- NZXKDOXHBHYTKP-UHFFFAOYSA-N Metohexital Chemical compound CCC#CC(C)C1(CC=C)C(=O)NC(=O)N(C)C1=O NZXKDOXHBHYTKP-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 claims description 3
- 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 3
- ONBWJWYUHXVEJS-ZTYRTETDSA-N Normorphine Chemical compound C([C@@H](NCC1)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 ONBWJWYUHXVEJS-ZTYRTETDSA-N 0.000 claims description 3
- 239000008896 Opium Substances 0.000 claims description 3
- MFOCDFTXLCYLKU-CMPLNLGQSA-N Phendimetrazine Chemical compound O1CCN(C)[C@@H](C)[C@@H]1C1=CC=CC=C1 MFOCDFTXLCYLKU-CMPLNLGQSA-N 0.000 claims description 3
- MWQCHHACWWAQLJ-UHFFFAOYSA-N Prazepam Chemical compound O=C1CN=C(C=2C=CC=CC=2)C2=CC(Cl)=CC=C2N1CC1CC1 MWQCHHACWWAQLJ-UHFFFAOYSA-N 0.000 claims description 3
- IKMPWMZBZSAONZ-UHFFFAOYSA-N Quazepam Chemical compound FC1=CC=CC=C1C1=NCC(=S)N(CC(F)(F)F)C2=CC=C(Cl)C=C12 IKMPWMZBZSAONZ-UHFFFAOYSA-N 0.000 claims description 3
- ZRIHAIZYIMGOAB-UHFFFAOYSA-N Secbutobarbitone Natural products CCC(C)C1(CC)C(=O)NC(=O)NC1=O ZRIHAIZYIMGOAB-UHFFFAOYSA-N 0.000 claims description 3
- 101710142969 Somatoliberin Proteins 0.000 claims description 3
- SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 claims description 3
- 108010069102 Thromboxane-A synthase Proteins 0.000 claims description 3
- 206010046543 Urinary incontinence Diseases 0.000 claims description 3
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 claims description 3
- 108010004977 Vasopressins Proteins 0.000 claims description 3
- 102000002852 Vasopressins Human genes 0.000 claims description 3
- 229920002494 Zein Polymers 0.000 claims description 3
- 239000003741 agents affecting lipid metabolism Substances 0.000 claims description 3
- 229960001391 alfentanil Drugs 0.000 claims description 3
- KGYFOSCXVAXULR-UHFFFAOYSA-N allylprodine Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CCN(C)CC1CC=C KGYFOSCXVAXULR-UHFFFAOYSA-N 0.000 claims description 3
- 229950004361 allylprodine Drugs 0.000 claims description 3
- UVAZQQHAVMNMHE-XJKSGUPXSA-N alphaprodine Chemical compound C=1C=CC=CC=1[C@@]1(OC(=O)CC)CCN(C)C[C@@H]1C UVAZQQHAVMNMHE-XJKSGUPXSA-N 0.000 claims description 3
- 229960001349 alphaprodine Drugs 0.000 claims description 3
- 229960004538 alprazolam Drugs 0.000 claims description 3
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 claims description 3
- 229960001301 amobarbital Drugs 0.000 claims description 3
- 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 3
- 229960002512 anileridine Drugs 0.000 claims description 3
- 230000000507 anthelmentic effect Effects 0.000 claims description 3
- 229940124339 anthelmintic agent Drugs 0.000 claims description 3
- 239000000921 anthelmintic agent Substances 0.000 claims description 3
- 239000003242 anti bacterial agent Substances 0.000 claims description 3
- 239000004004 anti-anginal agent Substances 0.000 claims description 3
- 230000001430 anti-depressive effect Effects 0.000 claims description 3
- 230000003178 anti-diabetic effect Effects 0.000 claims description 3
- 230000003556 anti-epileptic effect Effects 0.000 claims description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- 230000000078 anti-malarial effect Effects 0.000 claims description 3
- 239000000883 anti-obesity agent Substances 0.000 claims description 3
- 230000003262 anti-osteoporosis Effects 0.000 claims description 3
- 229940124345 antianginal agent Drugs 0.000 claims description 3
- 239000003416 antiarrhythmic agent Substances 0.000 claims description 3
- 239000003146 anticoagulant agent Substances 0.000 claims description 3
- 229940127219 anticoagulant drug Drugs 0.000 claims description 3
- 239000001961 anticonvulsive agent Substances 0.000 claims description 3
- 239000000935 antidepressant agent Substances 0.000 claims description 3
- 229940005513 antidepressants Drugs 0.000 claims description 3
- 229960003965 antiepileptics Drugs 0.000 claims description 3
- 239000003429 antifungal agent Substances 0.000 claims description 3
- 229940121375 antifungal agent Drugs 0.000 claims description 3
- 239000002255 antigout agent Substances 0.000 claims description 3
- 229960002708 antigout preparations Drugs 0.000 claims description 3
- 239000002220 antihypertensive agent Substances 0.000 claims description 3
- 229940030600 antihypertensive agent Drugs 0.000 claims description 3
- 239000003430 antimalarial agent Substances 0.000 claims description 3
- 229940033495 antimalarials Drugs 0.000 claims description 3
- 229940125684 antimigraine agent Drugs 0.000 claims description 3
- 239000002282 antimigraine agent Substances 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940034982 antineoplastic agent Drugs 0.000 claims description 3
- 229940125710 antiobesity agent Drugs 0.000 claims description 3
- 239000000939 antiparkinson agent Substances 0.000 claims description 3
- 239000003904 antiprotozoal agent Substances 0.000 claims description 3
- 239000003200 antithyroid agent Substances 0.000 claims description 3
- 229940043671 antithyroid preparations Drugs 0.000 claims description 3
- 239000002249 anxiolytic agent Substances 0.000 claims description 3
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 claims description 3
- YXKTVDFXDRQTKV-HNNXBMFYSA-N benzphetamine Chemical compound C([C@H](C)N(C)CC=1C=CC=CC=1)C1=CC=CC=C1 YXKTVDFXDRQTKV-HNNXBMFYSA-N 0.000 claims description 3
- 229960002837 benzphetamine Drugs 0.000 claims description 3
- RDJGWRFTDZZXSM-RNWLQCGYSA-N benzylmorphine Chemical compound O([C@@H]1[C@]23CCN([C@H](C4)[C@@H]3C=C[C@@H]1O)C)C1=C2C4=CC=C1OCC1=CC=CC=C1 RDJGWRFTDZZXSM-RNWLQCGYSA-N 0.000 claims description 3
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims description 3
- FLKWNFFCSSJANB-UHFFFAOYSA-N bezitramide Chemical compound O=C1N(C(=O)CC)C2=CC=CC=C2N1C(CC1)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 FLKWNFFCSSJANB-UHFFFAOYSA-N 0.000 claims description 3
- 229960004611 bezitramide Drugs 0.000 claims description 3
- 229960002729 bromazepam Drugs 0.000 claims description 3
- 229940015694 butabarbital Drugs 0.000 claims description 3
- UZVHFVZFNXBMQJ-UHFFFAOYSA-N butalbital Chemical compound CC(C)CC1(CC=C)C(=O)NC(=O)NC1=O UZVHFVZFNXBMQJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960002546 butalbital Drugs 0.000 claims description 3
- 239000000480 calcium channel blocker Substances 0.000 claims description 3
- 230000000747 cardiac effect Effects 0.000 claims description 3
- 210000004027 cell Anatomy 0.000 claims description 3
- 229950007046 chlorphentermine Drugs 0.000 claims description 3
- 229960005132 cisapride Drugs 0.000 claims description 3
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 claims description 3
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 claims description 3
- GPZLDQAEBHTMPG-UHFFFAOYSA-N clonitazene Chemical compound N=1C2=CC([N+]([O-])=O)=CC=C2N(CCN(CC)CC)C=1CC1=CC=C(Cl)C=C1 GPZLDQAEBHTMPG-UHFFFAOYSA-N 0.000 claims description 3
- 229950001604 clonitazene Drugs 0.000 claims description 3
- 229960004362 clorazepate Drugs 0.000 claims description 3
- HXCXASJHZQXCKK-UHFFFAOYSA-N clortermine Chemical compound CC(C)(N)CC1=CC=CC=C1Cl HXCXASJHZQXCKK-UHFFFAOYSA-N 0.000 claims description 3
- 229950000649 clortermine Drugs 0.000 claims description 3
- 230000019771 cognition Effects 0.000 claims description 3
- 239000003246 corticosteroid Substances 0.000 claims description 3
- 229960001334 corticosteroids Drugs 0.000 claims description 3
- 229940111134 coxibs Drugs 0.000 claims description 3
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 claims description 3
- 229960004281 desmopressin Drugs 0.000 claims description 3
- NFLWUMRGJYTJIN-NXBWRCJVSA-N desmopressin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 NFLWUMRGJYTJIN-NXBWRCJVSA-N 0.000 claims description 3
- LNNWVNGFPYWNQE-GMIGKAJZSA-N desomorphine Chemical compound C1C2=CC=C(O)C3=C2[C@]24CCN(C)[C@H]1[C@@H]2CCC[C@@H]4O3 LNNWVNGFPYWNQE-GMIGKAJZSA-N 0.000 claims description 3
- 229950003851 desomorphine Drugs 0.000 claims description 3
- 229960003701 dextromoramide Drugs 0.000 claims description 3
- INUNXTSAACVKJS-OAQYLSRUSA-N dextromoramide Chemical compound C([C@@H](C)C(C(=O)N1CCCC1)(C=1C=CC=CC=1)C=1C=CC=CC=1)N1CCOCC1 INUNXTSAACVKJS-OAQYLSRUSA-N 0.000 claims description 3
- 229960004193 dextropropoxyphene Drugs 0.000 claims description 3
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 claims description 3
- 229960003461 dezocine Drugs 0.000 claims description 3
- 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 3
- 229960002069 diamorphine Drugs 0.000 claims description 3
- RXTHKWVSXOIHJS-UHFFFAOYSA-N diampromide Chemical compound C=1C=CC=CC=1N(C(=O)CC)CC(C)N(C)CCC1=CC=CC=C1 RXTHKWVSXOIHJS-UHFFFAOYSA-N 0.000 claims description 3
- 229950001059 diampromide Drugs 0.000 claims description 3
- 229960003529 diazepam Drugs 0.000 claims description 3
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 claims description 3
- XXEPPPIWZFICOJ-UHFFFAOYSA-N diethylpropion Chemical compound CCN(CC)C(C)C(=O)C1=CC=CC=C1 XXEPPPIWZFICOJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960004890 diethylpropion Drugs 0.000 claims description 3
- 229960000920 dihydrocodeine Drugs 0.000 claims description 3
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 claims description 3
- RHUWRJWFHUKVED-UHFFFAOYSA-N dimenoxadol Chemical compound C=1C=CC=CC=1C(C(=O)OCCN(C)C)(OCC)C1=CC=CC=C1 RHUWRJWFHUKVED-UHFFFAOYSA-N 0.000 claims description 3
- 229950011187 dimenoxadol Drugs 0.000 claims description 3
- CANBGVXYBPOLRR-UHFFFAOYSA-N dimethylthiambutene Chemical compound C=1C=CSC=1C(=CC(C)N(C)C)C1=CC=CS1 CANBGVXYBPOLRR-UHFFFAOYSA-N 0.000 claims description 3
- 229950005563 dimethylthiambutene Drugs 0.000 claims description 3
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims description 3
- 239000002934 diuretic Substances 0.000 claims description 3
- 229940030606 diuretics Drugs 0.000 claims description 3
- 239000003623 enhancer Substances 0.000 claims description 3
- ZOWQTJXNFTWSCS-IAQYHMDHSA-N eptazocine Chemical compound C1N(C)CC[C@@]2(C)C3=CC(O)=CC=C3C[C@@H]1C2 ZOWQTJXNFTWSCS-IAQYHMDHSA-N 0.000 claims description 3
- 229950010920 eptazocine Drugs 0.000 claims description 3
- 229960002336 estazolam Drugs 0.000 claims description 3
- CDCHDCWJMGXXRH-UHFFFAOYSA-N estazolam Chemical compound C=1C(Cl)=CC=C(N2C=NN=C2CN=2)C=1C=2C1=CC=CC=C1 CDCHDCWJMGXXRH-UHFFFAOYSA-N 0.000 claims description 3
- GXRZIMHKGDIBEW-UHFFFAOYSA-N ethinamate Chemical compound NC(=O)OC1(C#C)CCCCC1 GXRZIMHKGDIBEW-UHFFFAOYSA-N 0.000 claims description 3
- 229960002209 ethinamate Drugs 0.000 claims description 3
- WGJHHMKQBWSQIY-UHFFFAOYSA-N ethoheptazine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCCN(C)CC1 WGJHHMKQBWSQIY-UHFFFAOYSA-N 0.000 claims description 3
- 229960000569 ethoheptazine Drugs 0.000 claims description 3
- 229960004578 ethylmorphine Drugs 0.000 claims description 3
- PXDBZSCGSQSKST-UHFFFAOYSA-N etonitazene Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC([N+]([O-])=O)=CC=C2N1CCN(CC)CC PXDBZSCGSQSKST-UHFFFAOYSA-N 0.000 claims description 3
- 229950004538 etonitazene Drugs 0.000 claims description 3
- 229960001582 fenfluramine Drugs 0.000 claims description 3
- OFBIFZUFASYYRE-UHFFFAOYSA-N flumazenil Chemical group C1N(C)C(=O)C2=CC(F)=CC=C2N2C=NC(C(=O)OCC)=C21 OFBIFZUFASYYRE-UHFFFAOYSA-N 0.000 claims description 3
- 229960004381 flumazenil Drugs 0.000 claims description 3
- 239000004083 gastrointestinal agent Substances 0.000 claims description 3
- 229940125695 gastrointestinal agent Drugs 0.000 claims description 3
- 229960002442 glucosamine Drugs 0.000 claims description 3
- 229960002972 glutethimide Drugs 0.000 claims description 3
- 239000003163 gonadal steroid hormone Substances 0.000 claims description 3
- 229960002158 halazepam Drugs 0.000 claims description 3
- 229960002897 heparin Drugs 0.000 claims description 3
- 229920000669 heparin Polymers 0.000 claims description 3
- WTJBNMUWRKPFRS-UHFFFAOYSA-N hydroxypethidine Chemical compound C=1C=CC(O)=CC=1C1(C(=O)OCC)CCN(C)CC1 WTJBNMUWRKPFRS-UHFFFAOYSA-N 0.000 claims description 3
- 229950008496 hydroxypethidine Drugs 0.000 claims description 3
- 239000003326 hypnotic agent Substances 0.000 claims description 3
- 230000000147 hypnotic effect Effects 0.000 claims description 3
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 3
- 239000003018 immunosuppressive agent Substances 0.000 claims description 3
- 201000001881 impotence Diseases 0.000 claims description 3
- 230000006872 improvement Effects 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 230000002458 infectious effect Effects 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- 229940125396 insulin Drugs 0.000 claims description 3
- 229940047124 interferons Drugs 0.000 claims description 3
- 230000001057 ionotropic effect Effects 0.000 claims description 3
