MXPA06009535A - Abuse resistant opioid transdermal delivery device containing opioid antagonist microspheres - Google Patents
Abuse resistant opioid transdermal delivery device containing opioid antagonist microspheresInfo
- Publication number
- MXPA06009535A MXPA06009535A MXPA/A/2006/009535A MXPA06009535A MXPA06009535A MX PA06009535 A MXPA06009535 A MX PA06009535A MX PA06009535 A MXPA06009535 A MX PA06009535A MX PA06009535 A MXPA06009535 A MX PA06009535A
- Authority
- MX
- Mexico
- Prior art keywords
- delivery device
- transdermal delivery
- microspheres
- opioid
- transdermal
- Prior art date
Links
- 230000037317 transdermal delivery Effects 0.000 title claims abstract description 101
- 239000004005 microsphere Substances 0.000 title claims description 128
- 239000003401 opiate antagonist Substances 0.000 title claims description 67
- 230000003364 opioid Effects 0.000 title claims description 24
- 239000003402 opiate agonist Substances 0.000 claims abstract description 64
- 208000002193 Pain Diseases 0.000 claims abstract description 9
- 230000036407 pain Effects 0.000 claims abstract description 8
- 239000010410 layer Substances 0.000 claims description 109
- 239000000203 mixture Substances 0.000 claims description 108
- 229920000642 polymer Polymers 0.000 claims description 83
- 239000003814 drug Substances 0.000 claims description 57
- 229940079593 drugs Drugs 0.000 claims description 54
- 239000011159 matrix material Substances 0.000 claims description 51
- -1 ciprenorphine Chemical compound 0.000 claims description 45
- 239000000853 adhesive Substances 0.000 claims description 37
- 230000001070 adhesive Effects 0.000 claims description 37
- 239000003795 chemical substances by application Substances 0.000 claims description 34
- 210000003491 Skin Anatomy 0.000 claims description 33
- 239000005557 antagonist Substances 0.000 claims description 29
- 230000003042 antagnostic Effects 0.000 claims description 27
- 229920001577 copolymer Polymers 0.000 claims description 27
- 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 18
- 229960003086 Naltrexone Drugs 0.000 claims description 18
- 239000011780 sodium chloride Substances 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 229920001296 polysiloxane Polymers 0.000 claims description 15
- 229920001710 Polyorthoester Polymers 0.000 claims description 13
- 239000000463 material Substances 0.000 claims description 12
- 229920000728 polyester Polymers 0.000 claims description 11
- 229920002678 cellulose Polymers 0.000 claims description 10
- 229920001661 Chitosan Polymers 0.000 claims description 9
- 150000004676 glycans Polymers 0.000 claims description 9
- 239000000014 opioid analgesic Substances 0.000 claims description 9
- 239000002245 particle Substances 0.000 claims description 9
- 229920001282 polysaccharide Polymers 0.000 claims description 9
- 239000005017 polysaccharide Substances 0.000 claims description 9
- 150000004804 polysaccharides Polymers 0.000 claims description 9
- 239000011241 protective layer Substances 0.000 claims description 9
- PJMPHNIQZUBGLI-UHFFFAOYSA-N Fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 claims description 8
- 239000000556 agonist Substances 0.000 claims description 7
- 229920001400 block copolymer Polymers 0.000 claims description 7
- 229920000570 polyether Polymers 0.000 claims description 7
- 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 6
- 229960002428 Fentanyl Drugs 0.000 claims description 6
- 230000036592 analgesia Effects 0.000 claims description 6
- RMRJXGBAOAMLHD-CTAPUXPBSA-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-CTAPUXPBSA-N 0.000 claims description 6
- 229960001736 buprenorphine Drugs 0.000 claims description 6
- 201000008125 pain agnosia Diseases 0.000 claims description 6
- 102100001249 ALB Human genes 0.000 claims description 5
- 101710027066 ALB Proteins 0.000 claims description 5
- YQYVFVRQLZMJKJ-UHFFFAOYSA-N Cyclazocine Chemical compound CC1C2CC3=CC=C(O)C=C3C1(C)CCN2CC1CC1 YQYVFVRQLZMJKJ-UHFFFAOYSA-N 0.000 claims description 5
- 229950002213 Cyclazocine Drugs 0.000 claims description 5
- 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 5
- 229920002367 Polyisobutene Polymers 0.000 claims description 5
- 229940050528 albumin Drugs 0.000 claims description 5
- 239000001913 cellulose Substances 0.000 claims description 5
- 239000012528 membrane Substances 0.000 claims description 5
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Antorphin 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 4
- 229920000858 Cyclodextrin Polymers 0.000 claims description 4
- 229940097362 Cyclodextrins Drugs 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229960005181 morphine Drugs 0.000 claims description 4
- 229930014694 morphine Natural products 0.000 claims description 4
- 229960000938 nalorphine Drugs 0.000 claims description 4
- 229920000193 polymethacrylate Polymers 0.000 claims description 4
- 229920002635 polyurethane Polymers 0.000 claims description 4
- 239000004814 polyurethane Substances 0.000 claims description 4
- PPBRXRYQALVLMV-UHFFFAOYSA-N styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 4
- 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
- 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 3
- WVLOADHCBXTIJK-YNHQPCIGSA-N Hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 claims description 3
- 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 3
- 229960003406 Levorphanol Drugs 0.000 claims description 3
- 229940041655 Meperidine Drugs 0.000 claims description 3
- USSIQXCVUWKGNF-UHFFFAOYSA-N Methadone 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 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
- 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 3
- 229960004127 Naloxone Drugs 0.000 claims description 3
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycontin 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 3
- 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 3
- XADCESSVHJOZHK-UHFFFAOYSA-N Petidina Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004698 Polyethylene (PE) Substances 0.000 claims description 3
- 229960004739 Sufentanil Drugs 0.000 claims description 3
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N Tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 claims description 3
- 229960004380 Tramadol Drugs 0.000 claims description 3
- 238000007792 addition Methods 0.000 claims description 3
- 229960004126 codeine Drugs 0.000 claims description 3
- 229960000920 dihydrocodeine Drugs 0.000 claims description 3
- 229960000240 hydrocodone Drugs 0.000 claims description 3
- 229960001410 hydromorphone Drugs 0.000 claims description 3
- 229960001797 methadone Drugs 0.000 claims description 3
- 229960005297 nalmefene Drugs 0.000 claims description 3
- 229960002085 oxycodone Drugs 0.000 claims description 3
- 229960005118 oxymorphone Drugs 0.000 claims description 3
- 229960000482 pethidine Drugs 0.000 claims description 3
- 239000004417 polycarbonate Substances 0.000 claims description 3
- 229920000515 polycarbonate Polymers 0.000 claims description 3
- 229920000573 polyethylene Polymers 0.000 claims description 3
- 229920000139 polyethylene terephthalate Polymers 0.000 claims description 3
- 239000005020 polyethylene terephthalate Substances 0.000 claims description 3
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 3
- 239000004810 polytetrafluoroethylene Substances 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
- KUDUQBURMYMBIJ-UHFFFAOYSA-N 2-prop-2-enoyloxyethyl prop-2-enoate Chemical compound C=CC(=O)OCCOC(=O)C=C KUDUQBURMYMBIJ-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 229960001113 Butorphanol Drugs 0.000 claims description 2
- 239000004709 Chlorinated polyethylene Substances 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 229920001328 Polyvinylidene chloride Polymers 0.000 claims description 2
- 229920002433 Vinyl chloride-vinyl acetate copolymer Polymers 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 239000000017 hydrogel Substances 0.000 claims description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-M methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 2
- 229960005301 pentazocine Drugs 0.000 claims description 2
- 239000011505 plaster Substances 0.000 claims description 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 claims description 2
- 239000005033 polyvinylidene chloride Substances 0.000 claims description 2
- LGQCVMYAEFTEFN-JCURWCKSSA-N Alazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C)CC2 LGQCVMYAEFTEFN-JCURWCKSSA-N 0.000 claims 1
- OIJXLIIMXHRJJH-KNLIIKEYSA-N Diprenorphine 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)(C)O)OC)CN2CC1CC1 OIJXLIIMXHRJJH-KNLIIKEYSA-N 0.000 claims 1
- 229950002494 Diprenorphine Drugs 0.000 claims 1
- 229920000219 Ethylene vinyl alcohol Polymers 0.000 claims 1
- OZYUPQUCAUTOBP-QXAKKESOSA-N Levallorphan Chemical compound C([C@H]12)CCC[C@@]11CCN(CC=C)[C@@H]2CC2=CC=C(O)C=C21 OZYUPQUCAUTOBP-QXAKKESOSA-N 0.000 claims 1
- 229950008297 NALMEXONE Drugs 0.000 claims 1
- NETZHAKZCGBWSS-CEDHKZHLSA-N Nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 claims 1
- 229960000805 Nalbuphine Drugs 0.000 claims 1
- OHKCLOQPSLQCQR-MBPVOVBZSA-N Nalmexone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(CC=C(C)C)[C@@H]3CC5=CC=C4O OHKCLOQPSLQCQR-MBPVOVBZSA-N 0.000 claims 1
- VOKSWYLNZZRQPF-UHFFFAOYSA-N Talwin Chemical compound C1C2=CC=C(O)C=C2C2(C)C(C)C1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-UHFFFAOYSA-N 0.000 claims 1
- VOLSCWDWGMWXGO-UHFFFAOYSA-N cyclobuten-1-yl acetate Chemical compound CC(=O)OC1=CCC1 VOLSCWDWGMWXGO-UHFFFAOYSA-N 0.000 claims 1
- 239000005038 ethylene vinyl acetate Substances 0.000 claims 1
- 229960000263 levallorphan Drugs 0.000 claims 1
- 230000000202 analgesic Effects 0.000 abstract description 5
- 239000000839 emulsion Substances 0.000 description 38
- 239000003921 oil Substances 0.000 description 25
- 235000019198 oils Nutrition 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000012071 phase Substances 0.000 description 23
- 201000009032 substance abuse Diseases 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000009472 formulation Methods 0.000 description 16
- 238000000034 method Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 14
- 238000006731 degradation reaction Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 9
- 230000015556 catabolic process Effects 0.000 description 9
- 230000004059 degradation Effects 0.000 description 9
- 238000005470 impregnation Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 239000006211 transdermal dosage form Substances 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 238000004945 emulsification Methods 0.000 description 7
- 239000010408 film Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000003887 narcotic antagonist Substances 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 238000000935 solvent evaporation Methods 0.000 description 7
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 6
- 235000010980 cellulose Nutrition 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 229920001971 elastomer Polymers 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000002745 poly(ortho ester) Substances 0.000 description 6
- 229920002451 polyvinyl alcohol Polymers 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 150000001557 benzodiazepines Chemical class 0.000 description 5
- 238000006065 biodegradation reaction Methods 0.000 description 5
- 230000003628 erosive Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000003094 microcapsule Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 230000002035 prolonged Effects 0.000 description 5
- 230000001225 therapeutic Effects 0.000 description 5
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 5
- 229920002732 Polyanhydride Polymers 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 description 4
- 229920001963 Synthetic biodegradable polymer Polymers 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000000730 antalgic agent Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 238000009792 diffusion process Methods 0.000 description 4
- 238000005538 encapsulation Methods 0.000 description 4
- 230000002708 enhancing Effects 0.000 description 4
- 239000011888 foil Substances 0.000 description 4
- 230000000670 limiting Effects 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000005060 rubber Substances 0.000 description 4
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1H-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 3
- 229940035676 ANALGESICS Drugs 0.000 description 3
- 229940025084 Amphetamine Drugs 0.000 description 3
- HNYOPLTXPVRDBG-UHFFFAOYSA-N Barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 3
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 3
- YKPUWZUDDOIDPM-SOFGYWHQSA-N Capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Natural products OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 3
- 229940005483 OPIOID ANALGESICS Drugs 0.000 description 3
- 229920000954 Polyglycolide Polymers 0.000 description 3
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 3
- 239000004902 Softening Agent Substances 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 229960002734 amfetamine Drugs 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229920002988 biodegradable polymer Polymers 0.000 description 3
- 239000004621 biodegradable polymer Substances 0.000 description 3
- 230000001055 chewing Effects 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 229960000632 dexamfetamine Drugs 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 230000001965 increased Effects 0.000 description 3
- 238000011068 load Methods 0.000 description 3
- 230000018984 mastication Effects 0.000 description 3
- 239000004530 micro-emulsion Substances 0.000 description 3
- 229920005615 natural polymer Polymers 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 230000003000 nontoxic Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 239000000346 nonvolatile oil Substances 0.000 description 3
- 230000036231 pharmacokinetics Effects 0.000 description 3
- 229920000058 polyacrylate Polymers 0.000 description 3
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 3
- 229920000915 polyvinyl chloride Polymers 0.000 description 3
- 239000004800 polyvinyl chloride Substances 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- 230000000699 topical Effects 0.000 description 3
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 2
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Adhd patch Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 2
- UPOYFZYFGWBUKL-UHFFFAOYSA-N Amiphenazole Chemical compound S1C(N)=NC(N)=C1C1=CC=CC=C1 UPOYFZYFGWBUKL-UHFFFAOYSA-N 0.000 description 2
- MTAZNLWOLGHBHU-UHFFFAOYSA-N Butadiene-styrene rubber Chemical compound C=CC=C.C=CC1=CC=CC=C1 MTAZNLWOLGHBHU-UHFFFAOYSA-N 0.000 description 2
- 210000003169 Central Nervous System Anatomy 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- VWTINHYPRWEBQY-UHFFFAOYSA-N Denatonium Chemical compound [O-]C(=O)C1=CC=CC=C1.C=1C=CC=CC=1C[N+](CC)(CC)CC(=O)NC1=C(C)C=CC=C1C VWTINHYPRWEBQY-UHFFFAOYSA-N 0.000 description 2
- 229940119750 Dextroamphetamine Drugs 0.000 description 2
