JP6462877B2 - オキシモルホンの安息香酸、安息香酸誘導体及びヘテロアリールカルボン酸結合体、プロドラッグ、その製造法及び使用 - Google Patents
オキシモルホンの安息香酸、安息香酸誘導体及びヘテロアリールカルボン酸結合体、プロドラッグ、その製造法及び使用 Download PDFInfo
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- JP6462877B2 JP6462877B2 JP2017529821A JP2017529821A JP6462877B2 JP 6462877 B2 JP6462877 B2 JP 6462877B2 JP 2017529821 A JP2017529821 A JP 2017529821A JP 2017529821 A JP2017529821 A JP 2017529821A JP 6462877 B2 JP6462877 B2 JP 6462877B2
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- Prior art keywords
- acid
- oxymorphone
- composition
- oral
- present technology
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- 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 title claims description 300
- 229960005118 oxymorphone Drugs 0.000 title claims description 299
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 title claims description 22
- 239000002253 acid Substances 0.000 title description 78
- 239000000651 prodrug Substances 0.000 title description 42
- 229940002612 prodrug Drugs 0.000 title description 42
- 239000005711 Benzoic acid Substances 0.000 title description 7
- 235000010233 benzoic acid Nutrition 0.000 title description 7
- 150000001558 benzoic acid derivatives Chemical class 0.000 title description 6
- 238000004519 manufacturing process Methods 0.000 title description 4
- -1 troches Substances 0.000 claims description 162
- 239000000203 mixture Substances 0.000 claims description 145
- 150000001875 compounds Chemical class 0.000 claims description 42
- 230000000694 effects Effects 0.000 claims description 23
- 239000003826 tablet Substances 0.000 claims description 21
- 239000002552 dosage form Substances 0.000 claims description 19
- 230000002829 reductive effect Effects 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000000725 suspension Substances 0.000 claims description 15
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 14
- 239000002775 capsule Substances 0.000 claims description 14
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 12
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims description 12
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- 239000011230 binding agent Substances 0.000 claims description 9
- 235000001968 nicotinic acid Nutrition 0.000 claims description 9
- 239000011664 nicotinic acid Substances 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 8
- 239000007894 caplet Substances 0.000 claims description 7
- 239000000839 emulsion Substances 0.000 claims description 7
- 239000000796 flavoring agent Substances 0.000 claims description 7
- 238000001990 intravenous administration Methods 0.000 claims description 7