- IFKPLJWIEQBPGG-UHFFFAOYSA-N isomethadone Chemical compound C=1C=CC=CC=1C(C(C)CN(C)C)(C(=O)CC)C1=CC=CC=C1 IFKPLJWIEQBPGG-UHFFFAOYSA-N 0.000 claims description 3
- 229950009272 isomethadone Drugs 0.000 claims description 3
- 230000001530 keratinolytic effect Effects 0.000 claims description 3
- 239000003410 keratolytic agent Substances 0.000 claims description 3
- 229960004423 ketazolam Drugs 0.000 claims description 3
- PWAJCNITSBZRBL-UHFFFAOYSA-N ketazolam Chemical compound O1C(C)=CC(=O)N2CC(=O)N(C)C3=CC=C(Cl)C=C3C21C1=CC=CC=C1 PWAJCNITSBZRBL-UHFFFAOYSA-N 0.000 claims description 3
- 229960003029 ketobemidone Drugs 0.000 claims description 3
- 229940125722 laxative agent Drugs 0.000 claims description 3
- 239000003199 leukotriene receptor blocking agent Substances 0.000 claims description 3
- XBMIVRRWGCYBTQ-AVRDEDQJSA-N levacetylmethadol Chemical group 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 3
- 229960000263 levallorphan Drugs 0.000 claims description 3
- 229940087121 levomethadyl Drugs 0.000 claims description 3
- RCYBMSQOSGJZLO-BGWNEDDSSA-N levophenacylmorphan Chemical compound C([C@]12CCCC[C@H]1[C@H]1CC3=CC=C(C=C32)O)CN1CC(=O)C1=CC=CC=C1 RCYBMSQOSGJZLO-BGWNEDDSSA-N 0.000 claims description 3
- 229950007939 levophenacylmorphan Drugs 0.000 claims description 3
- 229950010274 lofentanil Drugs 0.000 claims description 3
- IMYHGORQCPYVBZ-NLFFAJNJSA-N lofentanil Chemical compound CCC(=O)N([C@@]1([C@@H](CN(CCC=2C=CC=CC=2)CC1)C)C(=O)OC)C1=CC=CC=C1 IMYHGORQCPYVBZ-NLFFAJNJSA-N 0.000 claims description 3
- 229960004391 lorazepam Drugs 0.000 claims description 3
- 230000001592 luteinising effect Effects 0.000 claims description 3
- 239000003120 macrolide antibiotic agent Substances 0.000 claims description 3
- 229940041033 macrolides Drugs 0.000 claims description 3
- 229960004119 mebutamate Drugs 0.000 claims description 3
- ALARQZQTBTVLJV-UHFFFAOYSA-N mephobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)N(C)C1=O ALARQZQTBTVLJV-UHFFFAOYSA-N 0.000 claims description 3
- 229960004815 meprobamate Drugs 0.000 claims description 3
- 229960000365 meptazinol Drugs 0.000 claims description 3
- JLICHNCFTLFZJN-HNNXBMFYSA-N meptazinol Chemical compound C=1C=CC(O)=CC=1[C@@]1(CC)CCCCN(C)C1 JLICHNCFTLFZJN-HNNXBMFYSA-N 0.000 claims description 3
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 claims description 3
- 229960004963 mesalazine Drugs 0.000 claims description 3
- 229950009131 metazocine Drugs 0.000 claims description 3
- YGSVZRIZCHZUHB-COLVAYQJSA-N metazocine Chemical compound C1C2=CC=C(O)C=C2[C@]2(C)CCN(C)[C@@]1([H])[C@@H]2C YGSVZRIZCHZUHB-COLVAYQJSA-N 0.000 claims description 3
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 claims description 3
- 229960001252 methamphetamine Drugs 0.000 claims description 3
- 229960002057 metharbital Drugs 0.000 claims description 3
- 229960002683 methohexital Drugs 0.000 claims description 3
- 229960001703 methylphenobarbital Drugs 0.000 claims description 3
- NPZXCTIHHUUEEJ-CMKMFDCUSA-N metopon Chemical compound O([C@@]1(C)C(=O)CC[C@@H]23)C4=C5[C@@]13CCN(C)[C@@H]2CC5=CC=C4O NPZXCTIHHUUEEJ-CMKMFDCUSA-N 0.000 claims description 3
- 229950006080 metopon Drugs 0.000 claims description 3
- 229960003793 midazolam Drugs 0.000 claims description 3
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 claims description 3
- 239000003149 muscarinic antagonist Substances 0.000 claims description 3
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical group CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 claims description 3
- 229960005297 nalmefene Drugs 0.000 claims description 3
- 229960000938 nalorphine Drugs 0.000 claims description 3
- 229960004300 nicomorphine Drugs 0.000 claims description 3
- HNDXBGYRMHRUFN-CIVUWBIHSA-N nicomorphine Chemical compound O([C@H]1C=C[C@H]2[C@H]3CC=4C5=C(C(=CC=4)OC(=O)C=4C=NC=CC=4)O[C@@H]1[C@]52CCN3C)C(=O)C1=CC=CN=C1 HNDXBGYRMHRUFN-CIVUWBIHSA-N 0.000 claims description 3
- 229960001454 nitrazepam Drugs 0.000 claims description 3
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 claims description 3
- 229950011519 norlevorphanol Drugs 0.000 claims description 3
- WCJFBSYALHQBSK-UHFFFAOYSA-N normethadone Chemical compound C=1C=CC=CC=1C(CCN(C)C)(C(=O)CC)C1=CC=CC=C1 WCJFBSYALHQBSK-UHFFFAOYSA-N 0.000 claims description 3
- 229960004013 normethadone Drugs 0.000 claims description 3
- 229950006134 normorphine Drugs 0.000 claims description 3
- WCDSHELZWCOTMI-UHFFFAOYSA-N norpipanone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)CC)CCN1CCCCC1 WCDSHELZWCOTMI-UHFFFAOYSA-N 0.000 claims description 3
- 229950007418 norpipanone Drugs 0.000 claims description 3
- 229960001027 opium Drugs 0.000 claims description 3
- 229960004535 oxazepam Drugs 0.000 claims description 3
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 claims description 3
- 229960003294 papaveretum Drugs 0.000 claims description 3
- 229960003868 paraldehyde Drugs 0.000 claims description 3
- SQYNKIJPMDEDEG-UHFFFAOYSA-N paraldehyde Chemical compound CC1OC(C)OC(C)O1 SQYNKIJPMDEDEG-UHFFFAOYSA-N 0.000 claims description 3
- 229940069533 paregoric Drugs 0.000 claims description 3
- 239000008414 paregoric Substances 0.000 claims description 3
- NRNCYVBFPDDJNE-UHFFFAOYSA-N pemoline Chemical compound O1C(N)=NC(=O)C1C1=CC=CC=C1 NRNCYVBFPDDJNE-UHFFFAOYSA-N 0.000 claims description 3
- 229960000761 pemoline Drugs 0.000 claims description 3
- 229960005301 pentazocine Drugs 0.000 claims description 3
- 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 3
- 229960001412 pentobarbital Drugs 0.000 claims description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 3
- LOXCOAXRHYDLOW-UHFFFAOYSA-N phenadoxone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)CC)CC(C)N1CCOCC1 LOXCOAXRHYDLOW-UHFFFAOYSA-N 0.000 claims description 3
- 229950004540 phenadoxone Drugs 0.000 claims description 3
- ZQHYKVKNPWDQSL-KNXBSLHKSA-N phenazocine Chemical compound C([C@@]1(C)C2=CC(O)=CC=C2C[C@@H]2[C@@H]1C)CN2CCC1=CC=CC=C1 ZQHYKVKNPWDQSL-KNXBSLHKSA-N 0.000 claims description 3
- 229960000897 phenazocine Drugs 0.000 claims description 3
- 229960000436 phendimetrazine Drugs 0.000 claims description 3
- 229960002695 phenobarbital Drugs 0.000 claims description 3
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 claims description 3
- CFBQYWXPZVQQTN-QPTUXGOLSA-N phenomorphan Chemical compound C([C@]12CCCC[C@H]1[C@H]1CC3=CC=C(C=C32)O)CN1CCC1=CC=CC=C1 CFBQYWXPZVQQTN-QPTUXGOLSA-N 0.000 claims description 3
- 229950011496 phenomorphan Drugs 0.000 claims description 3
- IPOPQVVNCFQFRK-UHFFFAOYSA-N phenoperidine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(O)C1=CC=CC=C1 IPOPQVVNCFQFRK-UHFFFAOYSA-N 0.000 claims description 3
- 229960004315 phenoperidine Drugs 0.000 claims description 3
- 229960003562 phentermine Drugs 0.000 claims description 3
- QCCDLTOVEPVEJK-UHFFFAOYSA-N phenylacetone Chemical compound CC(=O)CC1=CC=CC=C1 QCCDLTOVEPVEJK-UHFFFAOYSA-N 0.000 claims description 3
- PXXKIYPSXYFATG-UHFFFAOYSA-N piminodine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCCNC1=CC=CC=C1 PXXKIYPSXYFATG-UHFFFAOYSA-N 0.000 claims description 3
- 229950006445 piminodine Drugs 0.000 claims description 3
- 229960001286 piritramide Drugs 0.000 claims description 3
- IHEHEFLXQFOQJO-UHFFFAOYSA-N piritramide Chemical compound C1CC(C(=O)N)(N2CCCCC2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 IHEHEFLXQFOQJO-UHFFFAOYSA-N 0.000 claims description 3
- 229960004856 prazepam Drugs 0.000 claims description 3
- XJKQCILVUHXVIQ-UHFFFAOYSA-N properidine Chemical compound C=1C=CC=CC=1C1(C(=O)OC(C)C)CCN(C)CC1 XJKQCILVUHXVIQ-UHFFFAOYSA-N 0.000 claims description 3
- 229950004345 properidine Drugs 0.000 claims description 3
- JCRIVQIOJSSCQD-UHFFFAOYSA-N propylhexedrine Chemical compound CNC(C)CC1CCCCC1 JCRIVQIOJSSCQD-UHFFFAOYSA-N 0.000 claims description 3
- 229960000786 propylhexedrine Drugs 0.000 claims description 3
- 210000002307 prostate Anatomy 0.000 claims description 3
- 229960001964 quazepam Drugs 0.000 claims description 3
- 239000003488 releasing hormone Substances 0.000 claims description 3
- 229960002060 secobarbital Drugs 0.000 claims description 3
- KQPKPCNLIDLUMF-UHFFFAOYSA-N secobarbital Chemical compound CCCC(C)C1(CC=C)C(=O)NC(=O)NC1=O KQPKPCNLIDLUMF-UHFFFAOYSA-N 0.000 claims description 3
- 239000000932 sedative agent Substances 0.000 claims description 3
- 229940125723 sedative agent Drugs 0.000 claims description 3
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 claims description 3
- 229940035636 somatostatin and analogues Drugs 0.000 claims description 3
- 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 3
- 229960004739 sufentanil Drugs 0.000 claims description 3
- 229960003188 temazepam Drugs 0.000 claims description 3
- 229960003386 triazolam Drugs 0.000 claims description 3
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 claims description 3
- 229960003726 vasopressin Drugs 0.000 claims description 3
- 239000005019 zein Substances 0.000 claims description 3
- 229940093612 zein Drugs 0.000 claims description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 2
- 239000003263 anabolic agent Substances 0.000 claims description 2
- 229940070021 anabolic steroids Drugs 0.000 claims description 2
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 claims description 2
- 229960002327 chloral hydrate Drugs 0.000 claims description 2
- 229950008972 dioxaphetyl butyrate Drugs 0.000 claims description 2
- 229920006318 anionic polymer Polymers 0.000 claims 2
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims 2
- 125000003310 benzodiazepinyl group Chemical group N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims 2
- 150000001735 carboxylic acids Chemical group 0.000 claims 2
- 229920006317 cationic polymer Polymers 0.000 claims 2
- 239000000812 cholinergic antagonist Substances 0.000 claims 2
- XDDJGVMJFWAHJX-UHFFFAOYSA-N clorazepic acid Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(C(=O)O)N=C1C1=CC=CC=C1 XDDJGVMJFWAHJX-UHFFFAOYSA-N 0.000 claims 2
- MORSAEFGQPDBKM-UHFFFAOYSA-N ethylmethylthiambutene Chemical compound C=1C=CSC=1C(=CC(C)N(C)CC)C1=CC=CS1 MORSAEFGQPDBKM-UHFFFAOYSA-N 0.000 claims 2
- 229950006111 ethylmethylthiambutene Drugs 0.000 claims 2
- GODGZZGKTZQSAL-VXFFQEMOSA-N myrophine Chemical compound C([C@@H]1[C@@H]2C=C[C@@H]([C@@H]3OC4=C5[C@]23CCN1C)OC(=O)CCCCCCCCCCCCC)C5=CC=C4OCC1=CC=CC=C1 GODGZZGKTZQSAL-VXFFQEMOSA-N 0.000 claims 2
- 229950007471 myrophine Drugs 0.000 claims 2
- ZXWAUWBYASJEOE-UHFFFAOYSA-N proheptazine Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CCCN(C)CC1C ZXWAUWBYASJEOE-UHFFFAOYSA-N 0.000 claims 2
- 235000015112 vegetable and seed oil Nutrition 0.000 claims 2
- 239000008158 vegetable oil Substances 0.000 claims 2
- IGPROYLOGZTOAM-UHFFFAOYSA-N 3-phenylsulfanylpropanoic acid Chemical compound OC(=O)CCSC1=CC=CC=C1 IGPROYLOGZTOAM-UHFFFAOYSA-N 0.000 claims 1
- 241000237519 Bivalvia Species 0.000 claims 1
- 102000018997 Growth Hormone Human genes 0.000 claims 1
- 108010051696 Growth Hormone Proteins 0.000 claims 1
- 230000001195 anabolic effect Effects 0.000 claims 1
- 235000020639 clam Nutrition 0.000 claims 1
- 239000000122 growth hormone Substances 0.000 claims 1
- 210000000936 intestine Anatomy 0.000 claims 1
- 230000002475 laxative effect Effects 0.000 claims 1
- HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 claims 1
- 235000010980 cellulose Nutrition 0.000 description 28
- 239000000463 material Substances 0.000 description 28
- 229940079593 drug Drugs 0.000 description 25
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 23
- 239000003826 tablet Substances 0.000 description 23
- 239000004014 plasticizer Substances 0.000 description 21
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical group CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 19
- 229920003134 Eudragit® polymer Polymers 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 239000001856 Ethyl cellulose Substances 0.000 description 15
- 229920001249 ethyl cellulose Polymers 0.000 description 15
- 235000019325 ethyl cellulose Nutrition 0.000 description 15
- 239000003402 opiate agonist Substances 0.000 description 14
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 13
- 229920000058 polyacrylate Polymers 0.000 description 13
- 229920002301 cellulose acetate Polymers 0.000 description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 12
- 238000009472 formulation Methods 0.000 description 11
- 229920000178 Acrylic resin Polymers 0.000 description 10
- 239000004925 Acrylic resin Substances 0.000 description 10
- 239000006185 dispersion Substances 0.000 description 10
- 201000009032 substance abuse Diseases 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 230000002209 hydrophobic effect Effects 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 230000000144 pharmacologic effect Effects 0.000 description 8
- 229920001515 polyalkylene glycol Polymers 0.000 description 8
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 7