- LQZZUXJYWNFBMV-UHFFFAOYSA-N Dodecanol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 2
- 229940099191 Duragesic Drugs 0.000 description 2
- 229950005722 Flosulide Drugs 0.000 description 2
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N Indometacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- JOOXCMJARBKPKM-UHFFFAOYSA-N Levulinic acid Chemical compound CC(=O)CCC(O)=O JOOXCMJARBKPKM-UHFFFAOYSA-N 0.000 description 2
- 229960001344 Methylphenidate Drugs 0.000 description 2
- KTDZCOWXCWUPEO-UHFFFAOYSA-N N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1CCCCC1 KTDZCOWXCWUPEO-UHFFFAOYSA-N 0.000 description 2
- CXJONBHNIJFARE-UHFFFAOYSA-N N-[6-(2,4-difluorophenoxy)-1-oxo-2,3-dihydroinden-5-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCC(=O)C=2C=C1OC1=CC=C(F)C=C1F CXJONBHNIJFARE-UHFFFAOYSA-N 0.000 description 2
- BFYWWTIGNJJAHF-LTQSXOHQSA-N Nalorphine dinicotinate 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@]52CCN3CC=C)C(=O)C1=CC=CN=C1 BFYWWTIGNJJAHF-LTQSXOHQSA-N 0.000 description 2
- BAWFJGJZGIEFAR-NNYOXOHSSA-N Nicotinamide adenine dinucleotide Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 2
- 229940058401 Polytetrafluoroethylene Drugs 0.000 description 2
- 239000004820 Pressure-sensitive adhesive Substances 0.000 description 2
- 229960004063 Propylene glycol Drugs 0.000 description 2
- STECJAGHUSJQJN-FWXGHANASA-N Scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 2
- 210000002784 Stomach Anatomy 0.000 description 2
- 239000002174 Styrene-butadiene Substances 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N Valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229950001798 amiphenazole Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000019658 bitter taste Nutrition 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 230000003247 decreasing Effects 0.000 description 2
- 229960001610 denatonium benzoate Drugs 0.000 description 2
- 150000001991 dicarboxylic acids Chemical class 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000806 elastomer Substances 0.000 description 2
- 239000002895 emetic Substances 0.000 description 2
- 230000000095 emetic Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000002255 enzymatic Effects 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000000774 hypoallergenic Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000003522 irritant Effects 0.000 description 2
- 239000002085 irritant Substances 0.000 description 2
- 231100000021 irritant Toxicity 0.000 description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
- 229940040102 levulinic acid Drugs 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 229950006238 nadide Drugs 0.000 description 2
- 230000003533 narcotic Effects 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 229920000620 organic polymer Polymers 0.000 description 2
- 239000004031 partial agonist Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 2
- 229920000747 poly(lactic acid) polymer Polymers 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrugs Drugs 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 229960002646 scopolamine Drugs 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000000021 stimulant Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000011115 styrene butadiene Substances 0.000 description 2
- 229920003048 styrene butadiene rubber Polymers 0.000 description 2
- 229940086735 succinate Drugs 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000002459 sustained Effects 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 229920000428 triblock copolymer Polymers 0.000 description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N vinyl acetate Chemical class CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (-)-propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- POILWHVDKZOXJZ-ARJAWSKDSA-M (Z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N 1,2,3-propanetrioltrinitrate Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 229940043268 2,2,4,4,6,8,8-heptamethylnonane Drugs 0.000 description 1
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 1
- DCXHLPGLBYHNMU-UHFFFAOYSA-N 2-[1-(4-azidobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(N=[N+]=[N-])C=C1 DCXHLPGLBYHNMU-UHFFFAOYSA-N 0.000 description 1
- TYCOFFBAZNSQOJ-UHFFFAOYSA-N 2-[4-(3-fluorophenyl)phenyl]propanoic acid Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC(F)=C1 TYCOFFBAZNSQOJ-UHFFFAOYSA-N 0.000 description 1
- JIEKMACRVQTPRC-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-2-phenyl-1,3-thiazol-5-yl]acetic acid Chemical compound OC(=O)CC=1SC(C=2C=CC=CC=2)=NC=1C1=CC=C(Cl)C=C1 JIEKMACRVQTPRC-UHFFFAOYSA-N 0.000 description 1
- XKSAJZSJKURQRX-UHFFFAOYSA-N 2-acetyloxy-5-(4-fluorophenyl)benzoic acid Chemical compound C1=C(C(O)=O)C(OC(=O)C)=CC=C1C1=CC=C(F)C=C1 XKSAJZSJKURQRX-UHFFFAOYSA-N 0.000 description 1
- JRHWHSJDIILJAT-UHFFFAOYSA-N 2-hydroxypentanoic acid Chemical compound CCCC(O)C(O)=O JRHWHSJDIILJAT-UHFFFAOYSA-N 0.000 description 1
- ROGIWVXWXZRRMZ-UHFFFAOYSA-N 2-methylbuta-1,3-diene;styrene Chemical compound CC(=C)C=C.C=CC1=CC=CC=C1 ROGIWVXWXZRRMZ-UHFFFAOYSA-N 0.000 description 1
- BANXPJUEBPWEOT-UHFFFAOYSA-N 2-methylpentadecane Chemical compound CCCCCCCCCCCCCC(C)C BANXPJUEBPWEOT-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- SYCHUQUJURZQMO-UHFFFAOYSA-N 4-hydroxy-2-methyl-1,1-dioxo-N-(1,3-thiazol-2-yl)-1$l^{6},2-benzothiazine-3-carboxamide Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=CS1 SYCHUQUJURZQMO-UHFFFAOYSA-N 0.000 description 1
- 102000035257 5-HT3 receptors Human genes 0.000 description 1
- 108091005518 5-HT3 receptors Proteins 0.000 description 1
- KQPKPCNLIDLUMF-MRVPVSSYSA-N 5-[(2R)-pentan-2-yl]-5-prop-2-enyl-1,3-diazinane-2,4,6-trione Chemical compound CCC[C@@H](C)C1(CC=C)C(=O)NC(=O)NC1=O KQPKPCNLIDLUMF-MRVPVSSYSA-N 0.000 description 1
- OIRAEJWYWSAQNG-UHFFFAOYSA-N 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylic acid Chemical compound ClC=1C=C2C(C(=O)O)CCC2=CC=1C1CCCCC1 OIRAEJWYWSAQNG-UHFFFAOYSA-N 0.000 description 1
- UOBSVARXACCLLH-UHFFFAOYSA-M 6-methoxy-6-oxohexanoate Chemical compound COC(=O)CCCCC([O-])=O UOBSVARXACCLLH-UHFFFAOYSA-M 0.000 description 1
- 229960004892 Acemetacin Drugs 0.000 description 1
- FSQKKOOTNAMONP-UHFFFAOYSA-N Acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 description 1
- 229940022659 Acetaminophen Drugs 0.000 description 1
- 229940022663 Acetate Drugs 0.000 description 1
- 229920000800 Acrylic rubber Polymers 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229960003767 Alanine Drugs 0.000 description 1
- 229960001391 Alfentanil Drugs 0.000 description 1
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N Alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229960001301 Amobarbital Drugs 0.000 description 1
- VIROVYVQCGLCII-UHFFFAOYSA-N Amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 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
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 240000005781 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- UVAZQQHAVMNMHE-UHFFFAOYSA-N Betaprodine Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CCN(C)CC1C UVAZQQHAVMNMHE-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 230000036868 Blood Concentration Effects 0.000 description 1
- VMIYHDSEFNYJSL-UHFFFAOYSA-N Bromazepam Chemical compound C12=CC(Br)=CC=C2NC(=O)CN=C1C1=CC=CC=N1 VMIYHDSEFNYJSL-UHFFFAOYSA-N 0.000 description 1
- MOYGZHXDRJNJEP-UHFFFAOYSA-N Buclizine Chemical compound C1=CC(C(C)(C)C)=CC=C1CN1CCN(C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)CC1 MOYGZHXDRJNJEP-UHFFFAOYSA-N 0.000 description 1
- QWCRAEMEVRGPNT-UHFFFAOYSA-N Buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 description 1
- ZRIHAIZYIMGOAB-UHFFFAOYSA-N Butabarbital Chemical compound CCC(C)C1(CC)C(=O)NC(=O)NC1=O ZRIHAIZYIMGOAB-UHFFFAOYSA-N 0.000 description 1
- UZVHFVZFNXBMQJ-UHFFFAOYSA-N Butalbital Chemical compound CC(C)CC1(CC=C)C(=O)NC(=O)NC1=O UZVHFVZFNXBMQJ-UHFFFAOYSA-N 0.000 description 1
- DLJLYDQTHFIEQZ-UHFFFAOYSA-N C(C(C)C)[NH-] Chemical class C(C(C)C)[NH-] DLJLYDQTHFIEQZ-UHFFFAOYSA-N 0.000 description 1
- DYQCYTHCHNSRBF-UHFFFAOYSA-M C(CCCCCC)(=O)[N-]CC(C)C Chemical compound C(CCCCCC)(=O)[N-]CC(C)C DYQCYTHCHNSRBF-UHFFFAOYSA-M 0.000 description 1
- 240000000306 Carapichea ipecacuanha Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N Carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 235000003255 Carthamus tinctorius Nutrition 0.000 description 1
- 240000005801 Carthamus tinctorius Species 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N Celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960004782 Chlordiazepoxide Drugs 0.000 description 1
- ANTSCNMPPGJYLG-UHFFFAOYSA-N Chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N Chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 Chlorpromazine Drugs 0.000 description 1
- DLGJWSVWTWEWBJ-HGGSSLSASA-N Chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 description 1
- 229920002567 Chondroitin Polymers 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 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 description 1
- 229950001604 Clonitazene Drugs 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 239000004821 Contact adhesive Substances 0.000 description 1
- UVKZSORBKUEBAZ-UHFFFAOYSA-N Cyclizine Chemical compound C1CN(C)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 UVKZSORBKUEBAZ-UHFFFAOYSA-N 0.000 description 1
- 229960002500 DIPIPANONE Drugs 0.000 description 1
- 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 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 229960003701 Dextromoramide Drugs 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N Dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- 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 description 1
- 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 description 1
- XJQPQKLURWNAAH-UHFFFAOYSA-N Dihydrocapsaicin Chemical compound COC1=CC(CNC(=O)CCCCCCC(C)C)=CC=C1O XJQPQKLURWNAAH-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 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 description 1
- CANBGVXYBPOLRR-UHFFFAOYSA-N Dimethylthiambutene Chemical compound C=1C=CSC=1C(=CC(C)N(C)C)C1=CC=CS1 CANBGVXYBPOLRR-UHFFFAOYSA-N 0.000 description 1
- 229950005563 Dimethylthiambutene Drugs 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N Diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- CGHRJBLSXVCYQF-YXSUXZIUSA-N Dolasetron Chemical compound C1=CC=C[C]2C(C(O[C@@H]3C[C@@H]4C[C@@H]5C[C@@H](N4CC5=O)C3)=O)=CN=C21 CGHRJBLSXVCYQF-YXSUXZIUSA-N 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N Doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 229960005426 Doxepin Drugs 0.000 description 1
- 229940089114 Drug Delivery Device Drugs 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- AJFTZWGGHJXZOB-UHFFFAOYSA-N DuP 697 Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC(F)=CC=2)SC(Br)=C1 AJFTZWGGHJXZOB-UHFFFAOYSA-N 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 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 description 1
- 229960002336 Estazolam Drugs 0.000 description 1
- 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 description 1
- WGJHHMKQBWSQIY-UHFFFAOYSA-N Ethoheptazine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCCN(C)CC1 WGJHHMKQBWSQIY-UHFFFAOYSA-N 0.000 description 1
- OGDVEMNWJVYAJL-LEPYJNQMSA-N Ethyl morphine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OCC OGDVEMNWJVYAJL-LEPYJNQMSA-N 0.000 description 1
- MORSAEFGQPDBKM-UHFFFAOYSA-N Ethylmethylthiambutene Chemical compound C=1C=CSC=1C(=CC(C)N(C)CC)C1=CC=CS1 MORSAEFGQPDBKM-UHFFFAOYSA-N 0.000 description 1
- 229960004578 Ethylmorphine Drugs 0.000 description 1
- 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 description 1
- 229950004538 Etonitazene Drugs 0.000 description 1
- MNJVRJDLRVPLFE-UHFFFAOYSA-N Etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
- 239000001576 FEMA 2977 Substances 0.000 description 1
- 229950007979 FLUFENISAL Drugs 0.000 description 1
- 229960001419 Fenoprofen Drugs 0.000 description 1
- RDJGLLICXDHJDY-UHFFFAOYSA-N Fenoprofen Chemical compound OC(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-UHFFFAOYSA-N 0.000 description 1
- 102000013361 Fetuins Human genes 0.000 description 1
- 108060002885 Fetuins Proteins 0.000 description 1
- 229960004369 Flufenamic Acid Drugs 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N Flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- OFBIFZUFASYYRE-UHFFFAOYSA-N Flumazenil Chemical compound C1N(C)C(=O)C2=CC(F)=CC=C2N2C=NC(C(=O)OCC)=C21 OFBIFZUFASYYRE-UHFFFAOYSA-N 0.000 description 1
- 229960004381 Flumazenil Drugs 0.000 description 1
- 229950001284 Fluprofen Drugs 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
- SYTBZMRGLBWNTM-UHFFFAOYSA-N Flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 108010068370 Glutens Proteins 0.000 description 1
- 240000007842 Glycine max Species 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N Granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 1
- 229960003727 Granisetron Drugs 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229920002456 HOTAIR Polymers 0.000 description 1
- 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 description 1
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 1
- 229940120060 Heroin Drugs 0.000 description 1
- 240000008528 Hevea brasiliensis Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N Hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 229940021015 I.V. solution additive Amino Acids Drugs 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Ilacox Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 229960000905 Indomethacin Drugs 0.000 description 1
- RJMIEHBSYVWVIN-UHFFFAOYSA-N Indoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-UHFFFAOYSA-N 0.000 description 1
- 239000009471 Ipecac Substances 0.000 description 1
- 229940029408 Ipecac Drugs 0.000 description 1
- 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 description 1
- 229960004423 KETAZOLAM Drugs 0.000 description 1
- 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 description 1
- ALFGKMXHOUSVAD-UHFFFAOYSA-N Ketobemidone Chemical compound C=1C=CC(O)=CC=1C1(C(=O)CC)CCN(C)CC1 ALFGKMXHOUSVAD-UHFFFAOYSA-N 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N Ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- INUNXTSAACVKJS-NRFANRHFSA-N Levomoramide Chemical compound C([C@H](C)C(C(=O)N1CCCC1)(C=1C=CC=CC=1)C=1C=CC=CC=1)N1CCOCC1 INUNXTSAACVKJS-NRFANRHFSA-N 0.000 description 1
- 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 description 1
- 229950010274 Lofentanil Drugs 0.000 description 1
- DIWRORZWFLOCLC-UHFFFAOYSA-N Lorazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229950009131 METAZOCINE Drugs 0.000 description 1
- 229950001846 Mabuprofen Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- OCJYIGYOJCODJL-UHFFFAOYSA-N Meclizine Chemical compound CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 OCJYIGYOJCODJL-UHFFFAOYSA-N 0.000 description 1
- 229940041321 Meclizine Drugs 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- 229940057917 Medium chain triglycerides Drugs 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N Mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 229940041659 Mephobarbital Drugs 0.000 description 1