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- 239000003755 preservative agent Substances 0.000 claims description 7
- 239000007884 disintegrant Substances 0.000 claims description 6
- 239000010408 film Substances 0.000 claims description 6
- 235000019634 flavors Nutrition 0.000 claims description 6
- 239000000499 gel Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
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- 229960001860 salicylate Drugs 0.000 claims description 6
- 239000000829 suppository Substances 0.000 claims description 6
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 claims description 5
- 206010010774 Constipation Diseases 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000000576 coating method Methods 0.000 claims description 5
- 235000003599 food sweetener Nutrition 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 5
- 239000002002 slurry Substances 0.000 claims description 5
- 239000003765 sweetening agent Substances 0.000 claims description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 4
- 229940116871 l-lactate Drugs 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 3
- 208000030053 Opioid-Induced Constipation Diseases 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- 241000289690 Xenarthra Species 0.000 claims description 3
- 125000000129 anionic group Chemical group 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 125000002091 cationic group Chemical group 0.000 claims description 3
- 229950000206 estolate Drugs 0.000 claims description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 229930195712 glutamate Natural products 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 239000010409 thin film Substances 0.000 claims description 3
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 2
- YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 229920002126 Acrylic acid copolymer Polymers 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims description 2
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 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
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 claims description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229920002253 Tannate Polymers 0.000 claims description 2
- 239000005862 Whey Substances 0.000 claims description 2
- 102000007544 Whey Proteins Human genes 0.000 claims description 2
- 108010046377 Whey Proteins Proteins 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 229950010741 aceturate Drugs 0.000 claims description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 claims description 2