- 239000007931 coated granule Substances 0.000 description 7
- 229920003161 Eudragit® RS 30 D Polymers 0.000 description 6
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 6
- 206010047700 Vomiting Diseases 0.000 description 6
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 229920001600 hydrophobic polymer Polymers 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 5
- 229920003086 cellulose ether Polymers 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 229940126534 drug product Drugs 0.000 description 5
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 5
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 229920000747 poly(lactic acid) Polymers 0.000 description 5
- 239000008247 solid mixture Substances 0.000 description 5
- 239000001069 triethyl citrate Substances 0.000 description 5
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 5
- 235000013769 triethyl citrate Nutrition 0.000 description 5
- 206010015535 Euphoric mood Diseases 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 150000001557 benzodiazepines Chemical class 0.000 description 4
- 239000004359 castor oil Substances 0.000 description 4
- 235000019438 castor oil Nutrition 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 4
- 239000001087 glyceryl triacetate Substances 0.000 description 4
- 235000013773 glyceryl triacetate Nutrition 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 230000035699 permeability Effects 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 125000001453 quaternary ammonium group Chemical group 0.000 description 4
- 210000000813 small intestine Anatomy 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 229960002622 triacetin Drugs 0.000 description 4
- 239000001993 wax Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229920002284 Cellulose triacetate Polymers 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 3
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 3
- TYVWBCMQECJNSK-UHFFFAOYSA-N [2-methyl-3-(2-methylprop-2-enoyloxy)butan-2-yl]azanium;chloride Chemical compound [Cl-].CC([NH3+])(C)C(C)OC(=O)C(C)=C TYVWBCMQECJNSK-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 229920013820 alkyl cellulose Polymers 0.000 description 3
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 3
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000002743 euphoric effect Effects 0.000 description 3
- 229920001477 hydrophilic polymer Polymers 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 239000004922 lacquer Substances 0.000 description 3
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 3
- 125000005397 methacrylic acid ester group Chemical group 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000003887 narcotic antagonist Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- MUZQPDBAOYKNLO-RKXJKUSZSA-N oxycodone hydrochloride Chemical compound [H+].[Cl-].O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C MUZQPDBAOYKNLO-RKXJKUSZSA-N 0.000 description 3
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 3
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 3
- 239000004626 polylactic acid Substances 0.000 description 3
- 239000004926 polymethyl methacrylate Substances 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 230000011514 reflex Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 230000008673 vomiting Effects 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- VKNASXZDGZNEDA-UHFFFAOYSA-N 2-cyanoethyl 2-methylprop-2-enoate Chemical class CC(=C)C(=O)OCCC#N VKNASXZDGZNEDA-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 2
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- 229920008347 Cellulose acetate propionate Polymers 0.000 description 2
- DQEFEBPAPFSJLV-UHFFFAOYSA-N Cellulose propionate Chemical compound CCC(=O)OCC1OC(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C1OC1C(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C(COC(=O)CC)O1 DQEFEBPAPFSJLV-UHFFFAOYSA-N 0.000 description 2
- 208000019399 Colonic disease Diseases 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229920003149 Eudragit® E 100 Polymers 0.000 description 2
- 229920003157 Eudragit® RL 30 D Polymers 0.000 description 2
- 241001539473 Euphoria Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 229920002732 Polyanhydride Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 2
- 229920001710 Polyorthoester Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 159000000021 acetate salts Chemical class 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 229920006218 cellulose propionate Polymers 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 239000008199 coating composition Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 230000009429 distress Effects 0.000 description 2
- 206010013663 drug dependence Diseases 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 150000002169 ethanolamines Chemical class 0.000 description 2
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 150000004675 formic acid derivatives Chemical class 0.000 description 2
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000005395 methacrylic acid group Chemical group 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229940051877 other opioids in atc Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 2
- 229920002463 poly(p-dioxanone) polymer Polymers 0.000 description 2
- 229920002627 poly(phosphazenes) Polymers 0.000 description 2
- 229920002401 polyacrylamide Polymers 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 239000000622 polydioxanone Substances 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920000193 polymethacrylate Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 150000008054 sulfonate salts Chemical class 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 150000003892 tartrate salts Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- YQYVFVRQLZMJKJ-JBBXEZCESA-N (+)-cyclazocine Chemical compound C([C@@]1(C)C2=CC(O)=CC=C2C[C@@H]2[C@@H]1C)CN2CC1CC1 YQYVFVRQLZMJKJ-JBBXEZCESA-N 0.000 description 1
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- SWXOGPJRIDTIRL-DOUNNPEJSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s)-1-amino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pent Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 SWXOGPJRIDTIRL-DOUNNPEJSA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- WCOXQTXVACYMLM-UHFFFAOYSA-N 2,3-bis(12-hydroxyoctadecanoyloxy)propyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC(O)CCCCCC)COC(=O)CCCCCCCCCCC(O)CCCCCC WCOXQTXVACYMLM-UHFFFAOYSA-N 0.000 description 1
- SFPNZPQIIAJXGL-UHFFFAOYSA-N 2-ethoxyethyl 2-methylprop-2-enoate Chemical class CCOCCOC(=O)C(C)=C SFPNZPQIIAJXGL-UHFFFAOYSA-N 0.000 description 1
- DYUTXEVRMPFGTH-UHFFFAOYSA-N 4-(2,5-dimethylphenyl)-5-methyl-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C(=CC=C(C)C=2)C)=C1C DYUTXEVRMPFGTH-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Natural products CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QZCLKYGREBVARF-UHFFFAOYSA-N Acetyl tributyl citrate Chemical compound CCCCOC(=O)CC(C(=O)OCCCC)(OC(C)=O)CC(=O)OCCCC QZCLKYGREBVARF-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 244000284152 Carapichea ipecacuanha Species 0.000 description 1
- 229920001747 Cellulose diacetate Polymers 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 241000193163 Clostridioides difficile Species 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 229920003119 EUDRAGIT E PO Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229920003139 Eudragit® L 100 Polymers 0.000 description 1
- 229920003135 Eudragit® L 100-55 Polymers 0.000 description 1
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 1
- 229920003163 Eudragit® NE 30 D Polymers 0.000 description 1
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 1
- 229920003141 Eudragit® S 100 Polymers 0.000 description 1
- 206010017964 Gastrointestinal infection Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 239000009471 Ipecac Substances 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 229940127450 Opioid Agonists Drugs 0.000 description 1
- 208000026251 Opioid-Related disease Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- ZLGVJFWQQPUXQU-UHFFFAOYSA-N acetic acid;butanoic acid;octanoic acid Chemical compound CC(O)=O.CCCC(O)=O.CCCCCCCC(O)=O ZLGVJFWQQPUXQU-UHFFFAOYSA-N 0.000 description 1
- PPBFVJQAQFIZNS-UHFFFAOYSA-N acetic acid;ethylcarbamic acid Chemical compound CC(O)=O.CCNC(O)=O PPBFVJQAQFIZNS-UHFFFAOYSA-N 0.000 description 1
- OKTJLQBMTBEEJV-UHFFFAOYSA-N acetic acid;methylcarbamic acid Chemical compound CC(O)=O.CNC(O)=O OKTJLQBMTBEEJV-UHFFFAOYSA-N 0.000 description 1
- XBMIVRRWGCYBTQ-UHFFFAOYSA-N acetylmethadol Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(OC(C)=O)CC)C1=CC=CC=C1 XBMIVRRWGCYBTQ-UHFFFAOYSA-N 0.000 description 1
- 229950005506 acetylmethadol Drugs 0.000 description 1
- 125000005396 acrylic acid ester group Chemical group 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- SFNLWIKOKQVFPB-KZCPYJDTSA-N bunavail Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C.C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 SFNLWIKOKQVFPB-KZCPYJDTSA-N 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- XDDJGVMJFWAHJX-UHFFFAOYSA-M clorazepic acid anion Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(C(=O)[O-])N=C1C1=CC=CC=C1 XDDJGVMJFWAHJX-UHFFFAOYSA-M 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229950002213 cyclazocine Drugs 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940099371 diacetylated monoglycerides Drugs 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- LQGIXNQCOXNCRP-UHFFFAOYSA-N dioxaphetyl butyrate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)OCC)CCN1CCOCC1 LQGIXNQCOXNCRP-UHFFFAOYSA-N 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- WHYVWQHDUOALSV-UMJMSJQKSA-N ethyl (1s,2r)-2-(dimethylamino)-1-phenylcyclohex-3-ene-1-carboxylate;hydrate;dihydrochloride Chemical compound O.Cl.Cl.C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C.C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C WHYVWQHDUOALSV-UMJMSJQKSA-N 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- FSXVSUSRJXIJHB-UHFFFAOYSA-M ethyl prop-2-enoate;methyl 2-methylprop-2-enoate;trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium;chloride Chemical compound [Cl-].CCOC(=O)C=C.COC(=O)C(C)=C.CC(=C)C(=O)OCC[N+](C)(C)C FSXVSUSRJXIJHB-UHFFFAOYSA-M 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 230000006355 external stress Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 229960003528 flurazepam Drugs 0.000 description 1
- SAADBVWGJQAEFS-UHFFFAOYSA-N flurazepam Chemical compound N=1CC(=O)N(CCN(CC)CC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F SAADBVWGJQAEFS-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000007897 gelcap Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 125000005908 glyceryl ester group Chemical group 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229960002738 hydromorphone hydrochloride Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229940029408 ipecac Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007942 layered tablet Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 201000000988 opioid abuse Diseases 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- OQGYMIIFOSJQSF-DTOXXUQYSA-N pentazocine hcl Chemical compound Cl.C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 OQGYMIIFOSJQSF-DTOXXUQYSA-N 0.000 description 1
- 229960003809 pentazocine hydrochloride Drugs 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical class OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- GLLPUTYLZIKEGF-HAVVHWLPSA-N ridogrel Chemical compound C=1C=CC(C(F)(F)F)=CC=1C(=N/OCCCCC(=O)O)\C1=CC=CN=C1 GLLPUTYLZIKEGF-HAVVHWLPSA-N 0.000 description 1
- 229950006674 ridogrel Drugs 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229940014872 talwin nx Drugs 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
- 229960002730 vapreotide Drugs 0.000 description 1
- 108700029852 vapreotide Proteins 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
ORAL DOSAGE FORM COMPRISING A THERAPEUTIC AGENT AND AN ADVERSE-EFFECT AGENT Abstract This invention relates to an oral dosage form comprising a first composition and a 5 second composition. The first composition comprises an effective amount of a therapeutic agent and the second composition comprises an effective amount of an adverse-effect agent. The adverse-effect agent is covered with a coating that is substantially insoluble in the gastrointestinal tract. In one embodiment, the adverse-effect agent is coated with an outer base-soluble layer and an inner acid-soluble layer. The 10 therapeutic agent can be uncoated or can be coated with a coating having an outer acid-soluble layer and an inner base-soluble layer. The dosage form discourages administration of the therapeutic agent by other than oral administration.