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 1
- 229960004815 Meprobamate Drugs 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 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 description 1
- FWJKNZONDWOGMI-UHFFFAOYSA-N Metharbital Chemical compound CCC1(CC)C(=O)NC(=O)N(C)C1=O FWJKNZONDWOGMI-UHFFFAOYSA-N 0.000 description 1
- ALARQZQTBTVLJV-UHFFFAOYSA-N Methylphenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)N(C)C1=O ALARQZQTBTVLJV-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- DSDNAKHZNJAGHN-MXTYGGKSSA-N MolPort-003-983-798 Chemical compound C1=C(O)C(OC)=CC(CC(=O)OCC=2C[C@]3(O)C(=O)C(C)=C[C@H]3[C@@]34[C@H](C)C[C@@]5(O[C@@](O4)(CC=4C=CC=CC=4)O[C@@H]5[C@@H]3C=2)C(C)=C)=C1 DSDNAKHZNJAGHN-MXTYGGKSSA-N 0.000 description 1
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical compound C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 description 1
- JVGUNCHERKJFCM-UHFFFAOYSA-N N-(2-hydroxyethyl)-2-[4-(2-methylpropyl)phenyl]propanamide Chemical compound CC(C)CC1=CC=C(C(C)C(=O)NCCO)C=C1 JVGUNCHERKJFCM-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N Naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 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 description 1
- HNDXBGYRMHRUFN-CIVUWBIHSA-N Nicomorphine Chemical compound O([C@H]1C=C[C@H]2[C@H]3CC=4C5=C(C(=CC=4)OC(=O)C=4C=NC=CC=4)O[C@@H]1[C@]52CCN3C)C(=O)C1=CC=CN=C1 HNDXBGYRMHRUFN-CIVUWBIHSA-N 0.000 description 1
- 229960000916 Niflumic Acid Drugs 0.000 description 1
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 description 1
- HYWYRSMBCFDLJT-UHFFFAOYSA-N Nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 description 1
- 229960001454 Nitrazepam Drugs 0.000 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N Nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- 229940014995 Nitroglycerin Drugs 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- RGOVYLWUIBMPGK-UHFFFAOYSA-N Nonivamide Chemical compound CCCCCCCCC(=O)NCC1=CC=C(O)C(OC)=C1 RGOVYLWUIBMPGK-UHFFFAOYSA-N 0.000 description 1
- 229950011519 Norlevorphanol Drugs 0.000 description 1
- 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 description 1
- 229950006134 Normorphine Drugs 0.000 description 1
- 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 description 1
- 229940049964 Oleate Drugs 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 description 1
- 102000012404 Orosomucoid Human genes 0.000 description 1
- 108010061952 Orosomucoid Proteins 0.000 description 1
- ADIMAYPTOBDMTL-UHFFFAOYSA-N Oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 1
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 1
- 229950006445 PIMINODINE Drugs 0.000 description 1
- 229960001412 Pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N Pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 229960000762 Perphenazine Drugs 0.000 description 1
- 229960003893 Phenacetin Drugs 0.000 description 1
- CPJSUEIXXCENMM-UHFFFAOYSA-N Phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 1
- 229960000897 Phenazocine Drugs 0.000 description 1
- 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 description 1
- 229960002695 Phenobarbital Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N Phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960004315 Phenoperidine Drugs 0.000 description 1
- 229960005190 Phenylalanine Drugs 0.000 description 1
- PXXKIYPSXYFATG-UHFFFAOYSA-N Piminodine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCCNC1=CC=CC=C1 PXXKIYPSXYFATG-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N Piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 210000002381 Plasma Anatomy 0.000 description 1
- 229920001283 Polyalkylene terephthalate Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000005062 Polybutadiene Substances 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920001451 Polypropylene glycol Polymers 0.000 description 1
- 229960004856 Prazepam Drugs 0.000 description 1
- MWQCHHACWWAQLJ-UHFFFAOYSA-N Prazepam Chemical compound O=C1CN=C(C=2C=CC=CC=2)C2=CC(Cl)=CC=C2N1CC1CC1 MWQCHHACWWAQLJ-UHFFFAOYSA-N 0.000 description 1
- WIKYUJGCLQQFNW-UHFFFAOYSA-N Prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 description 1
- 229940069956 Propoxyphene Drugs 0.000 description 1
- 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 description 1
- 229960003110 Quinine Sulfate Drugs 0.000 description 1
- 229960003394 Remifentanil Drugs 0.000 description 1
- ZTVQQQVZCWLTDF-UHFFFAOYSA-N Remifentanil Chemical compound C1CN(CCC(=O)OC)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 ZTVQQQVZCWLTDF-UHFFFAOYSA-N 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N Rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229950005175 SUDOXICAM Drugs 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 210000003296 Saliva Anatomy 0.000 description 1
- 229950008243 Secbutabarbital Drugs 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 240000003670 Sesamum indicum Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229960000894 Sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N Sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960004492 Suprofen Drugs 0.000 description 1
- MDKGKXOCJGEUJW-UHFFFAOYSA-N Suprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-UHFFFAOYSA-N 0.000 description 1
- ROBFUDYVXSDBQM-UHFFFAOYSA-N Tartronic acid Chemical compound OC(=O)C(O)C(O)=O ROBFUDYVXSDBQM-UHFFFAOYSA-N 0.000 description 1
- 229960003188 Temazepam Drugs 0.000 description 1
- 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 description 1
- GUHPRPJDBZHYCJ-UHFFFAOYSA-N Tiaprofenic acid Chemical compound S1C(C(C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-UHFFFAOYSA-N 0.000 description 1
- WDEFBBTXULIOBB-WBVHZDCISA-N Tilidine Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C WDEFBBTXULIOBB-WBVHZDCISA-N 0.000 description 1
- MIMJSJSRRDZIPW-UHFFFAOYSA-N Tilmacoxib Chemical compound C=1C=C(S(N)(=O)=O)C(F)=CC=1C=1OC(C)=NC=1C1CCCCC1 MIMJSJSRRDZIPW-UHFFFAOYSA-N 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N Tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N Tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- RGCVKNLCSQQDEP-UHFFFAOYSA-N Tranquisan Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 RGCVKNLCSQQDEP-UHFFFAOYSA-N 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N Triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 1
- XSCGXQMFQXDFCW-UHFFFAOYSA-N Triflupromazine Chemical compound C1=C(C(F)(F)F)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 XSCGXQMFQXDFCW-UHFFFAOYSA-N 0.000 description 1
- 229960003904 Triflupromazine Drugs 0.000 description 1
- FEZBIKUBAYAZIU-UHFFFAOYSA-N Trimethobenzamide Chemical compound COC1=C(OC)C(OC)=CC(C(=O)NCC=2C=CC(OCCN(C)C)=CC=2)=C1 FEZBIKUBAYAZIU-UHFFFAOYSA-N 0.000 description 1
- 229960004441 Tyrosine Drugs 0.000 description 1
- KJIOQYGWTQBHNH-UHFFFAOYSA-N Undecanol Chemical compound CCCCCCCCCCCO KJIOQYGWTQBHNH-UHFFFAOYSA-N 0.000 description 1
- 229950007802 Zidometacin Drugs 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N Zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- UVITTYOJFDLOGI-LICQEQMYSA-N [(2S,5R)-1,2,5-trimethyl-4-phenylpiperidin-4-yl] propanoate Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)C[C@H](C)N(C)C[C@H]1C UVITTYOJFDLOGI-LICQEQMYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002998 adhesive polymer Substances 0.000 description 1
- 239000002390 adhesive tape Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910001583 allophane Inorganic materials 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 230000002238 attenuated Effects 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 229960005430 benoxaprofen Drugs 0.000 description 1
- 239000000749 benzodiazepine receptor blocking agent Substances 0.000 description 1
- 229960004611 bezitramide Drugs 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 229960002729 bromazepam Drugs 0.000 description 1
- 229960001705 buclizine Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229960002495 buspirone Drugs 0.000 description 1
- 229940015694 butabarbital Drugs 0.000 description 1
- 229960002546 butalbital Drugs 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 229930003833 capsaicin Natural products 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 229960004362 clorazepate Drugs 0.000 description 1
- 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 description 1
- 238000005354 coacervation Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229960005188 collagen Drugs 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000000110 cooling liquid Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 229960003564 cyclizine Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000002951 depilatory Effects 0.000 description 1
- 230000000881 depressing Effects 0.000 description 1
- 229950003851 desomorphine Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- 229960002069 diamorphine Drugs 0.000 description 1
- 229950001059 diampromide Drugs 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- 229920000359 diblock copolymer Polymers 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- JJTUDXZGHPGLLC-UHFFFAOYSA-N dilactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 1
- 229950011187 dimenoxadol Drugs 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960003413 dolasetron Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 229950010920 eptazocine Drugs 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- 229960000569 ethoheptazine Drugs 0.000 description 1
- IPOPQVVNCFQFRK-UHFFFAOYSA-N ethyl 1-(3-hydroxy-3-phenylpropyl)-4-phenylpiperidine-4-carboxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(O)C1=CC=CC=C1 IPOPQVVNCFQFRK-UHFFFAOYSA-N 0.000 description 1
- 229920001038 ethylene copolymer Polymers 0.000 description 1
- 229950006111 ethylmethylthiambutene Drugs 0.000 description 1
- 229960004945 etoricoxib Drugs 0.000 description 1
- 230000002743 euphoric Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000008369 fruit flavor Substances 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 235000021312 gluten Nutrition 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 229960002158 halazepam Drugs 0.000 description 1
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 239000000416 hydrocolloid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229960004187 indoprofen Drugs 0.000 description 1
- 229910052809 inorganic oxide Inorganic materials 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 229950009272 isomethadone Drugs 0.000 description 1
- 229950002252 isoxicam Drugs 0.000 description 1
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 description 1
- 229960003029 ketobemidone Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M laurate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229960004391 lorazepam Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 229960001474 meclozine Drugs 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 229960000365 meptazinol Drugs 0.000 description 1
- JLICHNCFTLFZJN-HNNXBMFYSA-N meptazinol Chemical compound C=1C=CC(O)=CC=1[C@@]1(CC)CCCCN(C)C1 JLICHNCFTLFZJN-HNNXBMFYSA-N 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229960002683 methohexital Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960001703 methylphenobarbital Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- IBMRTYCHDPMBFN-UHFFFAOYSA-N monomethyl glutaric acid Chemical compound COC(=O)CCCC(O)=O IBMRTYCHDPMBFN-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N nabumeton Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 229960004300 nicomorphine Drugs 0.000 description 1
- 229960000965 nimesulide Drugs 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 229940121367 non-opioid analgesics Drugs 0.000 description 1
- 230000001465 nonopioid Effects 0.000 description 1
- 229950007418 norpipanone Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 239000008601 oleoresin Substances 0.000 description 1
- BARWIPMJPCRCTP-CLFAGFIQSA-N oleyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC BARWIPMJPCRCTP-CLFAGFIQSA-N 0.000 description 1
- 201000000988 opioid abuse Diseases 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 229960004535 oxazepam Drugs 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 229940023569 palmate Drugs 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 229960003294 papaveretum Drugs 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 229960004662 parecoxib Drugs 0.000 description 1
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- URWXJEHYXOTXBD-UHFFFAOYSA-N pentazocine Chemical compound C1=CN=NN=NN=C1 URWXJEHYXOTXBD-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000003285 pharmacodynamic Effects 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000079 pharmacotherapeutic Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229960001286 piritramide Drugs 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 1
- 229920000111 poly(butyric acid) Polymers 0.000 description 1
- 229920000218 poly(hydroxyvalerate) Polymers 0.000 description 1
- 229920002463 poly(p-dioxanone) polymer Polymers 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920002857 polybutadiene Polymers 0.000 description 1
- 239000000622 polydioxanone Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920003225 polyurethane elastomer Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Chemical class 0.000 description 1
- 239000011118 polyvinyl acetate Chemical class 0.000 description 1
- 229920001290 polyvinyl ester Polymers 0.000 description 1
- 229920001289 polyvinyl ether Polymers 0.000 description 1
- 229920001291 polyvinyl halide Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960003111 prochlorperazine Drugs 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 229960001964 quazepam Drugs 0.000 description 1
- RONWGALEIBILOG-VMJVVOMYSA-N quinine sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 RONWGALEIBILOG-VMJVVOMYSA-N 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 238000004621 scanning probe microscopy Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229960002060 secobarbital Drugs 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 230000037384 skin absorption Effects 0.000 description 1
- 231100000274 skin absorption Toxicity 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003068 static Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 150000003445 sucroses Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- ZQZCOBSUOFHDEE-UHFFFAOYSA-N tetrapropyl silicate Chemical compound CCCO[Si](OCCC)(OCCC)OCCC ZQZCOBSUOFHDEE-UHFFFAOYSA-N 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960001312 tiaprofenic acid Drugs 0.000 description 1
- 229960001402 tilidine Drugs 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- 229960004161 trimethobenzamide Drugs 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical compound CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 239000008307 w/o/w-emulsion Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
Abstract
The present invention provides abuse-resistant transdermal delivery devices containing an opioid agonist intended for analgesic purposes in pain patients.