- 239000003463 adsorbent Substances 0.000 claims description 2
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 229940113720 aminosalicylate Drugs 0.000 claims description 2
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- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 229940099352 cholate Drugs 0.000 claims description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 2
- 229940120124 dichloroacetate Drugs 0.000 claims description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 2
- 235000011180 diphosphates Nutrition 0.000 claims description 2
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
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- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 claims description 2
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- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 229950000177 hibenzate Drugs 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
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- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 2
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- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 2
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- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims description 2
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- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims description 2
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 2
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- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims description 2
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- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 claims description 2
- 229950010765 pivalate Drugs 0.000 claims description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
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- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 claims description 2
- 239000011833 salt mixture Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 claims description 2
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Description
[0001]本願は、2014年12月2日出願の米国仮特許出願第62/086,326号に基づく優先権を主張し、前記出願は引用によってその全文を本明細書に援用する。
[0002]適用なし
HCl=塩酸塩
MW=分子量
fBA=非修飾オキシモルホンと本発明のプロドラッグ又は結合体との間のバイオアベイラビリティにおける差を説明する補正係数。
[00142]本技術のいくつかのプロドラッグ結合体について、経口PK曲線を求めた。ラットに2mg/kgの遊離塩基オキシモルホンに相当する量の結合体を経口投与し、放出されたオキシモルホンの血漿中濃度をLC−MS/MSにより経時的に測定した。結果を以下の表1にまとめた。
[00158]本技術のいくつかのプロドラッグ結合体について、鼻腔内PK曲線を求めた。ラットに0.2mg/kgの遊離塩基オキシモルホンに相当する量の結合体を鼻腔内投与し、放出されたオキシモルホンの血漿中濃度をLC−MS/MSにより経時的に測定した。