Description
AUSTRALIA Patents Act 1990 Euro-Celtique S.A. ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Oral dosage form comprising a therapeutic agent and an adverse-effect agent The following statement is a full description of this invention, including the best method of performing it known to us: 1a This application is a divisional of Australian Patent Application No 2008202531, which is a divisional of Australian Patent Application No 2002326529, which is the Australian national phase application corresponding to PCT/US02/24889 which claims priority from US patent application Nos 60/309,791 and US 10/208,817, the entire 5 contents of which are hereby incorporated by cross-reference for all purposes. 1. FIELD OF THE INVENTION This invention relates generally to an oral dosage form comprising a therapeutic agent and an adverse-effect agent. 2. BACKGROUND OF THE INVENTION 10 Many therapeutic agents are highly effective for improving quality of life but, because of their abuse potential, may attract drug abusers. For example, opioids are excellent analgesic agents that can control sever and/or chronic pain, such as cancer pain and post-operative pain, but are also subject to abuse by drug users. Opioids, also known as opioid agonists, are a group of drugs that exhibit opium- or 15 morphine-like properties. Opioids are employed primarily as moderate to strong analgesic agents but provide other pharmacological effects as well. There have been previous attempts in the art to control the potential for abuse of opioid analgesics. For example, sustained release forms enable an active ingredient to work over many hours, and such slow release tends to deter illicit use of opioids because 20 abusers tend to prefer the quick euphoric rush, also known as the 'burst', provided by immediate release opioids. Drug abusers, however, can defeat the controlled release design by crushing or dissolving the original drug form, for example a tablet, giving them access to snortable and/or injectable opioids that provide the burst. Accordingly, there is an important need for more effective methods'of deterring opioid abuse while still 25 keeping orally administered opioids available to patients who have a legitimate need for them. Prior art approaches to this problem have involved combining an opioid with an opioid antagonist. When administered orally, these combinations provide the pharmacologic action of the opioid with minimal action of the antagonist. When 30 administered parenterally, however, the antagonist can be profoundly antagonistic to the 2 opioid. Particular examples of such combinations include compositions comprising naloxone and morphine or oxymorphone (U.S Patent No. 3,493,657 to Lewenstein et al); methadone and naloxone (U.S. Patent No. 3,773,955 to Pachter et al.); methadol or acetyl methadol and naloxone (U.S. Patent No. 3,966,940 to Pachter et al.); oxycodone and 5 naloxone (U.S. Patent No. 4,457,933 to Gordon et al.); and buprenorphine and naloxone (U.S. Patent No. 4,582,835 to Lewis et al.). Also, the combination of pentazocine hydrochloride and naloxone has been marketed in the United States as TALWIN NX (Sanofi-Winthrop); VALORON N, a combination of tilidine and naloxone, has been available in Germany for the management of severe pain since 1978; and TEMGESIC 10 NX, a combination of buprenophine and naloxone, has been available in New Zealand since 1991. U.S. Patent No. 6,228,863 to Palmero et al. discloses an oral dosage form of an opioid agonist and an opioid antagonist that reduces the abuse potential of the opioid by combining the agonist and antagonist such that at least two steps are required to separate 15 them. U.S. Patent No. 5m935m975 to Rose et al. discloses a method for treating drug dependency by the combined administration of the drug or an agonist of the drug and an antagonist of the drug. There remains, however, a clear need in the art for more advanced oral dosage 20 forms that are effective for preventing abuse and useful for delivering a therapeutic agent. Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or 25 steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these 30 matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this specification. - 2a 3. SUMMARY OF THE INVENTION The present invention relates to an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises a therapeutic agent and the second composition comprises an adverse-effect agent, wherein the second 5 composition is coated with an inner acid-soluble layer and an outer base-soluble layer, and wherein the dosage form does not release any adverse-effect agent when taken as directed. The invention further relates to an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises a therapeutic agent 10 and is coated with an inner base-soluble layer and an outer acid-soluble layer and the second composition comprises an adverse-effect agent and is coated with an inner acid-soluble layer and an outer base-soluble layer. The invention further relates to a method for treating or preventing pain, comprising administering to a patient in need thereof the oral dosage form of the 15 invention. In one embodiment the method comprises administering to a patient in need thereof an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises an effective amount of a therapeutic agent; the second composition 20 comprises an effective amount of an adverse-effect agent; an effective amount of the therapeutic agent is released in the patient's small intestine; and less than an effective amount of the adverse-effect agent is released in the patient's gastrointestinal tract. The invention still further relates to a method for preparing an oral dosage 5 form comprising a first composition and a second composition, wherein the first composition comprises a therapeutic agent and the second composition comprises an adverse-effect agent, wherein the second composition is coated with an inner acid-soluble layer and an outer base-soluble layer, the method comprising the step of preparing the oral dosage form as set forth herein. 10 The invention still further relates to a method for preparing an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises a therapeutic agent and is coated with an inner base-soluble layer and an outer acid-soluble layer and the second composition comprises an adverse-effect agent and is coated with an inner acid-soluble layer and an outer base-soluble layer, the 15 method comprising the step of preparing the oral dosage form as set forth herein. 4. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows a cross-sectional view of a coated granule of a first composition useful in the oral dosage forms of the invention. 20 Fig. 2 shows a cross-sectional view of a coated granule of a second composition useful in the oral dosage forms of the invention. Fig. 3 shows a cross-sectional view of a first embodiment of the invention, which is a capsule containing coated granules of a first composition and coated granules of a second composition. 25 Fig. 4 shows a cross-sectional view of a second embodiment of the invention, which is a two-layer tablet. Fig. 5 shows a cross-sectional view of a third embodiment of the invention, which is a tablet containing coated granules of a first composition and coated granules of a second composition. 30 Fig. 6 shows a cross-sectional view of a fourth embodiment of the invention, which is a coated tablet containing a first composition, with granules of a coated second composition dispersed throughout the first composition. Fig. 7 shows a cross-sectional view of a fifth embodiment of the invention, which is a tablet wherein a coated composition of the adverse-effect agent is further coated 35 with the therapeutic agent and then the therapeutic agent is coated. -3- 5. DETAILED DESCRIPTION OF THE INVENTION The oral dosage form of the present invention comprises a first composition and a second composition. The first composition comprises a therapeutic agent, and the second composition comprises an adverse-effect agent. 5 The term "therapeutic agent," as used herein, means any drug intended to have a beneficial effect when administered to a patient. The term "adverse-effect agent," as used herein, means an agent that (A) reduces or eliminates one or more pharmacological effects of the therapeutic agent, such as a euphoric or toxic effect or (B) causes an undesired physiological reaction, such as emesis. 10 In a first embodiment of the oral dosage form of the invention, the second composition is coated with a layer that is substantially insoluble in the gastrointestinal tract. Thus, when the oral dosage form of the present invention is orally administered to a patient as intended, only the therapeutic agent is released in the gastrointestinal tract of the patient, and the adverse-effect agent is not released. If the oral dosage form is tampered with so that 15 the coating on the second composition is damaged, however, then not only the therapeutic agent but also the adverse-effect agent are released upon administration. In a second embodiment the second composition is coated with an outer base-soluble layer and an inner acid-soluble layer, which is not dissolved when orally administered to a patient. 20 In a third embodiment of the oral dosage form of the invention, both the first composition and second composition have a coating comprising at least two layers, an acid soluble layer and a base-soluble layer, but the order of the layers in the coating on the first composition is different from that of the layers in the coating on the second composition. The coating covering the first composition comprises an outer acid-soluble layer and an 25 inner base-soluble layer, which are dissolved when orally administered to a patient. On the other hand, the coating covering the second composition comprises an outer base-soluble layer, which gets dissolved when orally administered, and an inner acid-soluble layer, which does not get dissolved when orally administered to a patient. When orally administered to a patient, the oral dosage form passes through 30 the stomach first, where its acidic environment dissolves the first composition's outer acid soluble layer, and then passes into the small intestine, where its basic environment dissolves the first composition's inner base-soluble layer. Here, the therapeutic agent can be absorbed by the body. In contrast, the second composition is coated with an outer base-soluble layer, which is substantially insoluble in the stomach's acidic environment. Therefore, the second 35 composition passes through the stomach with both the outer base-soluble layer and the inner -4acid-soluble layer intact. When the second composition enters the small intestine, the outer base-soluble layer dissolves, exposing the inner acid-soluble layer, which is substantially insoluble in the small intestine's basic environment, so that the adverse-effect agent cannot be absorbed by the body. Thus, when the oral dosage form of the present invention is orally 5 administered to a patient, for example a human, as intended, only the therapeutic agent is released in the gastrointestinal tract and absorbed by the patient; the adverse-effect agent is not released and, therefore, not available for absorption into the body. Here, the therapeutic agent works as if it were administered alone without the adverse-effect agent, since only the therapeutic agent is available for absorption by the body. 10 However, if the oral dosage form of the present invention is tampered with, e.g., chewed, crushed, ground or dissolved, particularly in a solvent with heat (e.g., greater than about 45"C to about 50*C), then not only the therapeutic agent but also the adverse effect agent becomes available for absorption into the body. The adverse-effect agent can then exert its effect by either reducing the effect of the therapeutic agent or eliciting an 15 unpleasant effect in the patient. Thus, where the adverse-effect agent is an antagonist of the therapeutic agent, the effects of the therapeutic agent are drastically diminished or even eliminated by the effects of the adverse-effect agent. For example, where the therapeutic agent is an opioid agonist and the adverse-effect agent is an opioid antagonist, and the oral dosage form is tampered with, the opioid antagonist becomes bioavailable, interfering with 20 opioid-receptor binding and reducing the opioid antagonist's pharmacological effects. Accordingly, only patients who take the dosage form of the present invention as intended, i.e, orally as an intact dosage form, can experience the full pharmacological effects of the therapeutic agent. Where the adverse-effect agent is an emetic agent and the oral dosage form is tampered with, the emetic agent induces vomiting which discourages the user from 25 tampering with the dosage form. Moreover, where the adverse-effect agent causes vomiting the oral dosage form of the invention not only discourages users from tampering with it, but can also be effective to remove the therapeutic agent from subject's body. Abusing the therapeutic agent becomes less desirable when present in the oral dosage form of the present invention because, when tampered with, the adverse-effect agent exerts its undesirable 30 effects. In one embodiment of the present invention, the first composition is intended to be released slowly after it is orally administered to the subject. This prevents the burst, which some abusers seek. The first composition can be formulated as a slow release formulation, for example, by further coating the first composition with a sustained-release 35 coating that slowly dissolves so that all the therapeutic agent is not released at once. In the -5embodiments where the first composition is coated with an outer acid-soluble layer and an inner base-soluble layer, the sustained-release coating is an innermost layer. In another embodiment the first composition can be formulated as a slow release formulation by incorporating the therapeutic agent into a matrix that slowly releases the therapeutic agent 5 over time. Therapeutic agents intended to be released slowly, when orally administered to a subject, may have side effects if released all at once, rather than slowly. The coated second composition prevents tampering, which would result in immediate release of the therapeutic agent. Fig. 1 shows a cross-sectional view of an embodiment of the coated first 10 composition 10. A first composition 14 is covered with an innermost sustained-release coating 13 (optional), an inner base-soluble layer 12, and an outer acid-soluble layer 11. Fig. 2 shows a cross-sectional view of an embodiment of the coated second composition 20. A second composition 24 is covered with an inner acid-soluble layer 23, an outer base-soluble layer 22 and an outermost layer that is substantially insoluble in the 15 gastrointestinal tract 21 (optional). 5.1 THERAPEUTIC AGENT Any kind of therapeutic agent can be used in the oral dosage forms of the present invention. In one embodiment the oral dosage from is used in situations where there 20 is a potential toxicity or overdose associated with the uncontrolled release of the drug due to tampering with the dosage form. Examples of useful therapeutic agents include, but are not limited to, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, 25 anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile-dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, p-blockers, cardiac ionotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, 30 cox-2-inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, and non-essential fatty acids. The first composition can comprise more than one therapeutic 35 agent. -6- The phrase "therapeutic agent" is also meant to encompass all pharmaceutically acceptable salts of the therapeutic agent. Pharmaceutically acceptable salts include, but are not limited to, metal salts, such as sodium salts, potassium salts, and lithium salts; alkaline earth metals, such as calcium salts, magnesium salts, and the like; 5 organic amine salts, such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, and the like; inorganic acid salts such as hydrochloride salts, hydrobromide salts, sulfate salts, phosphate salts, and the like; organic acid salts such as formate salts, acetate salts, trifluoroacetate salts, maleate salts, tartrate salts, and the like; sulfonate salts such as 10 methanesulfonate salts, benzenesulfonate salts, p-toluenesulfonate salts, and the like; and amino acid salts, such as arginate salts, asparginate salts, glutamate salts, and the like. In another embodiment the therapeutic agent has potential for abuse. The abuse potential of a drug is established by many factors, which may include the following: (1) the capacity of the drug to produce the kind of physical dependence in which drug 15 withdrawal causes sufficient distress to bring about drug-seeking behavior; (2) the ability to suppress withdrawal symptoms caused by withdrawal from the drug; and (3) the degree to which the drug induces euphoria similar to that produced by morphine and other opioids. The term "a therapeutic agent having abuse potential," as used herein, refers to a therapeutic agent having at least one of the above-identified factors. Examples of 20 therapeutic agents having abuse potential include, but are not limited to, opioids, benzodiazepines, barbiturates, and stimulants, such as methylphenidate and amphetamines. The term "opioid" refers to a substance that binds, optionally stereo specifically, to any of several subspecies of opioid receptors and produces an agonist action. Opioids include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, 25 benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmcthylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone, hydromorphone, 30 hydromorphodone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine-, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, PANTOPON, papaveretum, paregoric, pentazocine, phenadoxone, phendimetrazine, 35 phendimetrazone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, -7propheptazine, promedol, properidine, propoxyphene, propylhexedrine, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof. In certain embodiments, the opioid agonist is selected from the group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, 5 meperidine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives thereof, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol, levorphanol, pharmaceutically acceptable salts thereof, and mixtures thereof In one embodiment the opioid agonist is oxycodone or hydrocodone. The term "benzodiazepines" refers to drugs that are derivatives of 10 benzodiazepine and are able to depress the central nervous system. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxied, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate, pharmaceutically acceptable salts thereof, and mixture thereof. 15 Barbiturates refer to sedative-hypnotic drugs derived from barbituric acid (2, 4, 6,-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, pharmaceutically acceptable salts thereof, and mixtures thereof. 20 Stimulants refer to drugs that stimulate the central nervous system. Stimulants include, but are not limited to, amphetamines, such as amphetamine, amphetamine, dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, pharmaceutically acceptable salts thereof and mixtures thereof. Other examples of therapeutic agent having potential for abuse include, but 25 are not limited to, dronabinol, glutethimide, methylphenidate, nabilone, anabolic steroids, methylprylon, ethchlorovynol, ethinamate, fenfluramine, meprobamate, pemoline, levomethadyl, benzphetamine, chlorphentermine, diethylpropion, phentermine, mebutamate, chlortermine, phenylacetone, dronabinol, nabilone, benphetamine, chloral hydrate, ethclorovynol, paraldehyde, midazolam, and detropropoxyphene. 30 The therapeutic agent may also be an agent intended for delivery to the colon. Therapeutic agents intended for delivery to the colon include, but are not limited to, agents that act locally in the colonic region to treat a colon diseases such as irritable bowel syndrome, irritable bowel disease, Crohns disease, constipation, post operative atony, gastrointestinal infections, and therapeutic agents that deliver antigenic material to the 35 lymphoid tissue. Agents for the treatment of colon disease, include, but are not limited to 5-ASA; steroids, such as hydrocortisone and budesonide; laxatives; octreotide; cisapride; -8anticholinergics; opioids; calcium channel blockers; DNA for delivery to the cells of the colon; glucosamine; thromboxane A 2 synthetase inhibitors, such as Ridogrel; 5HT3-antagonists, such as ondansetron; antibodies against infectious bacteria, such as Clostridium difficile; and antiviral agents, for example, for the prophylaxis of HIV. 5 Alternatively, the therapeutic agent can be an agent that is systemically active and for which absorption is improved in the colon region. Such drugs include polar compounds such as: heparins; insulin; calcitonins; human growth hormone (HGH); growth hormone releasing hormone (GHRH); interferons; somatostatin and analogues such as octreotide and vapreotide; erythropoietin (EPO); granulocyte colony stimulating factor 10 (GCSF); parathyroid hormone (PTH); luteinising hormone releasing hormone (LHRH) and analogues thereof; atrial natriuretic factor (ANF); vasopressin; desmopressin; calcitonin gene related peptide (CGRP); and analgesics. 5.2 ADVERSE-EFFECT AGENT 15 The adverse-effect agent can be an agent that reduces or eliminates the therapeutic agent's pharmacological activities including, but not limited to: (1) the capacity of the drug to produce the kind of physical dependence in which drug withdrawal causes sufficient distress to bring about drug-seeking behavior; (2) the ability to suppress withdrawal symptoms caused by withdrawal from the drug; and (3) the induction of 20 euphoria similar to that produced by morphine and other opioids. Adverse-effect agents that reduce or eliminate the pharmacological effects of the therapeutic agent include, but are not limited to, antagonists of the therapeutic agent agonist. When an opioid agonist is used as the therapeutic agent in the oral dosage form of the present invention, an opioid antagonist can be used as the adverse-effect agent. Likewise, when a benzodiazepine is 25 used as the therapeutic agent in the oral dosage form of the present invention, a benzodiazepine antagonist can be used as the adverse-effect agent. When a barbiturate is used as a therapeutic agent in the oral dosage form of the present invention, a barbiturate antagonist can be used as the adverse-effect agent. When an amphetamine is used as a therapeutic agent in the oral dosage form of the present invention, an amphetamine 30 antagonist can be used as the adverse-effect agent. When the therapeutic agent is toxic when dosed above its normal therapeutic range, i.e., there is a potential for an overdose, then an antidote of the toxic therapeutic agent can be used as the adverse-effect agent. The phrase "adverse-effect agent" is also meant to encompass all pharmaceutically acceptable salts of the adverse-effect agent. Pharmaceutically acceptable 35 salts include, but are not limited to, metal salts, such as sodium salts, potassium salts, and lithium salts; alkaline earth metals, such as calcium salts, magnesium salts, and the like; -9organic amine salts, such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, and the like; inorganic acid salts such as hydrochloride salts, hydrobromide salts, sulfate salts, phosphate salts, and the like; organic acid salts such as formate salts, acetate salts, 5 trifluoroacetate salts, maleate salts, tartrate salts, and the like; sulfonate salts such as methanesulfonate salts, benzenesulfonate salts, p-toluenesulfonate salts, and the like; and amino acid salts, such as arginate salts, asparginate salts, glutamate salts, and the like. Opioid antagonists that can be used as the adverse-effect agent of the present invention include, but are not limited to, naloxone, naltrexone, nalmefene, cyclazacine, 10 levallorphan, and mixtures thereof. In certain embodiments, the opioid antagonist is naloxone or naltrexone. Benzodiazepine antagonists that can be used as the adverse-effect agent of the present invention include, but are not limited to, flumazenil. Barbiturate antagonist which can be used as the adverse-effect agent of the 15 present invention include, but are not limited to, amphetamines, described herein. Stimulant antagonists that can be used as the adverse-effect agent of the present invention include, but are not limited to, benzodiazepines, described herein. In another embodiment of the present invention, the adverse-effect agent is an agent that causes an undesired physiological reaction, such as emesis. This type of 20 adverse-effect agent can be used with any kind of therapeutic agent including an opioid, a benzodiazepine, a barbiturate, and a stimulant. Examples of emetic agents suitable for use as the adverse-effect agent in the present invention includes any drug that safely and effectively induces vomiting after administration including, but not limited to, ipecac and apomorphine. 25 5.4 COATINGS 5.4.1. COATINGS INSOLUBLE IN THE GASTROINTESTINAL TRACT Examples of useful coatings that are substantially insoluble in the gastrointestinal tract include, but are not limited to, coatings comprising a hydrophobic 30 material. In one embodiment the coating that is substantially insoluble in the gastrointestinal tract comprises a cellulose polymer. In certain embodiments, the cellulose polymer is a cellulose ether, a cellulose ester, or a cellulose ester ether. In one embodiment, the cellulose polymers have a degree of substitution, D.S., on the anhydroglucose unit of from zero up to and including 3. By "degree of substitution" is meant the average number 35 of hydroxyl groups present on the anhydroglucose unit of the cellulose polymer that are replaced by a substituting group. Representative cellulose polymers include, but are not -10limited to, polymers selected from cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono, di, and tricellulose alkanylates, mono, di, and tricellulose aroylates, and mono, di, and tricellulose alkenylates. Exemplary cellulose polymers include cellulose acetate having an acetyl content up to about 5 21%; cellulose acetate having an acetyl content up to about 32 to 39.8%; cellulose acetate having a D.S. of about 1 to 2 and an acetyl content of about 21 to 35%; and cellulose acetate having a D.S. of about 2 to 3 and an acetyl content of about 35 to 44.8%. In one embodiment, the cellulose polymer is ethylcellulose, cellulose acetate, cellulose propionate (low, medium, or high molecular weight), cellulose acetate propionate, cellulose acetate 10 butyrate, cellulose acetate phthalate, or cellulose triacetate. In one embodiment, the ethylcellulose has an ethoxy content of about 44 to 55%. More specific cellulose polymers include cellulose propionate having a D.S. of about 1.8 and a propyl content of about 39.2 to 45% and a hydroxyl content of about 2.8 to 5.4%; cellulose acetate butyrate having a D.S. of about 1.8, an acetyl content of about 13 15 to 15%, and a butyryl content of about 34 to 39%; cellulose acetate butyrate having an acetyl content of about 2 to 29%, a butyryl content of about 17 to 53%, and a hydroxyl content of about 0.5 to 4.7%; cellulose triacylate having a D.S. of about 2.9 to 3 such as cellulose triacetate, cellulose trivalerate, cellulose trilaurate, cellulose tripatmitate, cellulose trisuccinate, and cellulose trioctanoate; cellulose diacylates having a D.S. of about 2.2 to 2.6 20 such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipentanoate, and coesters of cellulose such as cellulose acetate butyrate, cellulose acetate octanoate butyrate, and cellulose acetate propionate. Additional cellulose polymers useful for coating the second composition with a coating that is substantially insoluble in the gastrointestinal tract include, but are not 25 limited to, acetaldehyde dimethyl cellulose acetate, cellulose acetate ethylcarbamate, cellulose acetate methylcarbamate, and cellulose acetate dirnethylaminocellulose acetate. Acrylic polymers are also useful for coating the second composition with a coating that is substantially insoluble in the gastrointestinal tract. Acrylic polymers include, but are not limited to, acrylic resins comprising copolymers synthesized from acrylic and 30 methacrylic acid esters (e.g., the copolymer of acrylic acid lower alkyl ester and methacrylic acid lower alkyl ester) containing about 0.02 to 0.03 moles of a tri (lower alkyl) ammonium group per mole of acrylic and methacrylic monomer. In one embodiment, the acrylic resin is Eudragit RS 30 D manufactured by R6hm Tech Inc. of Fitchburg, MA. Eudragit RS 30 D is a water insoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM) and 35 trimethylammonioethyl methacrylate chloride (TAM) in which the molar ratio of TAM to - 11 the remaining components (EA and MM) is 1:40. Aqueous suspensions of acrylic resins such as EUDRAGIT RS can be used to coat the adverse-effect agent of the invention. In certain embodiments of the invention, the acrylic polymer is selected from acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl 5 methacrylates, cyanoethyl methacrylates, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymers, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. When a cellulose polymer or an acrylic polymer is used as a coating that is 10 substantially insoluble in the gastrointestinal tract, suitable plasticizers, e.g., acetyl triethyl citrate and/or acetyl tributyl citrate, may also be admixed with the polymer. The coating that is substantially insoluble in the gastrointestinal tract may also contain additives such as coloring agents, talc, and/or magnesium stearate, which are well known in the coating art. Polymers useful for coating the second composition with a coating that is 15 substantially insoluble in the gastrointestinal tract also include, but not limited to, poly(lactic/glycolic acid) ("PLGA") copolymers, polylactides, polyglycolides, polyanhydrides, polyorthoesters, polycaprolactones, polyphosphazenes, polysaccharides, proteinaceous polymers, polyesters, polydioxanone, polygluconate, polylactic-acid polyethylene oxide copolymers, poly(hydroxybutyrate), polyphosphoesters, and mixtures 20 thereof. In certain embodiments, the polymer comprises a poly(lactic/glycolic acid) copolymer, a copolymer of lactic and glycolic acid, having a molecular weight of about 2,000 to about 500,000 daltons. The ratio of lactic acid to glycolic acid is from about 100:0 to about 25:75, in one embodiment from about 65:35. Poly(lactic/glycolic acid) may be 25 prepared by the procedure set forth in U.S. Patent No. 4,293,539 to Ludwig et al., the disclosure of which is expressly incorporated herein by reference thereto. The coating that is substantially insoluble in the gastrointestinal tract is of sufficient thickness to prevent release of the adverse-effect agent from the second composition while it is in the gastrointestinal tract. Many of the coatings that are 30 substantially insoluble in the gastrointestinal tract are slowly biodegraded or dissolved in an aqueous environment and, after sufficient time, will eventually release the adverse-effect agent. Accordingly, the coating should be of a sufficient thickness that does not permit the adverse effect agent to be released during the time that the adverse-effect agent is present in the gastrointestinal tract. The thickness of the coating will depend on the characteristics of 35 the coating composition being used. -12- 5.4.2 ACID-SOLUBLE LAYER In various embodiments, the coating useful in the present invention comprises an acid-soluble layer. The term "acid-soluble layer" refers to a layer that is substantially soluble at a pH of less than about pH 5.0, but substantially insoluble at a pH of 5 greater than about pH 5.5. In one embodiment, the acid-soluble layer is substantially soluble at a pH of less than about pH 4.0, but substantially insoluble at a pH of greater than about pH 4.5. In another embodiment, the acid-soluble layer is substantially soluble at a pH of less than about pH 3.0, but substantially insoluble at a pH of greater than about pH 3.5. The acid-soluble layer typically comprises an acid-soluble polymer. 10 As used herein, the phrase "substantially soluble," when used to describe a layer, means soluble to a degree that a portion of that which the layer covers, for example, an acid-soluble layer, a base-soluble layer, a first composition, or a second composition, is made available to the environment of the gastrointestinal tract in an effective amount. As used herein, the phrase "substantially insoluble," when used to describe a 15 layer, means that the layer does not dissolve or does so only to a degree that a portion of that which the layer covers, for example, an acid-soluble layer, a base-soluble layer, a first composition, or a second composition, is not made available to the environment of the gastrointestinal tract or is made available to the environment of the gastrointestinal tract in less than an effective amount. 20 In one embodiment, the acid-soluble polymer has a dimethylaminoethyl ammonium functionality. Such a polymer is commercially available as EUDRAGIT E 100 or Eudragit E PO from Rohm Pharma GmbH, Weiterstat, Germany. Examples of other suitable acid-soluble polymers can be found in "Materials Used in Pharmaceutical Formulations," edited by A.T. Florence, Society of Chemical Industries, 1984. 25 5.4.3 BASE-SOLUBLE LAYER In various embodiments, the coating of the present invention comprises a base-soluble layer. The term "base-soluble layer" refers to a layer that is substantially soluble at a pH of greater than about pH 5.5, but substantially insoluble at a pH of less than 30 about 5.0. In one embodiment, the base-soluble layer is substantially soluble at a pH of greater than about pH 6.5, but substantially insoluble at a pH of less than about 6.0. In another embodiment, the base-soluble layer is substantially soluble at a pH of greater than about pH 7.5, but substantially insoluble at a pH of less than about 7.0. The base-soluble layer generally comprises a base-soluble polymer. In one embodiment, the base-soluble 35 polymer is an anionic copolymer of methacrylic acid and methacrylates having carboxylic -13acid functionalities. Such a polymer is commercially available as EUDRAGIT L 100-55, EUDRAGIT L 30D-55, EUDRAGIT L, or EUDRAGIT S 100 (commercially available from Rohm Pharma GmbH, Weiterstat, Germany). Examples of other suitable base-soluble polymers can be found in "Materials Used in Pharmaceutical Formulations," edited by A.T. 5 Florence, Society of Chemical Industries, 1984. 