Description
DEVICE OF TRANSDERMAL ADMINISTRATION OF OPIODDE RESISTANT TO ABUSE
FIELD OF THE INVENTION The present invention relates to transdermal administration devices useful for the administration of opioid agonists while decreasing the potential for abuse. BACKGROUND OF THE INVENTION Prolonged-release opioid formulations are known in the art and provide a longer period of pharmacological effect that is commonly experienced after the administration of immediate-release opioid preparations. Such longer periods of efficacy achieved with sustained release formulations can provide many therapeutic benefits that are not achieved with the corresponding immediate release preparations. One approach to the prolonged release of the therapeutically active agent is the use of a transdermal delivery device such as the transdermal patch. Certain commercially available transdermal devices such as scopolamine or nitroglycerin, for example, contain a reservoir placed between an impermeable support and a face of the membrane and are generally adhered to the skin by means of a gel adhesive. In recent years, transdermal administration has been widely accepted in the management of chronic pain syndromes, for example, when analgesics are indicated for 24 hours. Transdermal administration devices in which the opioid analgesic is the active ingredient are known. Generally, a transdermal delivery device contains a therapeutically active agent (e.g., an opioid analgesic) in a reservoir or matrix and an adhesive that allows the transdermal device to adhere to the skin, allowing the passage of the active agent from the device through the Patient's skin Once the active agent has penetrated the skin layer, the drug is absorbed into the bloodstream where it can exert a desired pharmacotherapeutic effect such as analgesia. Examples of patents in this area include U.S. Patent No. 4,588,580 to Gale, which discloses transdermal delivery devices for the administration of fentanyl or its analgesically effective derivatives; U.S. Patent No. 5,908,846 to Bundgaard, which discloses a topical preparation of morphine derivatives together with a vehicle in the form of a transdermal patch; U.S. Patent No. 4,806,341 to Chien et al, which describes the transdermal administration of narcotic analgesics or opioid antagonists using a device containing a support layer, an adjoining layer of a solid polymer matrix containing narcotic morphine analgesics or antagonists Y
permeability enhancers in the skin and an adhesive polymer; U.S. Patent No. 4,626,539 to Aunst et al., which discloses transdermal patches containing a gel, a lotion or cream composed of an opioid, a penetration enhancer, and a pharmaceutical carrier such as propylene glycol; and U.S. Patent Nos. 5,968,547; 6,231,886; and 6,344,212 to Reder et al., which describe transdermal delivery devices containing buprenorphine to provide prolonged pain management. All references cited herein, including the foregoing, are incorporated herein by reference in their entirety.
A commercially available opioid analgesic transdermal device commercialized in the United States is the Duragesic® patch containing fentanyl as the active agent (commercially available from Janssen Pharmaceutical). The 0 Duragesic® patch is adapted to provide analgesia for up to 48 to 72 hours.
A greater concern associated with the use of opioids is the abuse of said drugs and the diversion of these drugs from a patient in need of such treatment to an individual who is not a patient, for example to an individual who is not a patient for illicit uses. It has been recognized in the art that transdermal opioid formulations can be abused when the delivery device is adulterated (eg by chewing), breaking or extracting the drug) to release the opioid for its illicit use (for example for oral or parenteral use). Additionally, transdermal fentanyl administration devices "used" previously have been reported, which are subsequently used to abuse the surplus. U.S. Patent No. 5,236,714 to Lee et al. and U.S. Patent No. 5,149,538 to Granger et al., describe opioid agonists in transdermal delivery devices that purportedly have a lower abuse potential.
There remains a need for a transdermal opioid delivery device that has a lower potential for opioid abuse than does the device. 0 SUMMARY OF THE INVENTION
It is an object of the present invention to provide a transdermal delivery device containing opioid analgesics and having a lower abuse potential.
, A further objective of the present invention is to provide a method of pain treatment with a transdermal administration device containing opioids, this device having a lower abuse potential.
In accordance with the above objectives and others, the present invention is directed in part to a transdermal administration device for the administration of an opioid analgesic comprising an analgesically effective amount of an opioid agonist and an opioid antagonist in substantially non-releasable form when the device of transdermal administration is applied topically and intact.
In certain formulations, the present invention is directed to a transdermal delivery device comprising a drug-containing layer, which contains an effective amount of an opioid agonist and a plurality of dispersed microspheres in the drug-containing layer, the microspheres they contain an opioid antagonist and are visually undetectable in the layer containing the drug.
In certain formulations, the present invention is directed to a transdermal delivery device comprising a support layer; and a layer containing the drug in contact with a surface of the support layer, the layer containing the drug, which contains an effective amount of an opioid agonist and a plurality of dispersed microspheres in the layer containing the drug, the microspheres comprise an opioid antagonist and a polymer selected from the group consisting of polyesters, polyethers, polyorthoesters, polysaccharides, cyclodextrins, chitosans, poly (S-caprolactones), polyanhydrides, albumin, combinations and copolymers thereof, the microspheres have an average size from about 1 to about 500 μm.
In certain formulations, the present invention is further directed to a transdermal delivery device comprising a support layer; and a layer containing the drug in contact with a surface of the support layer, the layer containing the drug comprises an effective amount of an opioid agonist and a plurality of scattered microspheres in the layer containing the drug, the microspheres contain a Opioid antagonist dispersed in a polymeric matrix, the microspheres have an average size from about 1 to about 500 μm. In certain formulations, the present invention is directed to a transdermal delivery device comprising a support layer; and a drug containing a layer connected to a surface of the support layer, the layer containing the drug contains an effective amount of an opioid agonist and a plurality of dispersed microspheres in the layer containing the drug, the microspheres have a size average from about 1 to about 500 μm and contain an opioid antagonist. In such a formulation, the size of the microspheres containing the antagonist will not readily separate from the opioid agonist in the event that an abuser attempts to abuse the opioid agonist that is in the transdermal device.
In certain formulations, the present invention is directed to a transdermal delivery device comprising a support layer; and a layer containing the drug in contact with a surface of the support layer, the layer containing the drug comprises an effective amount of an opioid agonist and a plurality of dispersed microspheres in the layer containing the drug. The microspheres consist essentially of an opioid antagonist and a polymer selected from the group consisting of polyesters, polyethers, polyorthoesters, polysaccharides, cyclodextrins, chitosans, poly (S-caprolactones), polyanhydrides, albumin, combinations and copolymers thereof.
In certain formulations, the present invention is further directed to a transdermal delivery device containing a support layer; and a layer containing the drug in contact with a surface of the support layer, the layer containing the drug comprises an effective amount of an opioid agonist and a plurality of dispersed microspheres in the layer containing the drug. The microspheres consist essentially of an opioid antagonist dispersed in a polymeric matrix.
In certain formulations, the layer containing an opioid agonist is selected from an adhesive layer, a matrix layer, a reservoir or a combination thereof.
In certain formulations, the antagonist is non-releasable or substantially non-releasable from the microspheres (and therefore not releasable or substantially non-releasable from the device) when the transdermal delivery device is applied topically and intact to the skin of the human patient . However, the antagonist is releasable from the microspheres when the transdermal delivery device is adulterated for example when chewing, wetting, piercing, breaking or, on the other hand, when it is subjected to any other treatment that alters the integrity of the microspheres.
In certain preferred formulations, the microspheres of the present invention that are dispersed in the matrix layer containing the opioid agonist, which have a visual appearance similar to the other components of the matrix layer (eg the opioid agonist, the / the polymer (s), etc.) so that the opioid agonist and the opioid antagonist can not be easily identified by visual inspection, thus increasing the difficulty in separating the opioid agonist from the antagonist.
In certain preferred formulations, the composition of the matrix layer inhibits the dissolution of the microspheres and the release of the opioid antagonist with topical application of the device on the intact skin of a human patient. In the present invention, the amount of antagonist released from a transdermal delivery device of the present invention that has been altered (eg, by chewing, wetting, piercing, breaking or being subjected to any other treatment that disrupts the integrity of the microspheres) ). is an amount that at least partially blocks the opioid agonist when administered (eg, orally, intranasally, parenterally or sublingually). Preferably, the euphoric effect of the opioid agonist will be attenuated or blocked, thereby reducing the tendency to misuse or abuse of the dosage form.
The physical / chemical characteristics of the polymers can be used to provide abuse resistance of the present invention. For example, the hydrolysis of poly (orthoester) is catalyzed by acid. Thus, abuse by oral intake of the opioid-containing portion in the transdermal delivery device, which contains microspheres comprising polyorthoester and opioid antagonist would result in degradation of the polymer and release of the opioid antagonist in the stomach acid environment . Additionally, the degradation of microspheres containing polysaccharides and proteins is catalyzed by enzymatic cleavage. Thus, abuse through oral ingestion of a transdermal delivery device of microspheres comprising dextrans would result in degradation of the polymer and release of the opioid antagonist in the gastrointestinal tract. In addition, an abuser could try to extract a transdermal formulation containing microspheres by immersing the complete formulation in diethyl ether. The microspheres would dissolve in the ether, releasing the antagonist, leaving the liquid unsuitable for abuse. In a further formulation, in the intraoral abuse scenario of a transdermal dosage form, the saliva would penetrate the transdermal formulation and dissolve the microspheres, releasing the antagonist and decreasing the value of the transdermal formulation for the abuser. In said formulation, the microspheres could contain a material such as starch which is degraded by salivary amylase.