[00166]ここに特許請求されている技術は、オピオイドのオキシモルホンと様々なアリールカルボン酸との共有結合を利用し、医薬品有効成分(API)のオキシモルホンが経口投与後にインビボで放出されるようにすることにより、過剰摂取又は乱用を引き起こす可能性を削減している。これらの結合体は、安全であることが確認されているが高度に乱用される親分子のプロドラッグとして意図されている。一般に受け入れられているプロドラッグの定義を満たすには、結合体は顕著な薬理活性を持ってはならず、インビボで活性部分が放出されて初めて効果を発揮することになる。
の関係当業者も同じことを実施できるほど十分、明確、簡潔、及び正確な言葉でここに明
記されている。上記の記載は本技術の好適な態様を述べていること、及び添付の特許請求
の範囲に記載された本発明の精神又は範囲から逸脱することなく、その中で変更が可能で
あることは理解されるはずである。
以下に、出願時の特許請求の範囲の記載を示す。
[請求項1]
少なくとも一つのカルボン酸、その誘導体、その塩、又はそれらの組合せに共有結合さ
れたオキシモルホンを含む組成物。
[請求項2]
カルボン酸がアリールカルボン酸である、請求項1に記載の組成物。
[請求項3]
少なくとも一つのアリールカルボン酸が、オキシモルホンのC−3ヒドロキシル基、オ
キシモルホンのC−6エノール互変異性体、又はオキシモルホンのC−14ヒドロキシル
基のいずれかに共有結合されているか;又は少なくとも二つの独立に選ばれるアリールカ
ルボン酸がオキシモルホンのC−3ヒドロキシル基とC−6エノール互変異性体、又はオ
キシモルホンのC−6エノール互変異性体とC−14ヒドロキシル基、又はオキシモルホ
ンのC−3ヒドロキシル基とC−14ヒドロキシル基の両方に結合されているか;又は少
なくとも三つの独立に選ばれるアリールカルボン酸がオキシモルホンのC−3ヒドロキシ
ル基、C−6エノール互変異性体及びC−14ヒドロキシル基に結合されている、請求項
2に記載の組成物。
[請求項4]
アリールカルボン酸が、下記構造:
X、Y及びZは、本質的に、H、O、S、NH及び−(CH2)x−からなる群から独
立に選ばれ;
R1、R2及びR3は、本質的に、H、アルキル、アルコキシ、アリール、アルケニル
、アルキニル、ハロ、ハロアルキル、アルキルアリール、アリールアルキル、ヘテロサイ
クル、アリールアルコキシ、シクロアルキル、シクロアルケニル及びシクロアルキニルか
らなる群から独立に選ばれ;
o、p、qは約0又は約1から独立に選ばれ;そして
xは、約1〜約10の間の整数である]
を有するベンゾエートである、請求項3に記載の組成物。
[請求項5]
アリールカルボン酸が、本質的に、アミノベンゾエート、アントラニル酸の類似体、フ
ェナメート、ヒドロキシベンゾエート、アミノヒドロキシベンゾエート、サリチル酸類似
体、又はそれらの誘導体からなる群から選ばれる、請求項3に記載の組成物。
[請求項6]
前記アリールカルボン酸が、本質的に、安息香酸、サリチル酸、アセチルサリチル酸(
アスピリン)、3−ヒドロキシ安息香酸、4−ヒドロキシ安息香酸、6−メチルサリチル
酸、o,m,p−クレソチン酸、アナカルジン酸類、4,5−ジメチルサリチル酸、o,
m,p−チモト酸、ジフルシナル、o,m,p−アニス酸、2,3−ジヒドロキシ安息香
酸(2,3−DHB)、α,β,γ−レゾルシン酸、プロトカテク酸、ゲンチジン酸、ピ
ペロニル酸、3−メトキシサリチル酸、4−メトキシサリチル酸、5−メトキシサリチル
酸、6−メトキシサリチル酸、3−ヒドロキシ−2−メトキシ安息香酸、4−ヒドロキシ
−2−メトキシ安息香酸、5−ヒドロキシ−2−メトキシ安息香酸、バニリン酸、イソバ
ニリン酸、5−ヒドロキシ−3−メトキシ安息香酸、2,3−ジメトキシ安息香酸、2,
4−ジメトキシ安息香酸、2,5−ジメトキシ安息香酸、2,6−ジメトキシ安息香酸、
ベラトルム酸(3,4−ジメトキシ安息香酸)、3,5−ジメトキシ安息香酸、没食子酸
、2,3,4−トリヒドロキシ安息香酸、2,3,6−トリヒドロキシ安息香酸、2,4
,5−トリヒドロキシ安息香酸、3−O−メチル没食子酸(3−OMGA)、4−O−メ
チル没食子酸(4−OMGA)、3,4−O−ジメチル没食子酸、シリング酸、3,4,
5−トリメトキシ安息香酸、又はそれらの誘導体からなる群から選ばれる、請求項3に記
載の組成物。
[請求項7]
前記アリールカルボン酸が、4−アミノサリチル酸、3−ヒドロキシアントラニル酸、
3−メトキシアントラニル酸、及びそれらの誘導体からなる群から選ばれるアミノヒドロ
キシベンゾエートである、請求項3に記載の組成物。
[請求項8]
前記アリールカルボン酸が、アントラニル酸、3−アミノ安息香酸、4,5−ジメチル
アントラニル酸、N−メチルアントラニル酸、N−アセチルアントラニル酸、フェナム酸
類(例えば、トルフェナム酸、メフェナム酸、フルフェナム酸)、2,4−ジアミノ安息
香酸(2,4−DABA)、2−アセチルアミノ−4−アミノ安息香酸、4−アセチルア
ミノ−2−アミノ安息香酸、2,4−ジアセチルアミノ安息香酸、及びそれらの誘導体か
らなる群から選ばれるアミノベンゾエートである、請求項3に記載の組成物。
[請求項9]
前記アリールカルボン酸が、サリチル酸、アセチルサリチル酸(アスピリン)、3−ヒ
ドロキシ安息香酸、4−ヒドロキシ安息香酸、6−メチルサリチル酸、o,m,p−クレ
ソチン酸、アナカルジン酸類、4,5−ジメチルサリチル酸、o,m,p−チモト酸、ジ
フルシナル、o,m,p−アニス酸、2,3−ジヒドロキシ安息香酸(2,3−DHB)
、α,β,γ−レゾルシン酸、プロトカテク酸、ゲンチジン酸、ピペロニル酸、3−メト
キシサリチル酸、4−メトキシサリチル酸、5−メトキシサリチル酸、6−メトキシサリ
チル酸、3−ヒドロキシ−2−メトキシ安息香酸、4−ヒドロキシ−2−メトキシ安息香
酸、5−ヒドロキシ−2−メトキシ安息香酸、バニリン酸、イソバニリン酸、5−ヒドロ
キシ−3−メトキシ安息香酸、2,3−ジメトキシ安息香酸、2,4−ジメトキシ安息香
酸、2,5−ジメトキシ安息香酸、2,6−ジメトキシ安息香酸、ベラトルム酸(3,4
−ジメトキシ安息香酸)、3,5−ジメトキシ安息香酸、没食子酸、2,3,4−トリヒ