5.4.4 SLOW-RELEASE FORMULATIONS In one embodiment, the therapeutic agent is released slowly over time. Suitable controlled-release formulations known to those of ordinary skill in the art, 10 including those described herein, can be readily selected for use with the oral dosage forms of the invention. Single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, caplets, and the like, that are adapted for controlled-release are encompassed by the present invention. The controlled release of the therapeutic agent from the first composition can 15 be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The controlled release of the therapeutic agent can be achieved, for example by coating or admixing the therapeutic agent with a controlled release component. The term "controlled-release component" in the context of the present invention is defined herein as a compound or mixture of compounds, including polymers, 20 polymer matrices, gels, permeable membranes, liposomes, microspheres, or the like, or a combination thereof, that facilitates the controlled-release of the therapeutic agent from the first composition of the oral dosage form of the invention. As discussed above, in one embodiment of the invention the therapeutic agent is formulated for controlled release by coating the therapeutic agent with a sustained 25 release coating. The term "sustained-release coating" refers to a coating made of one or more materials that allows for the slow release of the drug over time. In one embodiment, the sustained-release coating is a pH-independent layer, i.e., a coating that has a defined permeability that is not influenced by pH. The term "pH-independent layer" means that the difference, at any given time, between the amount of drug released at, e.g., pH 1.6, and the 30 amount released at any other pH, e.g., pH 7.2, when measured using a specific method, such as, for example, the USP Paddle Method at 100 rpm in 900 ml aqueous buffer, is 10% (by weight) or less. Any sustained-release coating known to those of ordinary skill in the art can be used in the oral dosage form of the invention. Sustained-release coatings are well known 35 in the art (See, e.g., Remingtons Pharmaceutical Sciences, 18' ed. Mack Publishing Co., Easton, PA, 1990, p. 1670). Typically, the sustained-release coating comprises a water -14insoluble material, such as a wax or a wax-like substance, fatty alcohol, shellac, zein, hydrogenated vegetable oil, water insoluble cellulose, polymer of acrylic and/or methacrylic acid, or any other slowly digestible or dissolvable solid known in the art. The coating formulations useful in the present invention should be capable of producing a strong, 5 continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free. Generally, the film coat is applied to the first composition, for example when in the form of a tablet or a granule, to achieve a weight gain level from about 2 to about 25 percent. However, the film coat may be lesser or greater depending upon the physical properties of the therapeutic agent included in the formulation 10 and the desired release rate. In one embodiment, the sustained-release coating comprises a hydrophobic polymer. In another embodiment, the hydrophobic polymer comprises a water-insoluble cellulosic polymer, such as an alkylcellulose, for example ethylcellulose; an acrylic polymer; or mixtures thereof. 15 In another embodiment, the sustained-release coating comprises an acrylic polymer. Any acrylic polymer that is pharmaceutically acceptable can be used. For example, the acrylic polymer can be an acrylate or methacrylate, formed from one or more of acrylic acid, methacrylic acid, acrylic acid esters, and methacrylic acid esters. These polymers can be cationic, anionic, or non-ionic, so that it is possible to obtain polymers that 20 are soluble in, or resistant to dissolution, over a wide range of pH values. Some acrylic polymers useful for the purposes of the present invention are those that are marketed under the trade name EUDRAGIT (commercially available from Rohm Pharma GmbH, Weiterstat, Germany). Examples of suitable acrylic polymers include, but are not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate polymers, methyl 25 methacrylate copolymers, ethoxyethyl methacrylates polymers, cyanoethyl methacrylate polymers, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymers, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. 30 The acrylic polymer can comprise one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. In order to obtain a desirable dissolution profile for a given therapeutic agent, it might be necessary to incorporate two or more anmonio methacrylate 35 copolymers having differing physical properties. For example, it is known that by changing the molar ratio of the quaternary ammonium groups to neutral (meth)acrylic esters, the - 15permeability properties of the resultant coating can be modified. One of ordinary skill in the art will readily know how to combine monomers to provide a copolymer that releases the therapeutic agent at the desired release rate. Copolymers of acrylate and methacrylate having a quaternary ammonium group functionality are commercially available as 5 EUDRAGIT RS and EUDRAGIT RL from Rohm Pharma GmbH, Weiterstat, Germany. Other polymers suitable for use in the invention include, but are not limited to, hydroxyalkylcelluloses; poly(lactic/glycolic acid) ("PLGA"); polylactide; polyglycolide; polyanhydrides; polyorthoesters; polycaprolactone; polyphosphazenes; polysaccharides; proteinaceous polymers; polyesters; polydioxanone; polygluconate; polylactic-acid 10 polyethylene oxide copolymers; poly(hydroxybutyrate) polyphosphoesters; or mixtures thereof. The inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic polymer can further improve the physical properties of the film. For example, because ethylcellulose has a relatively high glass-transition temperature 15 ("Tg") and does not form flexible films under normal coating conditions, it is often necessary to plasticize the ethylcellulose before using it as a coating material. The suitability of a plasticizer may relate to its affinity or solvating power for the polymer and its effectiveness for interfering with polymer-polymer attachments. Such activity imparts a desired flexibility to the polymer by relieving molecular rigidity. An 20 important parameter in determining the suitability of a plasticizer for a polymer is related to the Tg of the polymer. The Tg is related to the temperature or temperature range where there is a fundamental change in the physical properties of the polymer. This change does not reflect a change in state, but rather a change in the macromolecular mobility of the polymer. Below the Tg, polymer chain mobility is severely restricted. Thus, for a given polymer, if 25 the Tg is above room temperature, the polymer will behave as a glass at room temperature, being hard, non-pliable, and rather brittle: properties that are restrictive for a film coating since the coated dosage form may be subjected to a certain amount of external stress. Incorporation of suitable plasticizers into the polymer matrix effectively reduces the Tg, so that under ambient conditions the films are softer, more pliable and often stronger, and, 30 thus, better able to resist mechanical stress. Other aspects of suitable plasticizers include their ability to act as a good "swelling agent," especially for ethylcellulose, and to improve the solubility profile of the coating in water. Examples of suitable plasticizers for ethylcellulose include dibutyl sebacate, diethyl phthalate, triethyl citrate, and tributyl citrate, although other plasticizers (such as 35 acetylated monoglycerides, phthalate esters and castor oil) can be used. In one embodiment, triethyl citrate is a plasticizer for the aqueous dispersions of ethyl cellulose. - 16 - Examples of suitable plasticizers for the acrylic polymers useful in the present invention include, but are not limited to, citric acid esters such as triethyl citrate, tributyl citrate, dibutyl phthalate, and 1,2-propylene glycol. Other plasticizers suitable for enhancing the elasticity of the films formed from acrylic films, such as EUDRAGIT RIJRS 5 lacquer solutions, include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin. The plasticizer is typically added to a solution of the polymer in an aqueous or non-aqueous solvent that is used to coat the first composition. Generally, the amount of plasticizer included in a coating solution is based on the concentration of the coating. In one embodiment, the amount of plasticizer included 10 in a coating solution of ethylcellulose is from about 1 to about 50 percent by weight of the ethylcellulose. In another embodiment, the amount of plasticizer included in a coating solution of an aqueous dispersion of acrylic polymer is about 20%. The necessary concentration of the plasticizer for a particular coating solution and method of application can be readily determined by one of ordinary skill in the art without undue experimentation. 15 A commercially available aqueous dispersion of ethylcellulose suitable for use in the invention is AQUACOAT (commercially available from FMC Corp., Philadelphia, Pa., U.S.A.). AQUACOAT is prepared by dissolving ethylcellulose in a water-immiscible organic solvent and then emulsifying the organic solvent in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron 20 droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. Plasticizer is not incorporated in the pseudolatex during the manufacturing phase; therefore, prior to using the pseudolatex as a coating, it is necessary to intimately mix the AQUACOAT with a suitable plasticizer. Another commercially available aqueous dispersion of ethylcellulose suitable 25 for use in the invention is SURELEASE (commercially available from Colorcon, Inc., West Point, Pa., U.S.A.). In one embodiment, the acrylic coating comprises an acrylic resin lacquer used in the form of an aqueous dispersion, such as EUDRAGIT. In further embodiments, the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available 30 from Rohm Pharma GmbH, Weiterstat, Germany under the tradenames EUDRAGIT RL 30 D and EUDRAGIT RS 30 D. These materials are copolymers of acrylic and methacrylic esters having a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in EUDRAGIT RL 30 D and 1:40 in EUDRAGIT RS 30 D. The mean molecular weight of these materials is about 35 150,000. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. EUDRAGIT RLRS mixtures are substantially -17insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids. The EUDRAGIT RIJRS dispersions useful in the present invention can be mixed together in any desired ratio in order to ultimately obtain a controlled-release formulation having a desirable dissolution 5 profile. Desirable controlled-release formulations can be obtained, for instance, from a coating derived from 100% EUDRAGIT RL; 50%EUDRAGIT RL, 50% EUDRAGIT RS; and 10% EUDRAGIT RL, 90% Eudragit RS (each commercially available from Rohi Pharma GmbH, Weiterstat, Germany). The sustained-release coating can also comprise a mixture of a hydrophobic 10 material and a hydrophilic material. The ratio of hydrophobic material to hydrophilic material is determined by, among other factors, the required release rate of the therapeutic agent and the solubility characteristics of the materials selected. Hydrophilic materials include, but are not limited to, polyvinylpyrrolidone and water soluble celluloses, such as hydroxypropylmethyl cellulose. Examples of combinations of hydrophobic material and 15 hydrophilic material useful for the sustained-release coating include, but are not limited, to a combination of shellac and polyvinylpyrrolidone and a combination of ethyl cellulose and hydroxypropylmethyl cellulose. Alternatively, the therapeutic agent can be dispersed in a controlled-release matrix. The phrase "controlled-release matrix," as used herein means a matrix that slowly 20 releases the therapeutic agent over time. Any controlled-release matrix can be used in the oral dosage form of the invention. Certain controlled-release matrices are known for oral formulations (See, e.g., Remingtons Pharmaceutical Sciences, 18 * ed. Mack Publishing Co., Easton, PA, 1990, p. 1684-1685). Other examples of useful controlled-release matrices are described in U.S. Patent Nos. 6,143,328 to Heafield et al.; 6,063,405 to Drizen et al.; 25 5,462,747 to Radebaugh et al.; 5,451,409 to Rencher et al.; 5,334,392 to Cuine et al.; and 5,266,331, 5,549,912, 5,508,042, 5,656,295, 5,324,351, 5,356,467, and 5,472,712, each to Oshlack et al., the contents of which are expressly incorporated herein by reference thereto. Particularly useful controlled-release matrices for opioids are described in U.S. Patent No. 6,143,328 to Heafield et al. and 5,266,331, 5,549,912, 5,508,042, 5,656,295, 5,324,351, 30 5,356,467, and 5,472,712, each to Oshlack et al. The controlled-release matrix can be a fusible hydrophobic material, optionally combined with a hydrophilic material. The hydrophobic fusible material can be, for example, a hydrophobic polymer or a natural or synthetic wax or oil, such as hydrogenated vegetable oil or hydrogenated castor oil, which in one embodiment has a 35 melting point of from about 35 to 100'C, and in another embodiment from about 45 to 90*C. The hydrophilic material can be a hydrophilic polymer; a water soluble fusible - 18material, such as polyethylene glycol; or a water soluble particulate material, such as dicalcium phosphate or lactose. The therapeutic agent dispersed in a controlled-release matrix can be prepared by formulating, e.g., using dry or wet granulation or by blending, the therapeutic 5 agent with a component other than the fusible component. Suitable non-fusible materials for inclusion in a controlled release matrix include, but are not limited to: (a) hydrophilic or hydrophobic polymers, such as gums, cellulose ethers, protein-derived materials, nylon, acrylic resins, polylactic acid, polyvinylchloride, starches, polyvinylpyrrolidones, and cellulose acetate phthalate. Of these polymers, cellulose 10 ethers, for example substituted cellulose ethers such as alkylcelluloses (e.g., ethylcellulose), C, - C. hydroxyalkylcelluloses (e.g., hydroxypropylcellulose and hydroxyethyl cellulose), and acrylic resins (e.g., methacrylates such as methacrylic acid copolymers) are used in one embodiment. The controlled-release matrix can conveniently contain between 1% and 80% (by weight) of the hydrophobic and/or hydrophilic polymer. 15 (b) digestible, long chain (C, - C 50 , in one embodiment C 8 - C 40 ) substituted or unsubstituted hydrocarbons, such as fatty acids; hydrogenated vegetable oils; fatty alcohols, such as lauryl, myristyl, stearyl, cetyl or, in one embodiment cetostearyl alcohol; glyceryl esters of fatty acids, for example, glyceryl monostearate; mineral oils; and waxes, such as beeswax, glycowax, castor wax, and carnauba wax. Hydrocarbons having a melting 20 point of between about 25*C and 90*C are used in one embodiment. Of these long chain hydrocarbon materials, fatty (aliphatic) alcohols are useful in one embodiment. The controlled-release matrix may contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon. (c) Polyalkylene glycols. The controlled-release matrix may contain up to 25 60% (by weight) of at least one polyalkylene glycol. A suitable controlled-release matrix for use in the oral dosage form of the invention comprises one or more cellulose ethers or acrylic resins, one or more C 12 - C 36 , in one embodiment C 12 - C 2 , aliphatic alcohols, and/or one or more hydrogenated vegetable oils. A particular suitable matrix comprises one or more alkylcelluloses, one or more 30 C1 2 - C 36 , in one embodiment C, 2 - C 22 , aliphatic alcohols, and optionally one or more polyalkylene glycols. In another embodiment the matrix contains between about 0.5% and 60%, and in another embodiment, between 1% and 50% (by weight) of the cellulose ether. The acrylic resin is for example a methacrylate such as methacrylic acid copolymer USNF Type A (EUDRAGIT L), Type B (EUDRAGIT S,), Type C (EUDRAGIT 35 L 100-55), EUDRAGIT NE 30 D, EUDRAGIT E, EUDRAGIT RL, or EUDRAGIT RS (commercially available from Rohm Pharma GmbH, Weiterstat, Germany). In one -19embodiment the matrix contains between about 0.5% and 60% by weight, and in another embodiment between 1% and 50% by weight of the acrylic resin. In the absence of polyalkylene glycol, the matrix in one embodiment contains between about 1% and 40%, in another embodiment between about 2% and 36% 5 (by weight) of the aliphatic alcohol. When polyalkylene glycol is present in the oral dosage form, then the combined weight of the aliphatic alcohol and the polyalkylene glycol in one embodiment constitutes between about 2% and 40%, in another embodiment between about 2 and 36% (by weight) of the matrix. The polyalkylene glycol may be, for example, polypropylene glycol or, in 10 one embodiment, polyethylene glycol. The number average molecular weight of the at least one polyalkylene glycol is in one embodiment between 200 and 15,000, and in another embodiment between 400 and 12,000.. The controlled-release matrix containing the therapeutic agent can readily be prepared by dispersing the therapeutic agent in the components of the matrix using 15 conventional pharmaceutical techniques including, but not limited to, melt granulation, wet granulation, dry blending, dry granulation, and co-precipitation. The controlled-release formulations slowly release the therapeutic agent when ingested and exposed to gastric and/or intestinal fluids. 20 5.4.5 COATING PROCESS In one embodiment the first and second compositions are solids, such as, but not limited to, granules, fine granules, pills, beads, capsules, tablets, or powders. Methods for preparing these solids are well known in the art. The compositions can additionally comprise any conventional pharmaceutically acceptable excipient such as a binding agent 25 (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); filler (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricant (e.g., magnesium stearate, talc or silica); disintegrant (e.g., potato starch or sodium starch -glycolate); or wetting agent (e.g., sodium lauryl sulphate). Such compositions, if desired, can also contain a minor amount of an emulsifying agent or a pH-buffering agent. In one 30 embodiment, the first and/or second composition comprises a hydrophobic material to provide the composition with a sustained-release property. Examples of useful hydrophobic material are disclosed in section 5.4.4, supra. Solid compositions can be prepared by using conventional methods known in the art, for example, wet granulation, melt extrusion, and tableting by compression. 