In certain preferred formulations, a separate adhesive layer may be included in contact with the opposing matrix layer on the side of the matrix layer in contact with the support layer. In other preferred formulations, the matrix layer containing the opioid agonist and antagonist microspheres comprises a pharmaceutically acceptable polymer that also acts as a transdermal adhesive, and an additional adhesive layer is not needed to allow the transdermal device to adhere to the skin. of the patient. In certain preferred formulations, the adhesive layer used to glue the transdermal delivery device to the patient's skin comprises a pressure sensitive adhesive. In certain formulations, the transdermal delivery device further comprises a removable protective layer that is in contact with the adhesive or matrix layer and that is removed prior to application of the transdermal delivery device to the skin.
In preferred formulations, the transdermal delivery device provides effective pain management for a period of 2 to 8 days when used on the intact skin of a human patient.
In certain formulations, the transdermal delivery device is a transdermal patch, a transdermal plaster, a transdermal disk, a transdermal iontophoretic device, or the like.
The term "prolonged release" is defined for purposes of the present invention as the release of an opioid agonist from a transdermal delivery device to a cup in which blood concentrations (levels) (eg plasma) are reached and maintained within the therapeutic range but low toxic levels for at least 1 day and for example, for 2 and 8 days.
For purposes of the present invention, the term "opioid agonist" is interchangeable with the term "opioid" or "opioid analgesic" and includes the base of the opioid and pharmaceutically acceptable salts thereof. The present invention also contemplates the administration of a prodrug thereof (for example ethers or esters) which becomes an active agonist in the patient's device. The opioid agonist can be a complete agonist, a mixed agonist-antagonist or a partial agonist.
For purposes of the present invention, the term "opioid antagonist" includes the base of the antagonist and pharmaceutically acceptable salts thereof. The present invention also contemplates the administration of a prodrug thereof. Examples of opioid antagonists include, for example, nalorphine, nalorphine dinicotinate, naloxone, nalmefene, cyclazocine, levalorfan, naltrexone, nadide, cyclazocine, amifenazole and pharmaceutically acceptable salts thereof and mixtures thereof.
The term "effective analgesia" is defined for purposes of the present invention as a satisfactory reduction in, or elimination of pain as determined by a human patient or through the use of a recognized pain scale. In a preferred formulation, effective analgesia has no side effects, or has a tolerable level of side effects as determined in a human patient.
The term "microsphere" as used herein means solid (or semi-solid) particles that contain an active agent dispersed in a biocompatible polymer (matrix type) or covered by (microcapsules), which serve to render the antagonist non-releasable or substantially non-releasable. The term "substantially non-releasable" means that the antagonist could be released in a small amount, as long as the amount released does not affect or does not significantly affect the analgesic efficacy when the dosage form is administered transdermally, as planned.
The term "flow" refers to the rate of penetration of a chemical entity such as an opioid agonist or an opioid antagonist, through the skin of the individual.
The term "emulsion", for purposes of the present invention, means a stable dispersion of a liquid in a second immiscible liquid. With respect to emulsions, the term "continuous phase" means the external phase compared to the "dispersed phase" which is the internal phase. For example, if an emulsion is a "water in oil" emulsion (w / o), the oil is the continuous phase, while in an "oil in water" emulsion (o / w), water is the continuous phase.
The term "pharmaceutically acceptable salt" means any suitable, non-toxic salt of an antagonist or opioid agonist having therapeutic properties in a mammal, particularly a human. The preparation of such salts is known to those skilled in the pharmaceutical arts. Forms of useful salts of opioid agonists and opioid antagonists may include for example the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, citrate, tartrate, bitartrate, lactate, phosphate, maleate, fumarate, succinate, acetate, palmate, stearate, oleate, palmitate, napsylate, tosylate, methanesulfonate, succinate, laurate and valerate among others.
In certain formulations, the present invention is further directed to a method for preparing a transdermal administration device of an opioid agonist having a lower abuse potential, the method comprising incorporating a plurality of microspheres containing an opioid antagonist, as disclosed in present, within a transdermal opioid device.
In certain formulations, the present invention is further directed to a method of treating pain, which comprises applying a transdermal delivery device, described herein, to a patient in need of such therapy.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows a cross section of a formulation of a transdermal delivery device of the present invention. The device has a waterproof support layer 10, such as metal foil, plastic film, or a laminate of different materials. In contact with and under the support layer 10 is located a matrix layer containing both the opioid agonist and the microspheres 11 containing the polymer and the opioid antagonist. The matrix layer of this formulation acts as a reservoir for the opioid agonist and as an adhesive, allowing this transdermal delivery device to adhere to the skin of a human patient.
Figure 2 shows a cross section of a formulation of a transdermal delivery device of the present invention. The device is similar to the device shown in Figure 1 in that it has an impermeable support layer 13 and a matrix layer 15 in contact with or under the support layer 13. The matrix layer contains both the opioid agonist and microspheres 14 containing the polymer and the opioid agonist. This transdermal delivery device further has a separate adhesive layer 16 in contact with the matrix layer and in contact with certain portions of the support layer, allowing this transdermal delivery device to adhere to the skin of a human patient.
Figure 3 shows a cross section of a formulation of a transdermal delivery device of the present invention. The device has an impermeable support layer 17 and a matrix layer 18 in contact with and below the support layer 17. The matrix layer contains an opioid agonist and microspheres 20 containing the polymer and the opioid agonist. The matrix layer acts as an adhesive, allowing the transdermal delivery device to adhere to the skin of a human patient. The transdermal delivery device further has a removable protective layer 19 in contact with and below the matrix layer that is removed prior to the application of the transdermal delivery device.
Figure 4 shows a cross section of a formulation of a transdermal delivery device of the present invention. The device is similar to the device shown in Figure 3, in that it has an impermeable support layer 21 and a matrix layer 22 in contact with and below the support layer 21. The matrix layer contains an opioid agonist and microspheres. containing the polymer and the opioid antagonist. Additionally, the transdermal delivery device has an adhesive layer 23 in contact with and below the matrix layer 22, allowing the transdermal delivery device to adhere to the skin of the human patient. This transdermal delivery device further has a removable protective layer 24 in contact with and below the adhesive layer that is removed prior to application of the transdermal delivery device.
Figure 5 depicts an in vitro release of naltrexone from the microspheres prepared according to Example 1.
DETAILED DESCRIPTION OF THE INVENTION
Certain devices prepared and used according to the present invention contain an opioid antagonist dispersed in microspheres. In certain formulations, the amount of opioid antagonist incorporated within the microspheres ranges from about 1% by weight to about 90% by weight, or from about 5% by weight to about 70% by weight, or from about 10% by weight. 30% up to 50% by weight of the microsphere (including the active).
In the present invention, the opioid antagonist is incorporated within the microspheres for use in the transdermal delivery devices to render the opioid antagonist non-releasable or substantially non-releasable with topical application to the intact skin of a transdermal delivery device that contains antagonist microspheres. Preferably, the microspheres comprise a polymeric substance.
Suitable polymers that can be used to form opioid-containing antagonist microspheres include soluble, insoluble, biodegradable and non-biodegradable polymers. The use of pharmaceutically acceptable non-toxic polymers is preferred.
Physicochemical characteristics of the polymers can be selected to provide greater abuse resistance of the present invention. For example, the hydrolysis of polyorthoester is catalyzed by acid. Thus, abuse via oral intake of the opioid-containing portion of the transdermal delivery device, which contains polyorthoester microspheres comprising an opioid antagonist would result in degradation of the polymer and release of the opioid antagonist in the acidic environment of the stomach. The degradation of microspheres comprising polysaccharides and proteins is catalyzed by enzymatic cleavage. Thus, for example, abuse via oral intake of the opioid-containing portion of the transdermal delivery device, which contains dextran microspheres would result in degradation of the polymer and release of the opioid antagonist in the gastrointestinal tract.
The polymers that can be used for the microspheres containing the opioid antagonist of the present invention can generally be classified into three types, for example, natural, semi-synthetic and synthetic, based on their origins. Natural biodegradable polymers can also be classified into proteins and polysaccharides.
Representative polymers derived from natural sources include proteins such as zaina, modified zaina, casein, gelatin, gluten, albumin, fetuin, orosomucoid, glycoproteins, collagen, synthetic polypeptides and elastin. Synthetic biodegradable polypeptides include, for example, poly- (N-hydroxyalkyl) -L-asparagine, poly- (N-hydroxyalkyl) -L-glutamine, and copolymers of N-hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutamine with other amino acids, for example, L-alanine, L-lysine, L-phenylalanine, L-valine, L-tyrosine and the like.
Polysaccharides (eg, cellulose, dextrans, polyhyaluronic acid, lipopolysaccharides), acrylic polymers and metracrylic esters and alginic acid can also be used. Natural, synthetically modified (ie semi-synthetic) polymers include alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters and nitrocelluloses among others.
Semi-synthetic biodegradable polymers are produced by modifying natural polymers to produce polymers that have altered physical and chemical properties such as thermogelling properties, mechanical strength and degradation rates. Examples of biodegradable, semi-synthetic polymers suitable for use in the present invention include modified chitosan complexes, Chitosan sulfate chondroitin / A complexes. and soluble water, phosphorylated chitosan (P-chitosan) and combinations thereof such as, for example, alginate-chitosan.
The lack of immunogenicity and more reproducible and predictable physical-chemical properties make synthetic biodegradable polymers preferable to natural polymers for drug administration uses. These polymers can be non-toxic and biodegradable and the delivery devices have been prepared from these polymers. Therefore, synthetic biodegradable polymers may be particularly suitable for the microspheres of the present invention.
Non-limiting examples of synthetic biodegradable polymers include: polyesters, polyethers, polyorthoesters, polyvinyl alcohols, polyamides, polycarbonates, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinyl pyrrolidone, polyglycolides, polysiloxanes , polylactides, polyurethanes and copolymers thereof. Non-limiting examples of polyesters include polylactic acid, polyglycolic acid, polylactide-co-glycolide, poly (e-caprolactone), polydioxanone, poly (ethylene terephthalate), poly (malic acid), poly (tartronic acid), polyphosphazenes, polyorthoester, poly (valeric acid), poly (butyric acid), polyhydroxybutyrate, polyhydroxyvalerate, polyanhydride and copolymers of monomers used to synthesize any of the polymers mentioned above, for example polylactic-co-glycolic acid or the polyhydroxybutyrate copolymer with hydroxyvaleric acid (Biopol ® by Zeneca). Copolymers of lactic and glycolic acids, for example, polylactic-co-glycolic acid (PLGA), have been widely studied for their use in drug delivery devices such as microspheres.
In certain formulations, the polymer (e.g., PLGA) can have a molecular weight of from about 1 KD to about 100 KD or greater, from about 5 KD to about 60 KD or from about 10 KD to about 40 KD. KD In certain formulations, a portion of PLGA (eg, from 10% to up to 90%) may have a molecular weight of less than 20 KD or less than 15 KD and the corresponding remaining portion (eg, from 90% to 10% ) may have a weight greater than 25 KD or greater than 35 KD.
The poly (e-caprolactone) can be used in preparing microspheres for use in the present invention. The degradation rate of poly (e-caprolactone) is much slower than that of polyglycolic acid or polylactic-co-glycolic acid. Poly (e-caprolactone) has an exceptional ability to form mixtures with many other polymers. Poly (e-caprolactone) copolymers can be used to control the permeability and mechanical properties of drug delivery devices.
The polyethers and polyorthoesters can be further used in preparing microspheres for use in the present invention. These polymers have been incorporated in multiblock for block polymers that have different rates of degradation, mechanical strength, porosity, diffusivity and inherent viscosity. Examples of polyethers include polyethylene glycol and polypropylene glycol. An example of a multiblock copolymer is poly (ether ester amide). Additionally, triblock copolymers of polyorthoesters with various polyethylene glycol contents are useful for their stability in water / oil emulsions (w / o) and have greater efficacy than the polyorthoester when used in preparing microspheres. Other useful block copolymers include diblock copolymers of polylactic acid-glycolic acid) and polyethylene glycol (PEG), triblock copolymers of PEG-PLGA-PEG, copolymers of PLGA and polylysine, and polyestereter block copolymers.
In certain formulations, the microspheres useful for practicing the present invention are spherically formed and from about up to about 500 microns, from about 1 to about 300 microns, from about 1 micron to about 10 microns.
200 microns, from around 1 to around 100 microns, from around
300 up to 500 microns, from 200 to 500 microns, from 100 to 500 microns, from 125 to 200 microns or from 50 to 100 microns in diameter. The size of the microsphere may depend on the type of polymer used. In certain formulations, rather than spherical, the microspheres may be formed irregularly, where the diameter is considered to be the largest cross-section of the microsphere.
In certain formulations, the microspheres used in the present invention comprise an opioid antagonist in an amount of from about 5% to up to 70% by weight of the microsphere (including the active).
In certain formulations, the opioid antagonist can be loaded into the microspheres via microencapsulation. The microencapsulation techniques to be used in accordance with the present invention are described in U.S. Patent Nos. 3,161,602; 3,396,117; 3,270,100; 3,405,070; 3,341,466; 3,567,650; 3,875,074; 4,652,441; 5,100,669; 4,438,253; 4,391,909; 4,145,184; 4,277,364; 5,288,502 and 5,665,428. In addition, the microspheres can be prepared by evaporation of the solvent as described for example in, E. Mathiowitz, et al., J. Scanning Microscopy, 4, 329 (1990); L.R. Beck, et al., Fertile. Steril., 31, 545 (1979); and S. Benita, et al, J. Pharm. Sci. 73, 1721 (1984); or by hot melt microencapsulation, as described for example in E. Mathowitz, et al., Reactive Polymers 6, 275 (1987); or by spray drying. The microspheres can be prepared by any method known in the art including but not limited to coacervation, phase separation, solvent evaporation, spray drying, spray solidification, pan coating, fluidized bed coating and the like.
For purposes of the present invention, a microcapsule can be functionally described as a small container enclosing the contents with a film. The film can be a synthetic, semi-synthetic or natural polymer, as described above, and can control the release (or provide non-release) of the contents. The rate of release of the contents from a microcapsule is determined primarily by the chemical structure and the thickness of the film of the capsule and the size of the microcapsule. In microcapsule formulations, small solid particles of opioid antagonist can be coated with a coating consisting of an organic polymer, hydrocolloid, sugar, wax, fat, metal or inorganic oxide.
In certain formulations, the opioid antagonist is incorporated into the microspheres using an oil / water emulsion (o / w), a water / oil emulsion (w / o), an oil / oil emulsion (o / o), an oil emulsion / water / oil (o / w / o), an oil / water / water emulsion (o / w / w), a water / oil / water emulsion (w / o / w) or a water / oil / oil emulsion (w / o / w) / o / o) or similar.
In certain formulations, the opioid antagonist is incorporated into the microspheres by microemulsification of a fixed oil and an aqueous solution of the water-soluble opioid antagonist. This emulsion is of the "water in oil" type. When the emulsion is of the "water in oil" type, the oil is the continuous phase or the external phase and the water is the internal phase or "dispersed" in the opposite way to the "oil in water" device, where the water is the phase keep going.
In certain preferred formulations, the opioid antagonist can be incorporated into the microspheres via a multi-phase emulsification device such as w / o / w. The opioid antagonist can be incorporated into the multi-phase microspheres prepared by the solvent evaporation technique from multiple emulsion. In this technique, the opioid antagonist is incorporated into the biodegradable polymer microspheres by an emulsification process. The device is suitable for water insoluble and soluble opioid antagonists. The microspheres of the present invention can be multiphasic polymeric microspheres in which the opioid antagonist is dispersed in oily droplets in a polymeric matrix. The microspheres can be prepared by a solvent evaporation technique from a multiple emulsion described in U.S. Patent No. 5,288,501, this patent describes a solvent evaporation technique from a multiple emulsion where the drug is protected within an oily droplet and contact with the polymer, organic solvent and other potentially denaturing agents is avoided.
Multiple emulsions are devices in which the droplets of the dispersed phase in oil contain in turn dispersed aqueous droplets consisting of a liquid identical to that of the continuous aqueous phase. These are emulsions of emulsions with a high capacity to trap the drug, protection of the trapped drug, ability to introduce incompatible substances within the same device and prolongation of the release.
Anyone within a variety of fixed oils can be used to prepare the microspheres, including safflower, soybean, peanut, cottonseed, sesame, cod liver oil, among others. In certain preferred formulations, soy, sesame and safflower oil are used. The oil phase may consist of isohexadecane or liquid paraffin. The concentration of oil influences the stability of the emulsion. Preferably, the stability is optimal with a percentage of oil in a range of 20-30% w / w of the total emulsion.
In the multiple emulsion process, the organic phase can be prepared by preparing an emulsion containing the opioid antagonist and a polymeric material. Preferably, the opioid antagonist is dispersed in an organic polymer solution in methylene chloride or ethyl acetate. The resulting primary w / o emulsion is then dispersed in an external aqueous phase to form a second emulsion comprising microspheres containing the opioid antagonist in the polymeric matrix material (i.e., emulsification in the external phase). The subsequent steps of the process are similar to the o / w method. The step of dissolving the drug in the internal aqueous phase is eliminated. In addition, a higher theoretical drug load is achieved because the internal drug phase consists only of solid particles and not a drug solution.
In yet another formulation, an o / w emulsion process can be used to incorporate the opioid antagonist into the microspheres. For the o / w dispersion method, the opioid antagonist is dispersed in the polymer phase followed by emulsification in the external aqueous phase. Then, the microspheres are separated from the external aqueous phase by wet screening followed by washing and drying by desiccator.
In certain formulations, the present invention utilizes encapsulation techniques that allow solid or liquid substances to be encapsulated by polymers. In certain preferred formulations, the opioid antagonist has a crystalline form. The crystalline opioid antagonist particles can be formed by solid state crystallization by exposure to solvent vapors. The crystalline form can decrease the water content of the preparation, thus preserving the stability of the opioid antagonist. The crystal can be encapsulated in a fixed oil, and mixed with a solution of polymer and solvent in dispersion oil. U.S. Patent No. 6,287,693 to Savoir discloses stable particles of crystalline organic compounds that are formed into microspheres to achieve storage stability. Alternatively, any suitable method can be used to produce crystalline particles of organic compounds.
The stability and release characteristics of the emulsion devices are influenced by a number of factors such as the composition of the emulsion, the size of the droplet, viscosity, phase volumes and pH. The effectiveness of the opioid antagonist encapsulation can be optimized by minimizing the migration of the drug from the polymer by altering the volume, temperature and chemical composition of the extraction medium (chilling solution) during the encapsulation process. The purpose of the chiller solution is to remove most of the organic solvent from the microspheres during the process.
The cooling liquid can be pure water, an aqueous solution or any other suitable liquid, the volume, quantity and type thereof depends on the solvents in the emulsion phase. The volume of the coolant is in the order of 10 times the saturated volume (ie 10 times the volume of cooler needed to fully absorb the volume of the solvent in the emulsion). The volume of the cooler can vary from about 2 to about 20 times the saturated volume.
After cooling, the microspheres are separated from the aqueous chilling solution by, for example, decanting or filtration with a sieving column. Various other separation techniques can be used.
The residual solvent in the microspheres accelerates the degradation process, thus reducing its conservation time. Therefore, the microspheres are preferably washed with water or a solvent miscible therewith to further remove the residual solvent, preferably at a level of from 0.2 to less than 2.0% or less. Aliphatic alcohols such as methanol, ethanol, propanol, butanol, and isomers of the foregoing are preferred for use in washing solutions. Ethanol is the most preferred.
Alternatively, the removal of the solvent can be achieved by evaporation. In formulations where the solvent evaporation method is used, the polymer can be dissolved in a volatile organic solvent. The opioid antagoma is dispersed or dissolved in a solution of the selected polymer and a volatile organic solvent such as methylene chloride, the resulting solution or dispersion is suspended in an aqueous solution containing a surface active agent such as polyvinyl alcohol, and is used a temperature gradient to remove the solvent.
The solvent evaporation method may involve dissolving the opioid antagonist and the polymer in a co-solvent device. However, alternative methods that omit the incorporation of unacceptable organic solvents can be used. The resulting emulsion is stirred until most of the organic solvent evaporates, leaving solid microspheres. The solution can be loaded with the opioid antagonist and suspended in 200 ml of vigorously stirred distilled water containing 1% (w / v) polyvinyl alcohol. After 4 hours of stirring, the organic solvent is evaporated from the polymer and the resulting microspheres can be washed with water and dried overnight in a lyophilizer.
In formulations where the spray drying method is used, the polymer can be dissolved in methylene chloride. Suspend a known amount of drug (where the opioid antagonist is insoluble) or co-dissolve (where the opioid antagonist is soluble) in the polymer solution. Then, the solution of the dispersion is spray dried. This method is used for small microspheres between 1-10 microns.
In certain formulations, a hot melt encapsulation method is used. By using this method, the polymer can be melted first and then mixed with solid drug particles that have been sieved to less than 50 microns. The mixture is suspended in a non-miscible solvent and with constant stirring, is heated to 5 ° C above the melting point of the polymer. Once the emulsion is stabilized, it cools until the polymer particles solidify. The resulting microspheres are washed by decanting with petroleum ether to provide a free-flowing powder. This technique is used for polyesters, polyanhydrides and polymers with high melting points and different molecular weights. The typical performance of the microspheres in this process is about 80-90%. The resulting microspheres have an encapsulated structure.
To create microspheres containing an opioid antagonist, an organic or oil phase (discontinuous) and an aqueous phase can be combined. The organic and aqueous phases are largely or substantially immiscible, with the aqueous phase constituting the continuous phase of the emulsion. The organic phase includes the active agent and the wall-forming polymer, i.e., the polymer matrix material. The organic phase is prepared by dispersing the active opioid antagonist in the organic solvent (s). Preferably, the organic and aqueous phases are combined under the influence of a mixing means, preferably a static mixer.
Opioid antagonists useful in the present invention include, but are not limited to, nalorphine, nalorphine dinicotinate, naloxone, nalmefene, cyclazocine, levalorfan, naltrexone, nadide, cyclazocine, amifenazole and pharmaceutically acceptable salts thereof and mixtures thereof. Preferably, the opioid antagonist is an orally bioavailable antagonist, for example, naltrexone or a pharmaceutically acceptable salt thereof. By using a bioavailable antagonist, the transdermal device will prevent both oral and parenteral abuse.
After the formation of the microspheres containing the opioid antagonist, the microspheres are incorporated into a transdermal delivery device containing an opioid agonist. Preferably, the microspheres are included in a transdermal delivery device so that they are substantially indistinguishable from the preparation volume containing the opioid agonist (e.g., the microspheres can be embedded in the matrix of the matrix delivery device). In certain formulations, the opioid agonist has a form that can be absorbed through the human skin, i.e., the opioid agonist can be administered effectively through the transdermal route. In some formulations, it may be necessary to further provide an absorption enhancer to facilitate transdermal absorption.
In the transdermal delivery devices of the present invention, the opioid agonist is available for absorption, passing through pores in the intact surface of the skin, typically at less than 50 nm to provide prolonged therapeutic levels over a longer period of time . Transdermal delivery devices that are prepared in accordance with the present invention can release the opioid agonist according to the first-order pharmacokinetics (eg, where the plasma concentrations of the opioid agonist increase over a specific period of time) or according to with zero order pharmacokinetics (for example, when plasma concentrations are maintained at relatively constant levels in a specific period of time) or with zero order and first order pharmacokinetics. Opioid agonists that can be selected for use in transdermal delivery devices of the present invention include any opioid agonist, mixed opioid agonist-antagonist, or partial agonist, including, but not limited to: alfentanil, allylprodin, alphaprodin, anileridin, benzinophil, bezitramide , buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimetheptanol, dimethylthiambutene, dioxafethylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levorphanol, levofenacilmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopona, morphine, mirofin, narcein, nicomorphine, norlevorphanol, normetadoma, nalorphine, nalbufen, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pent azocine, fenadoxone, fenomorphane, phenazocine, phenoperidine, piminodine, piritramide, profeptazine, promedol, properidin, propoxyphene, remifentanil, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, mixtures thereof and the like. In preferred formulations, the opioid agonist is selected from the group consisting of transdermally administrable forms of fentanyl, buprenorphine, sufentanil, hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, pharmaceutically acceptable salts of the same and mixtures thereof. Any type of transdermal delivery device can be used in accordance with the methods of the present invention, provided that the (a) pharmacokinetic and pharmacodynamic response (s) are obtained for at least a period of one day, such as, for example, from 2 to 8 days. Preferably, transdermal delivery devices include, for example, transdermal patches, transdermal plasters, transdermal disks, and the like. In a preferred formulation, the transdermal drug delivery device of the present invention is a patch, usually in the range from about 1 to 30 square centimeters, preferably 2 to 10 square centimeters. The term "patch", as used herein, includes any product having a support membrane and a surface with a pressure-sensitive adhesive face that allows adhesion to the patient's skin. Said products can be provided in various sizes and configurations such as tapes, bandages, sheets and the like. In the transdermal delivery device of the present invention, the opioid agonist is preferably dispersed along a matrix (such as, for example, a polymer matrix). In such a matrix device, the release of the opioid agonist can be controlled predominantly by diffusion of the opioid agonist out of the polymer or by erosion of the polymer to release the opioid agonist, or by the combination of these two mechanisms. When the diffusion of the opioid agonist is faster than the erosion of the polymer, the release of the drug is controlled by diffusion.
When the erosion of the polymer is faster than the diffusion of the opioid agonist, the release of the drug is controlled by the erosion of the polymer. If the delivery device is prepared with a polymer that undergoes supercifial erosion, the release of the drug can be controlled by varying the amount of drug loaded in the device and / or by varying the geometric dimension of the delivery device. Generally, the polymers used in the polymer matrix of the transdermal delivery device are those capable of forming thin walls or coatings, through which the opioid agonist can pass at a controlled rate. Examples of such polymers for use in the preparation of polymeric matrices include: polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethylacrylate copolymers, ethylene vinyl acetate copolymers, silicones, rubber, homopolymers, copolymers or synthetic block polymers similar to rubber, polyacrylic esters and copolymers thereof, polyurethanes, polyisobutylene, chlorinated polyethylene, polyvinylchloride, vinyl chloride-vinyl acetate copolymer, polymethacrylate (hydrogel) polymer, polyvinylidene chloride, poly (ethylene terephthalate), ethylene copolymer vinyl alcohol, ethylene-vinyl oxyethanol copolymer, silicones, including silicone copolymers, such as polysiloxane-polymethacrylate copolymers, cellulose polymers (for example, ethyl cellulose and cellulose esters), polycarbonates, polytetrafluoroethylene and mixtures thereof.
Preferred materials for use in the preparation of the polymer matrix are silicone elastomers of the general polydimethylsiloxane structures (eg, silicone polymers). Preferred silicone polymers are those which crosslink and which are pharmaceutically acceptable. For example, preferred materials for use in the preparation of the polymer matrix layer include silicone polymers that are crosslinkable copolymers, having dimethyl and / or dimethylvinyl siloxane units that can be crosslinked using an appropriate peroxide catalyst. Likewise, the preferred polymers are those consisting of block copolymers based on styrene and 1,3-dienes (particularly linear styrene-isoprene block copolymers of styrene-butadiene block copolymers), polyisobutylenes, acrylate-based polymers and / or methacrylate. In certain formulations, the polymer matrix includes a pharmaceutically acceptable crosslinking agent. Suitable crosslinking agents include, for example, tetrapropoxysilane, among others. Certain formulations of the present invention include a polymer matrix layer having an opioid agonist with interspersed microspheres of opioid antagonists. Preferably, for the opioid antagonist to become bioavailable, the integrity of the microspheres must be altered. The combination of microsphere with polymeric matrix prevents the release of the opioid antagonist from the microspheres embedded in the matrix in an intact device. The release of opioid antagonist from the microspheres can also be prevented by means of polymer coatings on the microspheres.
Preferably, the transdermal delivery device of the present invention comprises a support layer made of a pharmaceutically acceptable material that is impermeable to the opioid agonist. The support layer preferably serves as a protective coating for the opioid agonist and may also provide a support function. Examples of suitable materials for making the support layer are: polyethylene films, polypropylene, polyvinylchloride, polyurethane, high and low density polyesters such as polyethylene phthalate, metal foils, sheet metal laminates of said appropriate polymer films and fabrics. textiles .. Preferably, the materials used for the backing layer are laminates of said polymer films with a metal foil such as aluminum foil. The support layer may have any suitable thickness that provides the desired protection and support functions. A suitable thickness will be, for example, from 10 to 200 microns. In certain alternative formulations, the transdermal delivery device of the present invention may have microspheres contained in a reservoir. In said reservoir device, the opioid agonist and the microspheres of the opioid antagonist are dispersed in a reservoir (eg, a reservoir of liquid or gel), and the rate limiting the biodegradable membrane is located in the flow path of the reservoirs. drugs, thereby limiting the flow of the opioid agonist into the skin. Said device can provide a constant release rate of the opioid agonist, but serves to prevent the release of the opioid antagonist. A transdermal delivery device using a reservoir device may also have a support layer and, optionally, a removable protective layer, as described above with the array device.
Preferred transdermal devices used in accordance with the methods of the present invention, include, more preferably, an adhesive layer for adhering the delivery device to the skin of the patient for a desired period of administration, such as, for example, from 2 to 8. days. If the adhesive layer of the delivery device fails to provide adequate adhesion for the desired period, contact between the delivery device and the skin can be maintained by, for example, attaching the delivery device to the patient's skin with an adhesive tape. , as for example, a surgical tape. It is not relevant for the purposes of the present invention if the adhesion of the delivery device to the skin of the patient is achieved only by means of the adhesive layer of the delivery device or by the use of an external source of adhesion, such as surgical tape. , as long as the administration device adheres to the patient's skin for the required period. However, in all cases, the adhesive must allow the patch to firmly adhere to the patient's skin in need of treatment, but it ld not adhere as strongly to the patient when the patch is removed. The adhesive layer can be selected from any adhesive known in the art that is pharmaceutically compatible with the delivery device. The adhesive is preferably hypoallergenic. Examples of adhesives include: an adhesive polyacrylic polymer, an acrylate copolymer (eg, polyacrylate) or an adhesive polyisobutylene polymer. Other useful adhesives include silicones, polyisoalkylenes, rubbers, vinyl acetates, polybutadiene, styrene-butadiene (or isoprene) -styrene block copolymer rubber, acrylic rubber, and natural rubber; high molecular weight vinyl-based materials, such as polyvinyl alkyl ether; polyvinyl acetate, cellulose derivatives such as methylcellulose, carboxymethyl cellulose and hydroxypropyl cellulose; polysaccharides such as pullullan, dextrin and agar; and polyurethane elastomers and polyester elastomers. While many of these adhesives are virtually interchangeable, some combinations of a specific opioid analgesic and a specific adhesive may provide slightly better properties. In some formulations, the adhesive is a pressure sensitive contact adhesive, which is preferably hypoallergenic. In certain formulations, the transdermal drug delivery material provides the adhesive and matrix functions that the drug contains. In certain formulations with a separate adhesive layer, the drug will be distributed throughout the layers (with the exception of the support layer), according to its relative affinity with the different environments offered by the different layers. The matrix "layer" may consist of more than one simple sub-layer, with opioid loading in the different layers adjusted to optimize their administration characteristics and microspheres containing the opioid antagonist dispersed throughout them. In such formulations, the matrix containing the drug has direct contact with the skin and the transdermal delivery device is adhered to the skin by a peripheral adhesive or by the matrix itself. In certain formulations, the transdermal delivery device of the present invention optionally includes an agent that serves to enhance impregnation. Agents that serve to enhance impregnation are compounds that promote the penetration and / or absorption of the opioid agonist through the skin into the bloodstream of the patient. Due to these agents that serve to increase impregnation, almost any drug, to a certain extent, can be administered transdermally. The agents that serve to increase the impregnation, are generally characterized to be of the group of monovalent aromatic, aliphatic or linear cycloaliphatic or branched alcohols of 4-12 carbon atoms; aromatic or cycloaliphatic aldehydes or ketones of 4-10 carbon atoms; carbon cycloalkanoyl amides Cto-20; aliphatic, cycloaliphatic and aromatic esters; N, N-di-low alkyl sulfides; unsaturated oils, terpenes and glycol silicates. A non-limiting list of agents that serve to increase impregnation includes polyethylene glycols, surfactants and the like. The impregnation of the opioid agonist can also be increased by occlusion of the delivery device after application at the desired site in the patient with, for example, an occlusive bandage. The impregnation can also be increased by the removal of the beauty from the application site, such as cutting, shaving or by the use of a depilatory agent. Another way to increase impregnation is by applying heat to the adhesion site of the patch, such as with an infrared lamp. Other ways to increase the impregnation of the opioid agonist include the use of iontophoretic means. In certain formulations, the transdermal delivery device includes a softening agent to modify the skin at the time of adhesion, so as to promote absorption of the drug. Suitable softening agents include: higher alcohols such as dodecanol, undecanol, octanol, ethers of carboxylic acids, where the alcohol component can also be a polyethoxylated alcohol, diesters of dicarboxylic acids, such as di-n-butyladapate and triglycerides, particularly medium chain triglycerides of caprylic / capric acids or coconut oil. Other examples of softening agents are multivalent alcohols, such as, for example, levulinic acid, caprylic acids, glycerol and 1,2-propanediol, which can also be etherified by polyethylene glycols.
In certain formulations, a solvent for the opioid agonist is included in the transdermal delivery device of the present invention. Preferably, the solvent dissolves the opioid agonist to a sufficient degree, thus preventing complete salt formation. A non-limiting list of suitable solvents includes those with at least one acidic group. Monoesters of dicarboxylic acids such as monomethylglutarate and monomethyladipate are particularly suitable. Other pharmaceutically acceptable compounds that can be included in the transdermal delivery device of the present invention include agents that serve to increase viscosity, such as cellulose derivatives, natural or synthetic gums, such as guar gum and the like. In certain formulations of the present invention, the transdermal delivery device further includes a removable protective layer. The removable protective layer is removed prior to application, and may consist of materials used for the production of the support layer described above, as long as they are removable, such as, for example, by a silicone treatment. Other examples of removable protective layers are paper treated with polytetra-fluoroethylene, allophane, polyvinyl chloride and the like. Generally, the removable protective layer is in contact with the adhesive layer, and provides a convenient means to maintain the integrity of the adhesive layer until the desired period of application. In the art of transdermal delivery devices it is understood that, in order to maintain a desired flow rate for a desired dosage period, it is necessary to include a "surplus" of active agent in the transdermal delivery device in an amount that is substantially greater than the amount to be administered to the patient during the desired period. For example, to maintain the desired flow rate for a period of three days, it is considered necessary to include in the transdermal delivery device much more than would otherwise be 100% of a three-day dose of the active agent. The remainder of the active agent remains in the transdermal delivery device. Only that portion of the active agent leaving the transdermal delivery device becomes available for skin absorption. The term "surplus" means, for the purposes of the present invention, the amount of opioid analgesic in the transdermal delivery device that is not administered to the patient. The surplus is necessary to create a sufficient concentration gradient, whereby the active agent will migrate from the transdermal delivery device through the skin of the patient to produce a sufficient therapeutic effect. Preferably, the transdermal delivery device of the present invention is used to prolong the dosage, releasing the opioid agonist constantly or intermittently to the patient, while the opioid antagonist within the microspheres remains non-releasable or substantially non-releasable. Non-opioid analgesics that can be included in combination with the opioid agonist are, for example, acetaminophen, phenacetin and nonsteroidal anti-inflammatory agents. Suitable non-steroidal anti-inflammatory agents include; aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprocine, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucilloxic acid, indomethacin, sulindac, tolmetin, zomepirac, thiopinaco, zidometacin, acemetacin, fentiazaco, clidanaco, oxpinaco, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, pharmaceutically acceptable salts thereof and mixtures thereof . Other non-steroidal anti-inflammatory agents include: cox-2 inhibitors such as celecoxib, DUP-697, flosulide, meloxicam, 6-MNA, L-745337, rofecoxib, nabumetone, nimesulide, NS-398, SC-5766, T-614, L-768277, GR-253035, JTE-522, RS-57067 -000, SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367, SC-5766, PD-164387, etoricoxib, valdecoxib, parecoxib, pharmaceutically acceptable salts thereof and mixtures thereof . Other active agents that can be combined with the opioid agonist can be, for example, antiemetic / antiviral agents such as chlorpromazine, perphenazine, triflupromazine, prochlorperazine, triethylperazine, metoclopropramide, cyclizine, meclizine, scopolamine, diphenhydramine, buclizine, dimenhydrate and trimethobenzamide.; 5-HT3 receptor agonists such as ondasetron, granisetron and dolasetron; antianxiety agents such as meprobamate, benzodiazepines, buspirone, hydroxyzine, doxepin and the like. It is contemplated that previously known transdermal delivery devices can be modified, including in the matrix, reservoir and / or adhesive layers, microspheres containing opioid antagonists as described above, so as to diminish the abuse potential of said devices. For example, transdermal delivery devices for use in accordance with the present invention may use certain aspects described in U.S. Patent No. 5,240,711 to Hille, et. to the.; U.S. Patent No. 5,225,199 to Hidaka et. to the.; U.S. Patent No. 4,588,580 to Gale et. al, U.S. Patent No. 5,069,909 to Sharma et. to the.; U.S. Patent No. 4,806,341 to Chien et. to the.; U.S. Patent No. 5,026,556 to Drust et. to the.; and McQuinn, R. L. et. al, "Sustained Oral Mucosal Delivery in Human
Volunteers "J. Controlled Reléase; (34) 1995 (243-250) The present invention also relates to transdermal dosage forms described herein, using different active agent / antagonist (ie, non-opioid) combinations, for prevent abuse of the active agent For example, when a benzodiazepine is used as an active agent in the transdermal dosage form of the present invention, a non-releasable benzodiazepine antagonist can be formulated in the transdermal dosage form. an active agent in the transdermal dosage form of the present invention, a non-releasable barbiturate antagonist can be formulated in the transdermal dosage form When an amphetamine is used as an active agent in the transdermal dosage form of the present invention, a Non-releasable amphetamine antagonist can be formulated in the transdermal dosage form. benzodiazepines "refers to benzodiazepines and drugs that are derived from benzodiazepine capable of depressing the central nervous system. Benzodiazepines include, but are not limited to: alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate and mixtures thereof. Benzodiazepine antagonists that can be used in the present invention include, but are not limited to, flumazenil. Barbiturates refer to sedative-hypnotic drugs derived from barbituric acid
(2,4,6, -trioxohexahydropyrimidine). Barbiturates include, but are not limited to: amobarbital, aprobotal, butabarbital, butalbital, methohexital, mephobarbital, metarbital, pentobarbital, phenobarbital, secobarbital and mixtures thereof.
Barbiturate antagonists that can be used in the present invention include, but are not limited to amphetamines, as described herein. Stimulants refer to drugs that stimulate the central nervous system. Stimulants include, but are not limited to amphetamines, such as amphetamine, dextroamphetamine, dextroamphetamine-resin complex, dextroamphetamine, methamphetamine, methylphenidate, and mixtures thereof. Stimulating antagonists that can be used in the present invention include, but are not limited to, benzodiazepines, as described herein. The present invention also relates to transdermal dosage forms described herein, which utilize adverse agents other than antagonists, to prevent abuse of the active agent. The term "adverse agent" refers to any agent that can create an unpleasant effect with administration in a releasable form. Examples of adverse agents other than antagonists include emetics, irritants and those that produce bitterness. Emetics include, but are not limited to ipecac and apomorphine. Irritants include, but are not limited to: capsaicin, capsaicin analogues and mixtures thereof. Capsaicin analogues include: resiniferatoxin, denatonium benzoate; tiniatoxin, heptanoylisobutylamide, heptanoyl guaiacilamide, other isobutylamides or guaiacylamides, dihydrocapsaicin, homovainillyloctylester, nonanoyl vanillylamide and mixtures thereof.
Agents that produce bitterness include, but are not limited to, essential oils; aromatic flavorings; oleoresins; extracts derived from plants, leaves, flowers; fruit flavors; sucrose derivatives; chlorosucrose derivatives; quinine sulfate; denatonium benzoate; and combinations thereof.
The following examples are not intended to limit the invention in any way.
EXAMPLE 1 Using the procedure described in this example, multiple batches of microspheres loaded with naltrexone were prepared using polymers Lactide / Glycolide (65:35) of different molecular weights (40 KD), 40 KD with 0.01% calcium chloride, 50:50 mixture of 40 KD and low molecular weight (around 10 KD) and 11 KD). The microspheres loaded with naltrexone were made using a solvent extraction from double emulsion of water-in-oil-in water (w / o / w) / evaporation technique. In this process, naltrexone was dissolved in phosphate buffered saline (PBS) (pH 7.4) containing 0.05% polyvinyl alcohol (PVA) (w / v) as an emulsifier, and mixed with ethyl acetate which Contains polylactic acid-co-glycolide (PLGA). The emulsification was carried out by sonication for 15 seconds. The resulting emulsion was then injected in PBS (pH 7.4) containing 0.05% (w / v) PVA as an emulsifier, to produce a double w / o / w emulsion. The dispersion was then stirred at a constant temperature for 30 minutes. In order to extract the ethyl acetate from the first emulsion within the external phase, a second buffer solution (pH 7.4) containing 0.05% (w / v) PVA at a rate of 3 ml was continuously added. /minute. The temperature of the second emulsion throughout the solvent extraction / evaporation phase was kept constant, using a low temperature chiller. The resulting naltrexone loaded microspheres were collected by vacuum filtration and washed three times with PBS. The microspheres were then dried under vacuum overnight and stored at
4C.
The load of naltrexone for the microspheres is set forth below in Table 1.
TABLE 1 Polymer Naltrexone charge the complete microsphere 40KD 42.2% 40KD and 0.01% Calcium chloride 42.3% Mix 50:50 of 40KD and low molecular weight 39.3% (to the O KD) 11 KD 28, 8%
EXAMPLE 2 The microsphere prepared in Example 1 was exposed to simulated extraction conditions to determine the degree of in vitro release of naltrexone from the microspheres. The extractions were performed using 0.5N NaCl, phosphate buffer pH 6.5. The sample size was 100 mg microspheres and the release of naltrexone was measured at 0.5, 1 and 4 hours. The results are set forth in Table 2 and Figure 5. TABLE 2
H KD 42.3 mg as 2.4% 3.5% 5.9% Base
Based on the amount of antagonist released from any given microsphere formulation, the antagonist amount loaded into the microspheres can be adjusted to obtain the release of the desired amount with the adulteration.
EXAMPLE 3 (Prophetic) The microspheres are prepared as described below: Naltrexone is mixed with required amounts of gelatin, Tween 80 and water and heated, then the mixture is dispersed in a mixture of aluminum monostearate, Span 80 and Soybean oil to form a microemulsion The microemulsion is homogenized by a microfluidizer, then the microemulsion is dispersed in PLGA-acetonitrile solution, then the acetonitrile is removed from the emulsion by evaporation under atmospheric pressure, thus forming microspheres containing naltrexone for be incorporated into the transdermal delivery device.
EXAMPLE 4 (Prophetic) A transdermal patch is prepared in accordance with the disclosure in WO 96/19975 to LTS GMBH, published on July 4, 1996, with the addition of naltrexone containing microspheres, prepared according to Example 1, according to follow:
The following are homogenized: 1,139 g of a polyacrylate solution at 47.83 w / w% with a self-crosslinking acrylate copolymer, containing 2-ethylhexylacrylate, vinyl acetate, acrylic acid (solvent: ethyl acetate: heptane: isopropanol: toluene : acetylacetonate in the ratio 37: 26: 26: 4: 1), 100 g of levulinic acid, 150 g of oleyl oleate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate and 100 g of buprenorphine base. The mixture is stirred for 2 hours and then visually examined to confirm that all solids have dissolved. Evaporation loss is controlled by the method of replenishing and compensating the solvent with the addition of ethyl acetate, if required. Then, the mixture is combined with the naltrexone microspheres prepared as described above in Example 1. This mixture is then transferred to a transparent 420 mm wide polyester sheet. The solvent is removed by drying with hot air. Then, the sealing film is covered with a polyester sheet. A surface of 16 cm is cut with the help of the appropriate cutting tool.
Although the invention has been described and illustrated with reference to certain preferred formulations therein, those skilled in the art will appreciate that the modifications can be made without departing from the spirit and scope of the invention. It is contemplated that such variations are within the scope of the appended claims.
Claims (25)
1. TRANSDERMAL DELIVERY DEVICE CHARACTERIZED because the delivery device comprises: a drug-containing layer comprising an effective amount of an opioid agonist and a plurality of dispersed microspheres in the drug-containing layer, the * 0 microspheres comprising an opioid antagonist already) be visually indiscernible in the drug-containing layer; or b) in an average size of 1 to 500 μm in diameter.
2. Transdermal delivery device according to alternative a) of Claim 1, CHARACTERIZED in that the microspheres have an average size of 1 to 500 μm in diameter.
3. Transdermal delivery device according to alternative b) of Claim 1, CHARACTERIZED in that the microspheres have an average size of 1 to 300 μm in diameter.
4. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the plurality of microspheres comprise the opioid antagonist dispersed in a polymeric matrix.
5. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the microspheres further comprise a polymer selected from the group consisting of polyesters, polyethers, poly (orthoesters), polysaccharides, cyclodextrins, chitosans, poly (S-caprolactones), polydrides, albumin, combinations and copolymers thereof and mixtures thereof.
6. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the microspheres consist essentially of the opioid antagonist and a polymer selected from the group consisting of polyesters, polyethers, poly (orthoesters), polysaccharides, cyclodextrins, chitosans, poly (S-caprolactones), polydrides, albumin, combinations and copolymers thereof.
7. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the microspheres essentially consist of the antagonist 1 or opioid dispersed in a polymeric matrix.
8. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the microspheres have an average size of 300 to 500 microns, of 200 to 500 microns, of 125 to 200 microns, of 50 to 100 microns, of 1 to 200 microns, of 1 to 100 microns or 100 to 500 microns in diameter.
^ 9. Transdermal delivery device according to claim 1, CHARACTERIZED because the opioid antagonist becomes releasable if the transdermal delivery device is chewed, soaked, punctured, ruptured or exposed to any other treatment that disrupts the integrity of the microspheres.
10. Transdermal delivery device according to Claim 1, CHARACTERIZED because the effect of the opioid agonist is at least partially blocked when the delivery device is chewed, milled or dissolved in a solvent, or is exposed to any other treatment that disrupts the integrity of the microspheres, and administered orally, intranasally, parenterally or sublingually.
11. Transdermal delivery device according to Claim 1, CHARACTERIZED because the opioid antagonist is in the form of stable crystalline particles.
12. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the microspheres are dispersed uniformly within the drug layer.
13. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the opioid agonist is selected from the group consisting of fentanyl, sufentanil, buprenorphine, hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.
14. Transdermal delivery device according to Claim 1 or 13, CHARACTERIZED because the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, diprenorphine, nalmexone, ciprenorphine, alazocine, oxylorphan, cyclophane, nalorphine, nalbuphine, buprenorphine butorphanol, cyclazocine , pentazocine, levallorphan, pharmaceutically acceptable salts thereof, and mixtures thereof; and preferably is naltrexone or a pharmaceutically acceptable addition salt thereof.
15. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the opioid analgesic is in an amount effective to provide analgesia for a period of time from 2 to 8 days upon being adhered to the skin of a human patient.
16. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the drug-containing layer is a matrix layer, and the matrix preferably comprises a material selected from the group consisting of polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethylacrylate copolymers, copolymers ethylene vinyl acetate, silicones, gums, homo-synthetic rubber-type, co-or block polymers, polyacrylic esters and copolymers thereof, polyurethanes, polyisobutylene, chlorinated polyethylene, chloruropolivinyl, vinyl chloride-vinyl acetate copolymer, polymethacrylate polymer (hydrogel) , polyvinylidene chloride, poly (ethylene terephthalate), ethylene-vinyl alcohol copolymer, ethylene-vinyloxyethanol copolymer, silicones (e.g., silicone copolymers such as polysiloxane-polymethacrylate copolymers), cellulose copolymers (e.g., ethyl cellulose) , and cellulose esters), polycarbonates, polytetrafluoroethylene and m ezclas of the same.
17. Transdermal delivery device according to Claim 4, CHARACTERIZED because the matrix is selected from silicone polymers, silicone polymers that are crosslinkable, copolymers with dimethyl and / or dimethylvinyl siloxane units which may crosslink, block copolymers based on styrene and 1,3-dienes, polyisobutylenes, polymers based on acrylate and / or methacrylate.
18. Transdermal delivery device according to Claim 16, CHARACTERIZED in that it further comprises an adhesive layer adjacent to, and in contact with, the matrix layer and permeable to the therapeutically active agent.
19. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the drug-containing layer is an adhesive layer and / or reservoir layer.
20. Transdermal delivery device according to Claim 25, CHARACTERIZED in that the reservoir layer further comprises a speed controlling membrane layer superimposed on the reservoir layer and substantially coextensive therewithin; and preferably further comprising an adhesive layer adjacent to, and in contact with, the membrane layer and permeable to the therapeutically active agent.
21. Transdermal delivery device according to Claim 18, CHARACTERIZED in that it further comprises a protective layer adhered to the adhesive layer and removable therefrom for use of the transdermal delivery device.
22. Transdermal delivery device according to claim 1, CHARACTERIZED because the transdermal delivery device is a device selected from the group consisting of a transdermal patch, a transdermal plaster, a transdermal disk and a transdermal iontophoretic device.
23. The use of a transdermal delivery device according to claim 1 to produce a medicament useful for the treatment of pain.
24. The use of a transdermal delivery device according to claim 1 for preparing a medicament useful for preventing the abuse of an opoid agonist.
25. The use of a transdermal delivery device according to any one of Claims 1-22 for preparing a medicament useful for providing analgesia.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/547,196 | 2004-02-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA06009535A true MXPA06009535A (en) | 2007-04-10 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2005216053B2 (en) | Abuse resistance opioid transdermal delivery device | |
RU2700926C2 (en) | Transdermal systems preventing abuse and misuse | |
NZ542969A (en) | Tamper resistant transdermal dosage form comprising an active agent component and an adverse agent component at the distal site of the active agent layer | |
WO1998036728A9 (en) | Sustained analgesia achieved with buprenorphine | |
US8075912B2 (en) | Autodestructive transdermal therapeutic system | |
MXPA06009535A (en) | Abuse resistant opioid transdermal delivery device containing opioid antagonist microspheres | |
CZ20022707A3 (en) | Pharmaceutical preparation |