ドロキシ安息香酸、2,3,6−トリヒドロキシ安息香酸、2,4,5−トリヒドロキシ
安息香酸、3−O−メチル没食子酸(3−OMGA)、4−O−メチル没食子酸(4−O
MGA)、3,4−O−ジメチル没食子酸、シリング酸、3,4,5−トリメトキシ安息
香酸、及びそれらの誘導体からなる群から選ばれるヒドロキシベンゾエートである、請求
項3に記載の組成物。
[請求項10]
前記アリールカルボン酸が、下記構造:
X、Y及びZは、本質的に、H、O、S、NH及び−(CH2)x−からなる群から独
立に選ばれ;
R1、R2及びR3は、本質的に、H、アルキル、アルコキシ、アリール、アルケニル
、アルキニル、ハロ、ハロアルキル、アルキルアリール、アリールアルキル、ヘテロサイ
クル、アリールアルコキシ、シクロアルキル、シクロアルケニル及びシクロアルキニルか
らなる群から独立に選ばれ;
o、p、qは、約0又は約1から独立に選ばれ;そして
xは、約1〜約10の整数である]
の一つを有するヘテロアリールカルボン酸である、請求項3に記載の組成物。
[請求項11]
前記アリールカルボン酸が、本質的に、ニコチン酸(ナイアシン)、イソニコチン酸、
ピコリン酸、3−ヒドロキシピコリン酸、6−ヒドロキシニコチン酸、シトラジン酸、2
,6−ジヒドロキシニコチン酸、キヌレン酸、キサンツレン酸、6−ヒドロキシキヌレン
酸、8−メトキシキヌレン酸、7,8−ジヒドロキシキヌレン酸、7,8−ジヒドロ−7
,8−ジヒドロキシキヌレン酸、又はそれらの誘導体からなる群から選ばれるヘテロアリ
ールカルボン酸である、請求項3に記載の組成物。
[請求項12]
前記アリールカルボン酸が、下記構造:
X、Y及びZは、本質的に、H、O、S、NH及び−(CH2)x−からなる群から独
立に選ばれ;
R1、R2及びR3は、本質的に、H、アルキル、アルコキシ、アリール、アルケニル
、アルキニル、ハロ、ハロアルキル、アルキルアリール、アリールアルキル、ヘテロサイ
クル、アリールアルコキシ、シクロアルキル、シクロアルケニル及びシクロアルキニルか
らなる群から独立に選ばれ;
o、p、qは約0又は約1から独立に選ばれ;
xは、約1〜約10の整数であり;
Alkはアルキル鎖−(CH2)n−で、nは約0又は約1のいずれかであり;そして
R6は、H、OH又はカルボニルでありうる]
を有するフェニルアセテートの誘導体である、請求項3に記載の組成物。
[請求項13]
前記アリールカルボン酸が、本質的に、フェニルプロピオン酸、2−メチル−2−フェ
ニル酢酸、非ステロイド性抗炎症薬(NSAID)、プロフェン、チロシン代謝産物、又
はそれらの誘導体からなる群から選ばれる、請求項3に記載の組成物。
[請求項14]
前記アリールカルボン酸が、本質的に、フェニル酢酸(ヒドロアトロパ酸)、2−ヒド
ロキシフェニル酢酸、3−ヒドロキシフェニル酢酸、4−ヒドロキシフェニル酢酸、ホモ
プロトカテク酸、ホモゲンチジン酸、2,6−ジヒドロキシフェニル酢酸、ホモバニリン
酸、ホモイソバニリン酸、ホモベラトルム酸、アトロパ酸、d,l−トロパ酸、ジクロフ
ェナク、d,l−マンデル酸、3,4−ジヒドロキシ−d,l−マンデル酸、バニリル−
d,l−マンデル酸、イソバニリル−d,l−マンデル酸、イブプロフェン、フェノプロ
フェン、カルプロフェン、フルルビプロフェン、ケトプロフェン、ナプロキセン、又はそ
れらの誘導体からなる群から選ばれる、請求項3に記載の組成物。
[請求項15]
前記アリールカルボン酸が、下記構造:
X、Y及びZは、本質的に、H、O、S、NH及び−(CH2)x−からなる群から独
立に選ばれ;
R1、R2及びR3は、本質的に、H、アルキル、アルコキシ、アリール、アルケニル
、アルキニル、ハロ、ハロアルキル、アルキルアリール、アリールアルキル、ヘテロサイ
クル、アリールアルコキシ、シクロアルキル、シクロアルケニル及びシクロアルキニルか
らなる群から独立に選ばれ;
R4は、H又はOHであり;
R5は、H、OH又はカルボニルであり;
o、p、qは約0又は約1から独立に選ばれ;そして
xは約1〜約10の整数である]
の一つを有する桂皮酸又はフェニルプロピオン酸の類似体である、請求項3に記載の組成
物。
[請求項16]
前記アリールカルボン酸が、桂皮酸、o,m,p−クマル酸、2,3−ジヒドロキシ桂
皮酸、2,6−ジヒドロキシ桂皮酸、コーヒー酸、フェルラ酸、イソフェルラ酸、5−ヒ
ドロキシフェルラ酸、シナピン酸、2−ヒドロキシ−3−フェニルプロペン酸、又はそれ
らの誘導体である、請求項3に記載の組成物。
[請求項17]
前記アリールカルボン酸がフェニルプロピオン酸又はその置換誘導体である、請求項3
に記載の組成物。
[請求項18]
前記アリールカルボン酸が、フェニルプロピオン酸、メリロート酸、3−ヒドロキシフ
ェニルプロパン酸、4−ヒドロキシフェニルプロパン酸、2,3−ジヒドロキシフェニル
プロパン酸、d,l−フェニル乳酸、o,m,p−ヒドロキシ−d,l−フェニル乳酸、
フェニルピルビン酸、又はそれらの誘導体である、請求項3に記載の組成物。
[請求項19]
前記アリールカルボン酸が、フェニル酢酸(ヒドロアトロパ酸)、2−ヒドロキシフェ
ニル酢酸、3−ヒドロキシフェニル酢酸、4−ヒドロキシフェニル酢酸、ホモプロトカテ
ク酸、ホモゲンチジン酸、2,6−ジヒドロキシフェニル酢酸、ホモバニリン酸、ホモイ
ソバニリン酸、ホモベラトルム酸、アトロパ酸、d,l−トロパ酸、ジクロフェナク、d
,l−マンデル酸、3,4−ジヒドロキシ−d,l−マンデル酸、バニリル−d,l−マ
ンデル酸、イソバニリル−d,l−マンデル酸、イブプロフェン、フェノプロフェン、カ
ルプロフェン、フルルビプロフェン、ケトプロフェン、ナプロキセン、又はそれらの誘導
体である、請求項3に記載の組成物。
[請求項20]
オキシモルホンのC−6エノール互変異性体に共有結合されているアリールカルボン酸
が、アリール部分の環炭素に共有結合されたカルボキシル基を有する、請求項3に記載の
組成物。
[請求項21]
オキシモルホンのC−6エノール互変異性体に共有結合されているアリールカルボン酸
が、アリール部分から約1個の炭素によって隔てられたカルボキシル基を有する、請求項
3に記載の組成物。
[請求項22]
オキシモルホンのC−6エノール互変異性体に共有結合されているアリールカルボン酸
が、アリール部分から約2個の炭素によって隔てられたカルボキシル基を有する、請求項
3に記載の組成物。
[請求項23]
オキシモルホンのC−14ヒドロキシル基に共有結合されているアリールカルボン酸が
、アリール部分の環炭素に共有結合されたカルボキシル基を有する、請求項3に記載の組
成物。
[請求項24]
オキシモルホンのC−14ヒドロキシル基に共有結合されているアリールカルボン酸が
、アリール部分から約1個の炭素によって隔てられたカルボキシル基を有する、請求項3
に記載の組成物。
[請求項25]
オキシモルホンのC−14ヒドロキシル基に共有結合されているアリールカルボン酸が
、アリール部分から約2個の炭素によって隔てられたカルボキシル基を有する、請求項3
に記載の組成物。
[請求項26]
オキシモルホンのC−3ヒドロキシル基に共有結合されているアリールカルボン酸が、
アリール部分の環炭素に共有結合されたカルボキシル基を有する、請求項3に記載の組成
物。
[請求項27]
オキシモルホンのC−3ヒドロキシル基に共有結合されているアリールカルボン酸が、
アリール部分から約1個の炭素によって隔てられたカルボキシル基を有する、請求項3に
記載の組成物。
[請求項28]
オキシモルホンのC−3ヒドロキシル基に共有結合されているアリールカルボン酸が、
アリール部分から約2個の炭素によって隔てられたカルボキシル基を有する、請求項3に
記載の組成物。
[請求項29]
アリールカルボン酸の少なくとも一つが、オキシモルホンのC−3ヒドロキシル基、オ
キシモルホンのC−14ヒドロキシル基、オキシモルホンのC−6エノール互変異性体、
又はそれらの組合せに共有結合され、そしてアリール部分の環炭素に共有結合されたカル
ボキシル基を有する、請求項3に記載の組成物。
[請求項30]
アリールカルボン酸の少なくとも一つが、オキシモルホンのC−3ヒドロキシル基、オ
キシモルホンのC−14ヒドロキシル基、オキシモルホンのC−6エノール互変異性体、
又はそれらの組合せに共有結合され、そしてアリール部分から1個の炭素によって隔てら
れたカルボキシル基を有する、請求項3に記載の組成物。
[請求項31]
アリールカルボン酸の少なくとも一つが、オキシモルホンのC−3ヒドロキシル基、オ
キシモルホンのC−14ヒドロキシル基、オキシモルホンのC−6エノール互変異性体、
又はそれらの組合せに共有結合され、そしてアリール部分から約2個の炭素によって隔て
られたカルボキシル基を有する、請求項3に記載の組成物。
[請求項32]
組成物が、錠剤、カプセル、カプレット、軟質ゲル、坐剤、トローチ、ロゼンジ、経口
散剤、溶液、経口フィルム、薄片、スラリー、及び懸濁液からなる群から選ばれる剤形で
ある、請求項3に記載の組成物。
[請求項33]
治療上有効量の少なくとも一つの結合体を含有する包装された特定量の個別用量を含む
医薬キットであって、前記結合体は少なくとも一つのオキシモルホンと少なくとも一つの
アリールカルボン酸とを含む医薬キット。
[請求項34]
少なくとも一つのNSAID、その誘導体、その塩、又はそれらの組合せに共有結合さ
れたオキシモルホンを含む組成物。
[請求項35]
少なくとも一つのNSAIDが、オキシモルホンのC−3ヒドロキシル基、オキシモル
ホンのC−6エノール互変異性体、又はオキシモルホンのC−14ヒドロキシル基のいず
れかに共有結合されているか;又は少なくとも二つの独立に選ばれるNSAIDsがオキ
シモルホンのC−3ヒドロキシル基とC−6エノール互変異性体、又はオキシモルホンの
C−6エノール互変異性体とC−14ヒドロキシル基、又はオキシモルホンのC−3ヒド
ロキシル基とC−14ヒドロキシル基の両方に結合されているか;又は少なくとも三つの
独立に選ばれるNSAIDsがオキシモルホンのC−3ヒドロキシル基、C−6エノール
互変異性体及びC−14ヒドロキシル基に結合されている、請求項34に記載の組成物。
[請求項36]
少なくとも一つのNSAIDが、本質的に、アスピリン、ジフルシナル、サリチレート
、及びそれらの誘導体からなる群から選ばれるサリチレートである、請求項34に記載の
組成物。
[請求項37]
少なくとも一つのNSAIDが、本質的に、イブプロフェン、デクスイブプロフェン、
ナプロキセン、フェノプロフェン、ケトプロフェン、デクスケトプロフェン、フルルビプ
ロフェン、オキサプロジン、ロキソプロフェン、及びそれらの誘導体からなる群から選ば
れるプロピオネートである、請求項34に記載の組成物。
[請求項38]
少なくとも一つのNSAIDが、本質的に、インドメタシン、トルメチン、スリンダク
、エトドラク、ケトロラク、ジクロフェナク、及びそれらの誘導体からなる群から選ばれ
るアセテートである、請求項34に記載の組成物。
[請求項39]
少なくとも一つのNSAIDが、本質的に、ピロキシカム、メロキシカム、テノキシカ
ム、ロルノキシカム、イソキシカム、及びそれらの誘導体からなる群から選ばれるオキシ
カムである、請求項34に記載の組成物。
[請求項40]
少なくとも一つのNSAIDが、本質的に、メフェナム酸、メクロフェナム酸、フルフ
ェナム酸、トルフェナム酸、及びそれらの誘導体からなる群から選ばれるフェナメートで
ある、請求項34に記載の組成物。
[請求項41]
少なくとも一つのNSAIDが、本質的に、セレコキシブ、バルデコキシブ、ルミラコ
キシブ、及びそれらの誘導体からなる群から選ばれるCOX−2阻害薬である、請求項3
4に記載の組成物。
[請求項42]
組成物が、錠剤、カプセル、カプレット、坐剤、トローチ、ロゼンジ、経口散剤、溶液
、経口フィルム、薄片、スラリー、及び懸濁液からなる群から選ばれる剤形である、請求
項34に記載の組成物。
[請求項43]
前記結合体が、錠剤、カプセル、カプレット、坐剤、トローチ、ロゼンジ、経口散剤、
溶液、経口フィルム、薄片、スラリー、及び懸濁液からなる群から選ばれる剤形である、
請求項33に記載の医薬キット。
[請求項44]
約0.5mg〜約200mg/用量のオキシモルホンの用量に相当する投与量範囲での
前記結合体の使用に向けた説明書をさらに含む、請求項33に記載の医薬キット。
[請求項45]
組成物が、麻薬又はオピオイド乱用の治療;麻薬又はオピオイドの離脱症状の防止;中
等度〜重度の疼痛の治療;経口、鼻腔内又は静脈内薬物乱用の低減又は防止;又は経口、
鼻腔内もしくは非経口薬物乱用抵抗性の提供に使用される、請求項3に記載の組成物。
[請求項46]
組成物が、経口投与された場合、長時間にわたり、同じ時間で非結合オキシモルホンと
比較した場合に改良されたAUC及び放出速度を示し;非結合オキシモルホンと比較した
場合に経口PKプロフィールの変動の少なさを示し;又は非結合オキシモルホンと比較し
た場合に低減された副作用を有する、請求項3に記載の組成物。
[請求項47]
低減された副作用が、低減されたオピオイド誘発性便秘を含む、請求項46に記載の組
成物。
[請求項48]
組成物が、経口投与された場合、非結合オキシモルホンと比較した場合に治療上等価の
AUCを提供するのに足る量である、請求項3に記載の組成物。
[請求項49]
組成物が、経口投与された場合、等モル量の非結合オキシモルホンと比較した場合に治
療上等価のAUC及びCmaxを提供するのに足る量である、請求項3に記載の組成物。
[請求項50]
組成物が、経口投与された場合、等モル量の非結合オキシモルホンと比較した場合に治
療上等価のAUC及びより低いCmaxを提供するのに足る量である、請求項3に記載の
組成物。
[請求項51]
少なくとも一つの結合体の鼻腔内又は静脈内投与が、等モル量の非結合オキシモルホン
と比較した場合に、より低いAUC及び/又はCmaxを提供する、請求項3に記載の組
成物。
[請求項52]
少なくとも一つの結合体の経口投与が、等モル量の非結合オキシモルホンと比較した場
合に低減された過剰摂取可能性を提供する、請求項3に記載の組成物。
[請求項53]
少なくとも一つの結合体が、非結合オキシモルホンと比較した場合に増大した不正変更
抵抗性を提供する、請求項3に記載の組成物。
[請求項54]
少なくとも一つのオピオイドを患者の一つ又は複数のオピオイド受容体に結合させるこ
とによって媒介される疾患、障害又は状態を有する患者の治療法であって、治療上有効量
の少なくとも一つの請求項3の組成物を患者に経口投与することを含む方法。
[請求項55]
少なくとも一つの結合体代謝産物が患者のオピオイド受容体に可逆的に結合する、請求
項54に記載の方法。
[請求項56]
少なくとも一つの結合体代謝産物がオピオイド受容体に非可逆的に結合する、請求項5
4に記載の方法。
Claims (22)
- 請求項1に記載の化合物、その塩、又はそれらの組合せを含む組成物。
- 塩が、薬学的に許容可能なアニオン性の塩形、薬学的に許容可能なカチオン性の塩形、又はそれらの塩混合物である、請求項2に記載の組成物。
- 錠剤、カプセル、カプレット、軟質ゲル、坐剤、トローチ、ロゼンジ、経口散剤、溶液
、経口フィルム、薄片、スラリー、及び懸濁液からなる群から選ばれる剤形である、請求
項3に記載の組成物。 - 非結合オキシモルホンと比較した場合に低減された副作用を有する、請求項3に記載の
組成物。 - 低減された副作用が、低減されたオピオイド誘発性便秘を含む、請求項5に記載の組成
物。 - 前記化合物が、経口投与された場合、非結合オキシモルホンと比較した場合に治療上等価のAUCを提供するのに足る量である、請求項3に記載の組成物。
- 前記化合物が、経口投与された場合、等モル量の非結合オキシモルホンと比較した場合に治療上等価のAUC及びCmaxを提供するのに足る量である、請求項3に記載の組成物。
- 前記化合物が、経口投与された場合、等モル量の非結合オキシモルホンと比較した場合に治療上等価のAUC及びより低いCmaxを提供するのに足る量である、請求項3に記載の組成物。
- 前記化合物の鼻腔内又は静脈内投与が、等モル量の非結合オキシモルホンと比較した場合に、より低いAUC及び/又はCmaxを提供する、請求項3に記載の組成物。
- 前記化合物の経口投与が、等モル量の非結合オキシモルホンと比較した場合に低減された過剰摂取可能性を提供する、請求項3に記載の組成物。
- 前記化合物が、非結合オキシモルホンと比較した場合に増大した不正変更抵抗性を提供する、請求項3に記載の組成物。
- 前記薬学的に許容可能なアニオン性の塩形が、酢酸塩、l−アスパラギン酸塩、ベシル酸塩、炭酸水素塩、炭酸塩、d−カンシル酸塩、l−カンシル酸塩、クエン酸塩、エジシル酸塩、ギ酸塩、フマル酸塩、グルコン酸塩、臭化水素酸塩/臭化物、塩酸塩/塩化物、d−乳酸塩、l−乳酸塩、d,l−乳酸塩、d,l−リンゴ酸塩、l−リンゴ酸塩、メシル酸塩、パモ酸塩、リン酸塩、コハク酸塩、硫酸塩、硫酸水素塩、d−酒石酸塩、l−酒石酸塩、d,l−酒石酸塩、メソ−酒石酸塩、安息香酸塩、グルセプト酸塩、d−グルクロン酸塩、ヒベンズ酸塩、イセチオン酸塩、マロン酸塩、メチル硫酸塩、2−ナプシル酸塩、ニコチン酸塩、硝酸塩、オロチン酸塩、ステアリン酸塩、トシル酸塩、チオシアン酸塩、アセフィリネート(acefyllinate)、アセチュレート(aceturate)、アミノサリチル酸塩、アスコルビン酸塩、ホウ酸塩、酪酸塩、樟脳酸塩(camphorate)、樟脳炭酸塩(camphocarbonate)、デカン酸塩、ヘキサン酸塩、コール酸塩、シピオン酸塩、ジクロロ酢酸塩、エデンテート(edentate)、エチル硫酸塩、フレート(furate)、フシジン酸塩、ガラクタル酸塩、ガラクツロン酸塩、没食子酸塩、ゲンチジン酸塩、グルタミン酸塩、グルタル酸塩、グリセロリン酸塩、ヘプタン酸塩、ヒドロキシ安息香酸塩、馬尿酸塩、フェニルプロピオン酸塩、ヨウ化物、キシナホ酸塩、ラクトビオン酸塩、ラウリン酸塩、マレイン酸塩、マンデル酸塩、メタンスルホン酸塩、ミリスチン酸塩、ナパジシル酸塩、オレイン酸塩、シュウ酸塩、パルミチン酸塩、ピクリン酸塩、ピバル酸塩、プロピオン酸塩、ピロリン酸塩、サリチル酸塩、サリチル硫酸塩、スルホサリチル酸塩、タンニン酸塩、テレフタル酸塩、チオサリチル酸塩、トリブロフェネート(tribrophenate)、吉草酸塩、バルプロ酸塩、アジピン酸塩、4−アセトアミド安息香酸塩、カンシル酸塩、オクタン酸塩、エストレート(estolate)、エシレート(esylate)、グリコール酸塩、チオシアン酸塩、及びウンデシレン酸塩、又はそれらの混合物からなる群から選択される、請求項3に記載の組成物。
- 前記カチオン性の塩形が、ナトリウム、カリウム、カルシウム、マグネシウム、亜鉛、
アルミニウム、リチウム、コリネート、リシニウム、アンモニウム、トロメタミン、又は
それらの混合物からなる群から選択される、請求項3に記載の組成物。 - 前記化合物が、単位投与量あたり約1mg〜約100mgの、単位投与量あたりの量で存在し、単位投与量あたりの当該量は、オキシモルホンの含有量に基づく、請求項3に記載の組成物。
- 経口投与用、坐剤投与用、注射用粉末用、静脈内投与用、鼻腔内投与用、又は脊髄内投与用に製剤化されている、請求項3に記載の組成物。
- 経口投与用に製剤化されている組成物が、錠剤、カプセル、軟質ゲル、カプレット、ピル、経口散剤、トローチ、ロゼンジ、スラリー、溶液、懸濁液、エマルション、エリキシル、または経口薄膜(OTF)である、請求項16に記載の組成物。
- 錠剤、溶液、懸濁液、又は軟質ゲルの形態に製剤化されている、請求項17に記載の組
成物。 - 当該錠剤形態に製剤化されている組成物が一又はそれを超える賦形剤をさらに含み、当該賦形剤が、付着防止剤、結合剤、コーティング、崩壊剤、充填剤、フレーバー、色素、着色剤、流動促進剤、滑沢剤、保存剤、吸着剤、甘味剤、それらの誘導体、及びそれらの組合せからなる群から選択される、請求項18に記載の組成物。
- 結合剤が、ヒドロキシプロピルメチルセルロース、エチルセルロース、ポビドン、アク
リル酸及びメタクリル酸コポリマー、製薬用グレーズ、ガム、及びホエーからなる群から
選択される、請求項19に記載の組成物。 - 経口投与された場合、前記化合物が、長時間にわたり、同じ時間で非結合オキシモルホンと比較した場合に改良されたAUC及び放出速度を示す、請求項3に記載の組成物。
- 非結合オキシモルホンと比較した場合に、前記化合物が、経口PKプロフィールの変動の少なさを示す、請求項3に記載の組成物。
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RU2657803C1 (ru) * | 2017-03-21 | 2018-06-15 | федеральное государственное бюджетное образовательное учреждение высшего образования "Алтайский государственный университет" | Средство, обладающее противовоспалительным и анальгезирующим действием |
MX2020000638A (es) | 2017-07-20 | 2020-07-29 | Suzhou Runxindatai Pharmaceutics Ltd Co | Profármacos opioides de acción prolongada resistentes al abuso. |
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CO2017005203A2 (es) | 2017-08-31 |
MX2017006935A (es) | 2017-08-10 |
EP3226907A1 (en) | 2017-10-11 |
US9682076B2 (en) | 2017-06-20 |
US20160151352A1 (en) | 2016-06-02 |
PH12017500859A1 (en) | 2017-11-06 |
US20180338968A1 (en) | 2018-11-29 |
CL2017001417A1 (es) | 2018-02-09 |
US10758528B2 (en) | 2020-09-01 |
RU2683274C2 (ru) | 2019-03-27 |
WO2016089951A1 (en) | 2016-06-09 |
AU2015358606A1 (en) | 2017-05-25 |
SG11201704309YA (en) | 2017-06-29 |
JP2017538696A (ja) | 2017-12-28 |
JP2019077695A (ja) | 2019-05-23 |
US10071091B2 (en) | 2018-09-11 |
CA2969221A1 (en) | 2016-06-09 |
NZ731586A (en) | 2018-06-29 |
HK1244209A1 (zh) | 2018-08-03 |
US20200030316A1 (en) | 2020-01-30 |
CA2969221C (en) | 2021-01-12 |
CN106999487A (zh) | 2017-08-01 |
IL252472A0 (en) | 2017-07-31 |
US20170312270A1 (en) | 2017-11-02 |
BR112017011764A2 (pt) | 2018-07-10 |
RU2017123161A3 (ja) | 2019-01-09 |
MA40937A (fr) | 2017-10-11 |
AU2015358606B9 (en) | 2019-05-02 |
AU2015358606B2 (en) | 2019-04-18 |
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