35 The solid compositions are coated with layers by applying one or more coating mixtures. Coating mixtures are prepared by any conventional means, for example, -20- ~ by dissolving the above-mentioned polymers and optionally plasticizers in a suitable solvent or mixture of solvents, for example water, methanol, ethanol, isopropanol, acetone, . ethylacetate, ethylene chloride, or mixtures thereof. Examples of plasticizers include, but are not limited to, citric acid esters, such as triethyl citrate and tributyl citrate; dibutyl 5 phthalate; 1,2-propylene glycol; polyethylene glycols; castor oil; and triacetin. If the coating mixture is an aqueous dispersion, a small amount of talc, glyceral monostearate, or colloidal silicon dixide may be added to reduce the tendency of the aqueous dispersion to stick during processing. The coating mixture can also contain additives such as coloring agents and/or magnesium stearate, which are well known in the coating art. 10 The coating solution can be applied to the solid composition by any means available to those of ordinary skill in the art such as, for example, spraying or dipping. Conventional coating apparatuses, well known to those of ordinary skill in the art, can be used to coat the solid composition (See, e.g., Remingtons Pharmaceutical Sciences, 18' ed. Mack Publishing Co., Easton, PA, 1990). Conventional coating apparatuses include, but 15 are not limited to, coating-granulating apparatuses of the centrifugal fluidized type, pan coating apparatuses, and fluidized-bed granulating coating apparatuses. For example, a Wuster fluidized-bed system can be used in which an air jet, injected from underneath, fluidizes the coated material and effects drying while the polymer coating is sprayed on. When the solid composition is coated with more than one coating, the first coating solution 20 is applied and then allowed to dry before the second coating solution is applied. In one embodiment, the coating solutions are applied to provide a dosage form that has a dissolution profile substantially unaffected by exposure to accelerated-storage conditions. The phrase "accelerated-storage conditions," as used herein, means storage conditions of elevated temperature and/or elevated relative humidity to which the oral 25 dosage form is subjected for the purpose of obtaining regulatory approval, e.g., the FDA for approval in the U.S., and an expiration date. For example, a generally accepted test employed in FDA guidelines relates to the storage of a drug product (i.e., in its container and package) at 40* C and 75% Relative Humidity (RH). The length of time that the drug product can be stored under these conditions without chemically degrading and with its 30 dissolution and physical characteristics remaining unchanged, is used to determine the expiration date of the drug product. For example, storage for three months without chemical degradation and without change in dissolution or appearance can result in the drug product being accorded a two year expiration date. Other generally accepted accelerated tests include those where the drug product is subjected to storage at 37* C and 80% relative 35 humidity for one month or longer, in one embodiment three months. - 21 - 5.5 ORAL DOSAGE FORM 5.5.1 AMOUNT PER DOSAGE UNIT In the oral dosage form of the present invention, the amount of the therapeutic agent per dosage unit is that which is an effective amount for its particular 5 indication and is independent of the amount of the adverse-effect agent. For example, if the therapeutic agent is an opioid agonist, the amount of the opioid agonist in the oral dosage form of the present invention is generally from about 75 ng to about 1000 mg, in one embodiment from about 75 ng to about 750 mg. One of ordinary skill in the art can readily determine, without undue experimentation, the amount of therapeutic agent needed for a 10 particular indication. The amount of the adverse-effect agent in the oral dosage form of the present invention is such that the adverse-effect agent can give the intended adverse effect. When the adverse-effect agent is intended to reduce or eliminate the pharmacological effects of the therapeutic agent, the amount of the adverse-effect agent in the oral dosage form is at least 15 sufficient to reduce or eliminate the effects of the therapeutic agent when both agents are released. In the present invention, the phrase "to reduce or eliminate the effects of the therapeutic agent," as used herein, means that the effects of the therapeutic agent.that attract potential abusers are eliminated or become lessened. For example, an adverse-effect agent 20 can reduce the euphoric effect of a therapeutic agent. When the adverse-effect agent is an opioid antgonist, the amount of the opioid antagonist, present in a oral dosage form of the present invention, can be from about 10 ng to 275 mg. The opioid antagonists cyclazocine and naltrexone, when administered orally, retain much of their efficacy with a long duration of action, approaching 24 hours, 25 Accordingly, amounts of less than 100 mg of these opioid antagonists are typically used in the oral formulations of the invention. When the adverse-effect agent is intended to cause an undesired physiological reaction, such as a emesis, the amount of the adverse-effect agent in the oral dosage form is at least sufficient to cause such effect upon release. 30 For safety reasons, the amount of the adverse-effect agent present in the oral dosage form should not be harmful to humans even if fully released. One of ordinary skill in the art can readily determine, without undue experimentation, the amount of adverse-effect agent needed to elicit the intended adverse-effect without being harmful. In certain embodiments of the present invention, the ratio of the therapeutic 35 agent to the adverse-effect agent in the oral dosage form is about 1:1 to about 50:1 by weight, in one embodiment about 1:1 to about 20:1 by weight. In certain other -22embodiments, the ratio is about 1:1 to about 10:1 by weight. In another embodiment of the invention, the therapeutic agent includes oxycodone or hydrocodone and is present in the amount of about 15-45 mg, and the adverse-effect agent includes naltrexone and is present in about 0.5-5 mg. 5 In another embodiment the first composition has a sustained-release coating, the therapeutic agent is an opioid agonist and the adverse-effect agent is an opioid antagonist. In embodiments in which the opioid agonist is hydrocodone, the sustained release oral dosage forms can include analgesic doses from about 5 mg to about 80 mg of hydrocodone per dosage unit. In oral dosage forms where the opioid agonist is 10 hydromorphone, it may be included in an amount from about 2 mg to about 64 mg hydromorphone hydrochloride per dosage unit. In another embodiment, the opioid agonist is morphine, and the oral dosage forms of the present invention include from about 2.5 mg to about 800 mg morphine per dosage unit. In yet another embodiment, the opioid agonist is oxycodone and the oral dosage forms include from about 2.5 mg to about 800 mg 15 oxycodone, in another embodiment from about 20 mg to about 30 mg oxycodone per dosage unit. Controlled-release oxycodone formulations are known in the art. The opioid agonist can be tramadol in an amount from about 25 mg to 800 mg tramadol per dosage unit. The dosage form can contain more than one opioid agonist. 20 5.5.2 EMBODIMENTS OF THE ORAL DOSAGE FORM In one embodiment, the first composition and the second composition are coated as explained in section 5.4, supra to provide the first coated composition and the second coated composition. As discussed above, the first composition, comprising a therapeutic agent, is coated with an outer acid-soluble layer, an inner base-soluble layer and, 25 optionally, an innermost sustained release coating; and the second composition, comprising an adverse-effect agent, is coated with an inner acid-soluble layer, an outer base-soluble layer, and, optionally, a layer substantially insoluble in the gastrointestinal tract. The first composition and the second composition are then combined to provide a unit dosage of the oral composition of the invention. In one embodiment, the first composition and the second 30 composition are similar in their size, shape and color so that they cannot be readily distinguished from each other. For example, the first composition and the second composition can each be powders, granules, or beads that are combined and incorporated into a capsule or tablet using methods well known to those of ordinary skill in the art. The capsule may be hard or soft, for example, gelatin. The capsule can also contain 35 pharmaceutically acceptable excipients. -23- Fig. 3 shows a cross-sectional view of a capsule 30, which has a first part 33 and a second part 34 and contains powders, granules, or beads of a first composition 31 and powders or granules of a second composition 32. Fig. 5 shows a cross-sectional view of a dosage form according to the 5 invention in the form of a tablet 50. The first composition is in the form of powders or granules 51 and the coated second composition is in the form-of powders, granules, or beads 52. The first composition and the coated second composition are mixed with a pharmaceutically acceptable matrix 53 and compressed into a tablet. In another embodiment the capsule or tablet contains the first composition 10 without the outer acid-soluble layer and without the inner base-soluble layer and the second composition coated with an outer base-soluble layer and an inner acid-soluble layer. Fig. 6. Depicts another embodiment of the oral dosage form of the invention in the form of a tablet comprising a core that is a mixture of an uncoated first composition 64 and a second composition coated with a base-soluble outer layer and an acid soluble 15 inner layer 65. The core is then coated with an inner base-soluble layer 62, and an outer acid-soluble layer 61, and an optional innermost sustained release coating 63. Alternatively, the second composition can be coated with a layer that is substantially insoluble in the gastrointestinal tract. Another embodiment of the oral dosage form of the invention is a two-layer 20 tablet 40 as shown in Fig. 4. A solid nucleus of the first composition 45 is covered with an innermost sustained-release coating 43 (optional), an inner base-soluble layer 42, and an outer acid-soluble layer 41. A solid nucleus of the second composition 44 is covered with an inner acid-soluble layer 46, an outer base-soluble layer 47, and an outermost layer that is substantially insoluble in the gastrointestinal tract 48 (optional). The two coated nuclei are 25 then compressed into a two-layer. tablet 40 using conventional tableting equipment and standard techniques to provide a two-layered tablet. The compressed two-layer tablet can then optionally be coated with an additional coating to provide a tablet of uniform appearance. In one embodiment, the additional coating is a coating that dissolves in the stomach after the tablet is swallowed. 30 In another embodiment of the two-layer tablet, the first composition is uncoated, i.e., is not covered with the outer acid-soluble layer or the inner base-soluble layer, but the second composition is coated with an outer base-soluble layer and an inner acid-soluble layer. Yet another embodiment of the oral dosage 70 is shown in Fig.7. A solid 35 nucleus of the second composition 77 is coated with an innermost acid-soluble layer 76 and - 24 an outer base-soluble layer 75. Then, the second composition is further coated with a layer of the first composition 74, an optional innermost pH-independent layer 73, an inner base soluble layer 72, and an outer acid-soluble layer 71. The oral dosage 70 may be a tablet or a granule. 5 6. EXAMPLES The following prophetic examples are set forth to assist in understanding the invention and should not, of course, be construed as specifically limiting the invention 10 described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein. 15 EXAMPLE 1: Capsule (1) Preparation of Oxycodone granules and Naltrexone HCl Granules Ingredient Amount/unit (mg) 20 Oxycodone HCl or 20.00 Naltrexone HCl 5.00 Spray Dried Lactose 59.25 Providone 5.00 Eudragit RS 30D (dry wt.) 10.00 25 Triacetin 2.00 Total 131.00 EUDRAGIT RS 30 D is plasticized by mixing with triacetin. The dispersion is then combined with the oxycodone HCI or naltrexene HCl, spray dried lactose, and 30 providone using a fluid-bed granulator. The resulting mixture is granulated. If necessary the granules are dried. The granules are then screened with a sieve to provide granules of an appropriate size. (2) Coating 35 -25- An acid-soluble coating solution is prepared by dispersing 15.0 g EUDRAGIT E100 in 200 ml of ethanol to provide a clear solution, and 4 g of the plasticizer triethyl citrate is added to the solution. A base-soluble coating solution is prepared by dispersing 15.0 g EUDRAGIT 5 L in 200 ml of ethanol to provide a clear solution. The oxycodone HCI granules are spray coated with the base-soluble coating solution and dried. After drying, the resulting oxycodone HCl granules coated with the base-soluble coating are then spray coated with the acid-soluble coating solution and the resulting granules dried. 10 The naltrexone HC1 granules are spray coated with the acid-soluble coating solution and dried. After drying, the resulting naltrexone HCl granules coated with the acid-soluble coating are then spray coated with the base-soluble coating solution and the resulting granules dried. (3) Encapsulating 15 The coated oxycodone HCl granules and the coated naltrexone HCl granules are mixed together to provide a mixture, and a gelatin capsule is filled with the mixture. EXAMPLE 2: Tablet Stearyl alcohol is melted, and the melted stearyl alcohol (25.00 mg per unit) 20 is mixed with the coated granules obtained in Example I to wax them. The waxed granules are cooled in a fluid bed dryer and then blended with talc (2.50 mg per unit) and magnesium stearate (1.25 mg per unit) to provide a blend. The resulting blend is compressed into a tablet using a tablet press. The present invention is not to be limited in scope by the specific 25 embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims. 30 A number of references have been cited, the entire disclosures of which are incorporated herein by reference. 35 -26-
Claims (79)
1. An oral dosage form comprising a first composition and a second composition, wherein the first composition comprises an effective amount of a therapeutic agent and the second composition comprises an effective amount of an 5 adverse-effect agent, wherein the second composition is coated with an inner acid soluble layer and an outer base-soluble layer, and wherein the dosage form does not release any adverse-effect agent when taken as directed.
2. The oral dosage form of claim 1, wherein the first composition and the second composition are in the form of powders, granules, or beads contained within a 10 capsule.
3. The oral dosage form of claim 1, wherein the first composition and the second composition are in the form of granules or a powder dispersed in a pharmaceutically acceptable matrix.
4. The oral dosage form of claim I in the form of a two-layer tablet having a 15 first layer comprising the first composition and a second layer comprising the second composition.
5. The oral dosage form of claim 4, wherein the two-layer tablet is further coated with a coating that dissolves in the stomach.
6. The oral dosage form of any one of claims 1 to 5, wherein the adverse-effect 20 agent is an antagonist of the therapeutic agent.
7. The oral dosage form of any one of claims 1 to 6, wherein the adverse-effect agent is an emetic.
8. The oral dosage form of any one of claims I to 7, wherein the acid-soluble layer is soluble at a pH value of less than about 5.0 and substantially insoluble at a pH 25 value of greater than about 5.5.
9. The oral dosage form of any one of claims I to 8, wherein the base-soluble layer is soluble at a pH value of greater than about 5.5 but substantially insoluble at a pH value of less than about 5.0.
10. The oral dosage form of any one of claims I to 9, wherein the acid-soluble 30 layer comprises a cationic polymer with dimethylaminoethyl ammonium functionalities. 28
11. The oral dosage form of any one of claims I to 10, wherein the base-soluble layer comprises an anionic polymer of methacrylic acid or a methacrylate with carboxylic acid functionalities.
12. The oral dosage form of any one of claims I to 11, wherein the first 5 composition is a controlled-release dosage form.
13. The oral dosage form of claim 12, wherein the first composition is coated with a sustained-release coating.
14. The oral dosage form of claim 13, wherein the sustained-release coating is selected from the group consisting of a wax, fatty alcohol, shellac, zein, hydrogenated 10 vegetable oil, water insoluble cellulose, polymers of acrylic acid, polymers of methacrylic acid, copolymers of acrylic acid and methacrylic acid, and mixtures thereof.
15. The oral dosage form of claim 12, wherein the first composition is dispersed in a controlled-release matrix.
16. The oral dosage form of any one of claims I to 15, wherein the therapeutic 15 agent is selected from a group consisting of analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, 20 immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, P-Blockers, cardiac ionotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2-inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, 25 protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
17. The oral dosage form of any one of clams I to 15, wherein the therapeutic 30 agent is an agent having a potential for abuse. 29
18. The oral dosage form of claim 17, wherein the therapeutic agent is an opioid, benzodiazepine, barbiturate, or a stimulant.
19. The oral dosage form of claim 18, wherein the therapeutic agent is an opioid and the adverse-effect agent is an opioid antagonist. 5 20. The oral dosage form of claim 19, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl 10 butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone, hydromorphone, hydromorphodone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, 15 nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, paregoric, pentazocine, phenadoxone, phendimetrazine, phendimetrazone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, propylhexedrine, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.
20
21. The oral dosage form of claim 20, wherein the opioid is selected from the group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives thereof, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol, levorphanol, pharmaceutically acceptable salts thereof, and mixtures 25 thereof.
22. The oral dosage form of claim 21, wherein the opioid is oxycodone or hydrocodone.
23. The oral dosage form of claim 19, wherein the adverse-effect agent is selected from the group consisting of naloxone, naltrexone, nalmefene, cyclazacine, and 30 levallorphan.
24. The oral dosage form of claim 23, wherein the adverse-effect agent is naloxone or naltrexone. 30
25. The oral dosage form of claim 18, wherein the therapeutic agent is a benzodiazepine and the adverse-effect agent is a benzodiazepine antagonist.
26. The oral dosage form of claim 25, wherein the benzodiazepine is selected from the group consisting of alprazolam, bromazepam, chlordiazepoxied, clorazepate, 5 diazepam, estazolam, flurazepan, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, pharmaceutically acceptable salts thereof, and mixtures thereof.
27. The oral dosage form of claim 25, wherein the benzodiazepine antagonist is flumazenil. 10
28. The oral dosage form of claim 18, wherein the therapeutic agent is a barbiturate and the adverse-effect agent is a barbiturate antagonist.
29. The oral dosage form of claim 28, wherein the barbiturate is selected from the group consisting of amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, pharmaceutically 15 acceptable salts thereof, and mixtures thereof.
30. The oral dosage form of claim 28, wherein the barbiturate antagonist is a stimulant.
31. The oral dosage form of claim 18, wherein the therapeutic agent is a stimulant and the adverse-effect agent is an a stimulant antagonist. 20
32. The oral dosage form of claim 31, wherein the stimulant is selected from the group consisting of amphetamine, amphetamine and dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, a pharmaceutically acceptable salt thereof, and mixtures thereof.
33. The oral dosage form of claim 31, wherein the stimulant antagonist is a 25 benzodiazepine.
34. The oral dosage form of claim 17, wherein the therapeutic agent is selected from a group consisting of dronabinol, glutethimide, methylphenidate, nabilone, anabolic steroids, methylprylon, ethchlorovynol, ethinamate, fenfluramine, meprobamate, pemoline, levomethadyl, benzphetamine, chlorphentermine, diethylpropion, phentermine, 30 mebutamate, chlortermine, phenylacetone, dronabinol, nabilone, benphetamine, chloral 31 hydrate, ethclorovynol, paraldehyde, midazolam, detropropoxyphene, pharmaceutically acceptable salts thereof, and mixtures thereof.
35. The oral dosage form of claim 1, wherein the therapeutic agent is selected from the group consisting of 5-ASA, steroids, laxatives, octreotide, cisapride, 5 anticholinergics, calcium channel blockers, DNA for delivery to the cells of the colon, glucosamine, thromboxane A 2 synthetase inhibitor, 5HT3-antagonists, antibodies against infectious bacteria, antiviral agents, heparins, insulin, calcitonins, human growth hormone, growth hormone releasing hormone, interferons, somatostatin and analogues thereof, erythropoietin, granulocyte colony stimulating factor, parathyroid hormone, 10 luteinising hormone releasing hormone and analogues thereof, atrial natriuretic factor, vasopressin, desmopressin, calcitonin gene related peptide, and analgesics.
36. The oral dosage form of any one of claims 1 to 35, wherein the ratio of therapeutic agent to adverse-effect agent is from about 1:1 to 50:1.
37. An oral dosage form comprising a first composition and a second 15 composition, wherein the first composition comprises an effective amount of a therapeutic agent and is coated with an inner base-soluble layer and an outer acid-soluble layer, and the second composition comprises an effective amount of an adverse-effect agent and is coated with an inner acid-soluble layer and an outer base-soluble layer.
38. The oral dosage form of claim 37, wherein the first composition and the 20 second composition are in the form of powders, granules, or beads contained within a capsule.
39. The oral dosage form of claim 37, wherein the first composition and the second composition are in the form of granules or a powder dispersed in a pharmaceutically acceptable matrix. 25
40. The oral dosage form of claim 37 in the form of a two-layer tablet having a first layer comprising the first composition and a second layer comprising the second composition.
41. The oral dosage form of claim 40, wherein the two-layer tablet is further coated with a coating that dissolves in the stomach. 32
42. The oral dosage form of claim 37 in the form of a tablet comprising a core, wherein the core comprises the second composition coated with an inner acid-soluble layer and an outer base-soluble layer dispersed within the therapeutic agent.
43. The oral dosage form of claim 37 in the form of a tablet comprising a core of 5 the second composition coated with (i) an inner acid-soluble layer, (ii) an outer base soluble layer, (iii) a coating of the first composition, (iv) an inner-base-soluble layer, and (v) an outer acid-soluble layer, in the order recited.
44. The oral dosage form of any one of claims 37 to 43, wherein the adverse effect agent is an antagonist of the therapeutic agent. 10
45. The oral dosage form of any one of claims 37 to 44, wherein the adverse effect agent is laxative.
46. The oral dosage form of any one of claims 37 to 45, wherein each acid soluble layer is soluble at a pH value of less than about 5.0 and substantially insoluble at a pH value of greater than about 5.5. 15
47. The oral dosage form of any one of claims 37 to 46, wherein each base soluble layer is soluble at a pH value of greater than about 5.5 but substantially insoluble at a pH value of less than about 5.0.
48. The oral dosage form of any one of claims 37 to 47, wherein each acid soluble layer comprises a cationic polymer with dimethylaminoethyl ammonium 20 functionalities.
49. The oral dosage form of any one of claims 37 to 48, wherein each base soluble layer comprises an anionic polymer of methacrylic acid or a methacrylate with carboxylic acid functionalities.
50. The oral dosage form of any one of claims 37 to 49, wherein the first 25 composition is a controlled-release dosage form.
51. The oral dosage form of claim 50, wherein the first composition is coated with an inner-most sustained-release coating.
52. The oral dosage form of claim 51, wherein the sustained-release coating is selected from the group consisting of a wax, fatty alcohol, shellac, zein, hydrogenated 30 vegetable oil, water insoluble cellulose, polymers of acrylic acid, polymers of methacrylic acid, copolymers of acrylic acid and methacrylic acid, and mixtures thereof. 33
53. The oral dosage form of claim 50, wherein the first composition is dispersed in a controlled-release matrix.
54. The oral dosage form of any one of claims 37 to 53, wherein the therapeutic agent is selected from a group consisting of analgesics, anti-inflammatory agents, 5 anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, 10 sedatives, hypnotics, neuroleptics, p-Blockers, cardiac ionotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2-inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, 15 anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
55. The oral dosage form of any one of claims 37 to 53, wherein the therapeutic agent is an agent having a potential for abuse. 20
56. The oral dosage form of claim 55, wherein the therapeutic agent is an opioid, benzodiazepine, barbiturate, or a stimulant.
57. The oral dosage form of claim 56, wherein the therapeutic agent is an opioid and the adverse-effect agent is an opioid antagonist.
58. The oral dosage form of claim 57, wherein the opioid is selected from the 25 group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, 30 etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone, hydromorphone, hydromorphodone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, 34 metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, paregoric, pentazocine, phenadoxone, phendimetrazine, phendimetrazone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, 5 promedol, properidine, propoxyphene, propylhexedrine, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.
59. The oral dosage form of claim 58, wherein the opioid selected from the group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives thereof, 10 dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol, levorphanol, pharmaceutically acceptable salts thereof, and mixtures thereof.
60. The oral dosage form of claim 59, wherein the opioid is oxycodone or hydrocodone.
61. The oral dosage form of claim 57, wherein the adverse-effect agent is 15 selected from the group consisting of naloxone, naltrexone, nalmefene, cyclazacine, and levallorphan.
62. The oral dosage form of claim 57, wherein the adverse-effect agent is naloxone or naltrexone.
63. The oral dosage form of claim 56, wherein the therapeutic agent is a 20 benzodiazepine and the adverse-effect agent is a benzodiazepine antagonist.
64. The oral dosage form of claim 63, wherein the benzodiazepine is selected from the group consisting of alprazolam, bromazepam, chlordiazepoxied, clorazepate, diazepam, estazolam, flurazepan, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, pharmaceutically acceptable 25 salts thereof, and mixtures thereof.
65. The oral dosage form of claim 63, wherein the benzodiazepine antagonist is flumazenil.
66. The oral dosage form of claim 56, wherein the therapeutic agent is a barbiturate and the adverse-effect agent is a barbiturate antagonist. 30
67. The oral dosage form of claim 66, wherein the barbiturate is selected from the group consisting of amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, 35 mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, pharmaceutically acceptable salts thereof, and mixture thereof.
68. The oral dosage form of claim 56, wherein the barbiturate antagonist is a stimulant. 5
69. The oral dosage form of claim 56, wherein the therapeutic agent is a stimulant and the adverse-effect agent is a stimulant antagonist.
70. The oral dosage form of claim 69, wherein the amphetamine is selected from the group consisting of amphetamine, amphetamine and dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, a pharmaceutically 10 acceptable salt thereof, and mixtures thereof.
71. The oral dosage form of claim 69, wherein the stimulant antagonist is a benzodiazepine.
72. The oral dosage form of claim 56, wherein the therapeutic agent is selected from a group consisting of dronabinol, glutethimide, methylphenidate, nabilone, anabolic 15 steroids, methylprylon, ethchlorovynol, ethinamate, fenfluramine, meprobamate, pemoline, levomethadyl, benzphetamine, chlorphentermine, diethylpropion, phentermine, mebutamate, chlortermine, phenylacetone, dronabinol, nabilone, benphetamine, chloral hydrate, ethclorovynol, paraldehyde, midazolam, detropropoxyphene, pharmaceutically acceptable salts thereof, and mixtures thereof. 20
73. The oral dosage form of claim 37, wherein the therapeutic agent is selected from the group consisting of 5-ASA, steroids, laxatives, octreotide, cisapride, anticholinergics, calcium channel blockers, DNA for delivery to the cells of the colon, glucosamine, thromboxane A 2 synthetase inhibitor, 5HT3-antagonists, antibodies against infectious bacteria, antiviral agents, heparins, insulin, calcitonins, human growth 25 hormone, growth hormone releasing hormon, interferons, somatostatin and analogues thereof, erythropoietin, granulocyte colony stimulating factor, parathyroid hormone, luteinising hormone releasing hormone and analogues thereof, atrial natriuretic factor, vasopressin, desmopressin, calcitonin gene related peptide, and analgesics.
74. The oral dosage form of any one of claims 37 to 73, wherein the ratio of 30 therapeutic agent to adverse-effect agent is from about 1:1 to 50:1. 36
75. A method for treating or preventing pain, comprising administering to a patient in need thereof the oral dosage form of any one of claims 1 to 36.
76. A method for treating or preventing pain, comprising administering to a patient in need thereof the oral dosage form of any one of claims 37 to 74. 5
77. A method for treating or preventing pain, comprising administering to a patient in need thereof an oral dosage form comprising a first composition and a second composition, wherein: the first composition comprises an effective amount of a therapeutic agent; the second composition comprises an effective amount of an adverse effect agent; effective amount of the therapeutic agent is released in the patient's small 10 intestine; and less than an effective amount of the adverse-effect agent is released in the patient's gastrointestinal tract.
78. A method for preparing the oral dosage form of claim 1, comprising the step of preparing the oral dosage form as set forth herein.
79. A method for preparing the oral dosage form of claim 37, comprising the step 15 of preparing the oral dosage form as set forth herein.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2011205217A AU2011205217B2 (en) | 2001-08-06 | 2011-08-08 | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/309,791 | 2001-08-06 | ||
US10/208,817 | 2002-08-01 | ||
AU2008202531A AU2008202531A1 (en) | 2001-08-06 | 2008-06-06 | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
AU2011205217A AU2011205217B2 (en) | 2001-08-06 | 2011-08-08 | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2008202531A Division AU2008202531A1 (en) | 2001-08-06 | 2008-06-06 | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2011205217A1 AU2011205217A1 (en) | 2011-08-25 |
AU2011205217B2 true AU2011205217B2 (en) | 2013-06-13 |
Family
ID=45420349
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2011205217A Expired AU2011205217B2 (en) | 2001-08-06 | 2011-08-08 | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
Country Status (1)
Country | Link |
---|---|
AU (1) | AU2011205217B2 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0759303A1 (en) * | 1994-04-22 | 1997-02-26 | Yamanouchi Pharmaceutical Co. Ltd. | Colon-specific drug release system |
WO2000044353A1 (en) * | 1999-01-29 | 2000-08-03 | Losan Pharma Gmbh | Pharmaceutical compositions |
-
2011
- 2011-08-08 AU AU2011205217A patent/AU2011205217B2/en not_active Expired
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0759303A1 (en) * | 1994-04-22 | 1997-02-26 | Yamanouchi Pharmaceutical Co. Ltd. | Colon-specific drug release system |
WO2000044353A1 (en) * | 1999-01-29 | 2000-08-03 | Losan Pharma Gmbh | Pharmaceutical compositions |
Also Published As
Publication number | Publication date |
---|---|
AU2011205217A1 (en) | 2011-08-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
USRE45822E1 (en) | Oral dosage form comprising a therapeutic agent and an adverse-effect agent | |
EP2283842B1 (en) | Tamper-resistant oral opioid agonist formulations | |
EP2034975B1 (en) | Pharmaceutical compositions | |
US20090041838A1 (en) | Anti-Misuse Microparticulate Oral Drug Form | |
AU2017204639A1 (en) | Pharmaceutical composition comprising opioid agonist and sequestered antagonist | |
MXPA05011071A (en) | Tamper resistant dosage form comprising co-extruded, adverse agent particles and process of making same. | |
AU2004232001A1 (en) | Pharmaceutical products | |
EP2073797A2 (en) | Pharmaceutical compositions | |
AU2011205217B2 (en) | Oral dosage form comprising a therapeutic agent and an adverse-effect agent | |
AU2002326529A1 (en) | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FGA | Letters patent sealed or granted (standard patent) | ||
MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |