JP5523706B2 - 新規投薬配合物 - Google Patents
新規投薬配合物 Download PDFInfo
- Publication number
- JP5523706B2 JP5523706B2 JP2008531674A JP2008531674A JP5523706B2 JP 5523706 B2 JP5523706 B2 JP 5523706B2 JP 2008531674 A JP2008531674 A JP 2008531674A JP 2008531674 A JP2008531674 A JP 2008531674A JP 5523706 B2 JP5523706 B2 JP 5523706B2
- Authority
- JP
- Japan
- Prior art keywords
- tablet composition
- lower alkyl
- pharmaceutical tablet
- composition according
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000000203 mixture Substances 0.000 title claims description 29
- 239000003814 drug Substances 0.000 title description 11
- 229940079593 drug Drugs 0.000 title description 10
- 238000009472 formulation Methods 0.000 title description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000007916 tablet composition Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- -1 cyclic tertiary amine Chemical class 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 239000000945 filler Substances 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 239000006057 Non-nutritive feed additive Substances 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 239000012943 hotmelt Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 239000010409 thin film Substances 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 6
- 238000009501 film coating Methods 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 239000011593 sulfur Chemical group 0.000 claims description 6
- 229910052717 sulfur Chemical group 0.000 claims description 6
- 229920002261 Corn starch Polymers 0.000 claims description 5
- 239000008120 corn starch Substances 0.000 claims description 5
- 239000004615 ingredient Substances 0.000 claims description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 238000007873 sieving Methods 0.000 claims description 5
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 229920001400 block copolymer Polymers 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 4
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 150000005846 sugar alcohols Chemical class 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- 238000009474 hot melt extrusion Methods 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000005647 linker group Chemical group 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- ZGNPLCMMVKCTHM-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n,2-dimethyl-n-[4-(2-methylphenyl)-6-morpholin-4-ylpyridin-3-yl]propanamide Chemical group C=1N=C(N2CCOCC2)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 ZGNPLCMMVKCTHM-UHFFFAOYSA-N 0.000 claims 2
- 229920005682 EO-PO block copolymer Polymers 0.000 claims 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims 1
- 229940069328 povidone Drugs 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 14
- 229920001983 poloxamer Polymers 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 8
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 7
- 229960000502 poloxamer Drugs 0.000 description 7
- 235000013305 food Nutrition 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910002019 Aerosil® 380 Inorganic materials 0.000 description 2
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 2
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000009246 food effect Effects 0.000 description 2
- 235000021471 food effect Nutrition 0.000 description 2
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001993 poloxamer 188 Polymers 0.000 description 2
- 229940044519 poloxamer 188 Drugs 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 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
- 229920000945 Amylopectin Polymers 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000019888 Vivapur Nutrition 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- WQZGKKKJIJFFOK-DVKNGEFBSA-N alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-DVKNGEFBSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000020650 eye health related herbal supplements Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229910021485 fumed silica Inorganic materials 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229920000140 heteropolymer Polymers 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229940047889 isobutyramide Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
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- 239000005017 polysaccharide Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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Description
*食物は、医薬の作用を加速または減速することがある。
*体内でのビタミンおよび無機質の吸収の減損。
*食欲の刺激または抑制。
*薬物は、どのように栄養素が体内で用いられるかを変化させ得る。
R1は、ハロゲンまたは水素であって、pが1のとき、R1は、上記置換基に加えて、Rと一緒になって−CH=CH−CH=CH−を形成してもよく;
R2およびR2'は、それぞれ、独立して、水素、ハロゲン、トリフルオロメチル、低級アルコキシまたはシアノであって、nが1のとき、R2およびR2'は、上記置換基に加えて、非置換であるか、あるいは低級アルキルまたは低級アルコキシから選ばれる一つもしくは二つの置換基で置換された−CH=CH−CH=CH−を形成してもよく;
R3およびR3'は、水素、低級アルキルであるか、または結合する炭素原子と一緒になって、シクロアルキル基を形成し;
R4は、水素、−N(R5)(CH2)nOH−、−N(R5)S(O)2−低級アルキル、−N(R5)S(O)2−フェニル、−N=CH−N(R5)2、−N(R5)C(O)R5、
R5は、水素、C3〜C6シクロアルキル、ベンジルまたは低級アルキルであり;
R6は、水素、ヒドロキシ、低級アルキル、−(CH2)nCOO−(R5)、−N(R5)CO−低級アルキル、ヒドロキシ低級アルキル、−(CH2)nCN、−(CH2)nO(CH2)nOH、−CHO、または酸素、窒素および硫黄からなる群より選ばれる1〜4個のヘテロ原子を有する5員もしくは6員の複素環であって、前記環の炭素原子の一つが非置換であるか、もしくはオキソ基で置換されており、複素環は、この分子の残余と直接、またはアルキレン基を介して結合しており;
Xは、−C(O)N(R5)−、−(CH2)mO−、−(CH2)mN(R5)−、−N(R5)C(O)−または−N(R5)(CH2)m−であり;
n、pおよびqは、それぞれ、独立して、1〜4であり;
mは、1または2である]
で示される、結晶形態でのNK−1レセプターアンタゴニストの一群、および薬学的に許容され得るその酸付加塩が、25℃で水(たとえば<0.0001mg/ml)および模擬的な胃液(たとえば0.08mg/ml)に事実上不溶であって、ヒトである患者に適切かつ適用可能である投薬配合物として処方し得ることが見出された。そのような配合物は、模擬的な腸液へのこれらの化合物についての事実上の不溶性という短所を克服し得る。好適な投薬配合物は、活性成分400mgを有する錠剤である。
(a)30〜60%の式Iの活性成分、
(b)10〜20%の水溶性ポロキサマー、
(c)20〜30%の充填剤、
(d)1〜10%の崩壊剤、
(e)0〜5%の加工助剤、および
(f)0〜5%の流動促進剤、ならびに望みであれば
(g)2〜5%の即放性薄膜被覆系、ならびに
(h)純水
を含む。
Opadry Yellow 03K 12429 25.00
純水 131.25
薄膜被覆された錠剤の総重量 825.00
を含む。
本発明による薬学的錠剤組成物を製造する方法は、下記の工程:
(1)薬学的活性成分を水溶性ポロキサマーと混合する工程、
(2)工程1の粉末混合物を用いて、熱間溶融押出物を製造する工程、
(3)押し出された材料を、ふるい分け機械を通過させて、粉砕された材料を得る工程、それによって望みの粒度範囲内の材料を得るために、二つ以上のふるい分け工程が必要となり得る、
(4)工程3からの粉砕された押出物を、初めに充填剤および崩壊剤と混合する工程、
(5)工程4からの混合物を加工助剤および流動促進剤と混合することによって、最終混合物を製造する工程、および
(6)工程5で製造された最終混合物を打錠する工程
を含む。
・薬学的活性成分/薬物物質の約50%を混合機、たとえばPK、BinまたはBohleミキサーに入れる。
・水溶性ポロキサマーを加え、次いで、薬物物質の残余を加える。
・材料を約30分間混合する。
・工程3からの粉末混合物を、ホッパー式供給装置(たとえばK−Tron Soder)を用いて熱間溶融押出装置(たとえばLeistritz)内に移し、粉末混合物を、熱間溶融押出装置を通過させる。
・熱間溶融押出物を室温で捕集する。
・その後、押し出された材料を、初めに、ふるい分け機械、たとえばFitzMillを、低速の刃を用いて3番ふるいを通して推進し、次いで中速の刃で2番ふるいを通して推進して、通過させる。
・粉砕された材料の約50%を、充填剤(たとえば、40番メッシュのふるい通過後のAvicel PH102またはParteck M 200)、トウモロコシ澱粉、崩壊剤(たとえばポリプラスドンXL)、および他の賦形剤(たとえば、12番メッシュのふるい通過後のAerosil 380)とともに、PK混合機またはそれと同等の機器に入れ、その後残余の粉砕された材料を加え、30分間混合する。
・粉末混合物の約50%を取り出し、流動促進剤(たとえば、40番メッシュのふるい通過後のステアリン酸マグネシウム)を混合機内の残余の材料に加え、粉末混合物の残余を再び加え、5分間混合し、
・最終混合物を、たとえば約18.7mm(0.738インチ)x約8.7mm(0.344インチ)の楕円形穿孔機を用いて、打錠する。
(1)ステンレス鋼製容器内で、完全薄膜被覆系、たとえばOpadry Yellowを純水に、完全に分散してコート懸濁液を形成するまで45分間混合することによって分散させ、
(2)核を、穿孔された被覆パンに入れ、45±5℃の吸入空気によって、間欠的に振とうしつつ、排出空気が40±5℃に達するまで加熱し、
(3)その後、吸入口温度を60±5℃まで上昇させ、連続的に撹拌しつつ、かつ空気吹き付け装置系を用いて乾量基準で1錠あたり一定量(錠剤重量の約2〜5%)の薄膜コートを塗布しつつ、核を被覆し、
(4)被覆された錠剤を、振とうすることによって含水量が2%未満になるまで乾燥し、
(5)錠剤を、室温まで冷却し、二重ポリエチレン製密閉容器内に貯蔵する。
Claims (11)
- 薬学的錠剤組成物の製造方法であって、式I:
[式中、Rは、低級アルキル、低級アルコキシ、ハロゲンまたはトリフルオロメチルであり;
R1は、ハロゲンまたは水素であって、pが1のとき、R1は、上記置換基に加えて、Rと一緒になって−CH=CH−CH=CH−を形成してもよく;
R2およびR2'は、それぞれ、独立して、水素、ハロゲン、トリフルオロメチル、低級アルコキシまたはシアノであって、nが1のとき、R2およびR2'は、上記置換基に加えて、非置換であるか、あるいは低級アルキルまたは低級アルコキシから選ばれる一つもしくは二つの置換基で置換された−CH=CH−CH=CH−を形成してもよく;
R3およびR3'は、水素、低級アルキルであるか、または結合する炭素原子と一緒になって、シクロアルキル基を形成し;
R4は、水素、−N(R5)(CH2)nOH、−N(R5)S(O)2−低級アルキル、−N(R5)S(O)2−フェニル、−N=CH−N(R5)2、−N(R5)C(O)R5、
であり;
R5は、水素、C3〜C6シクロアルキル、ベンジルまたは低級アルキルであり;
R6は、水素、ヒドロキシ、低級アルキル、−(CH2)nCOO−(R5)、−N(R5)CO−低級アルキル、ヒドロキシ低級アルキル、−(CH2)nCN、−(CH2)nO(CH2)nOH、−CHO、または酸素、窒素および硫黄からなる群より選ばれる1〜4個のヘテロ原子を有する5員もしくは6員の複素環であって、前記環の炭素原子の一つが非置換であるか、もしくはオキソ基で置換されており、複素環は、この分子の残余と直接、またはアルキレン基を介して結合しており;
は、酸素、窒素または硫黄からなる群より選ばれる更に一つのヘテロ原子を含んでもよい、環状の第三級アミンであり、ここで環に存在するいかなる硫黄も、チオであるか、またはスルホキシドもしくは二酸化硫黄に酸化されることができ、それによって前記環状の第三級アミンは、この分子の残余と直接結合しているか、またはリンカー−(CH2)nN(R5)−を介して結合しており;
Xは、−C(O)N(R5)−、−(CH2)mO−、−(CH2)mN(R5)−、−N(R5)C(O)−または−N(R5)(CH2)m−であり;
n、pおよびqは、それぞれ、独立して、1〜4であり;
mは、1または2である]
で示される薬学的活性成分、または薬学的に許容され得るその酸付加塩、およびエチレンオキシドおよびプロピレンオキシドのブロック共重合体を、熱間溶融押出によって一緒に処理してからその他の成分と混合し、ここで錠剤組成物を、その後即放性薄膜被覆剤および純水を含む組成物で被覆してもよい、製造方法。 - 請求項1記載の薬学的錠剤組成物の製造方法であって、下記の工程:
(1)薬学的活性成分をエチレンオキシドおよびプロピレンオキシドのブロック共重合体と混合する工程、
(2)工程1の粉末混合物を用いて、熱間溶融押出物を製造する工程、
(3)押し出された材料を、ふるい分け機械を通過させて、粉砕された材料を得る工程(望みの粒度範囲内の材料を得るために、二つ以上のふるい分け工程が必要となり得る)、
(4)工程3からの粉砕された押出物を、初めに充填剤および崩壊剤と混合する工程、
(5)工程4からの混合物を加工助剤および流動促進剤と混合することによって、最終混合物を製造する工程、
(6)工程5で製造された最終混合物を打錠する工程
を含む、製造方法。 - 錠剤重量の
(a)30〜60%の式Iの活性成分、
(b)10〜20%のエチレンオキシドおよびプロピレンオキシドのブロック共重合体、
(c)20〜30%の充填剤、
(d)1〜10%の崩壊剤、
(e)0〜5%の加工助剤、および
(f)0〜5%の流動促進剤
を含む、請求項1または2に従って製造された薬学的錠剤組成物。 - さらに、錠剤重量の
(g)2〜5%の即放性薄膜被覆剤、および
(h)純水
を含む、請求項3記載の薬学的錠剤組成物。 - 錠剤が式Iの活性成分400mgを含有する、請求項3または4記載の薬学的錠剤組成物。
- 活性成分が2−(3,5−ビス−トリフルオロメチルフェニル)−N−メチル−N−(6−モルホリン−4−イル−4−o−トリルピリジン−3−イル)イソブチルアミドである、請求項3または4記載の薬学的錠剤組成物。
- 充填剤がトウモロコシ澱粉、微結晶質セルロースおよび糖アルコールの混合物である、請求項3または4記載の薬学的錠剤組成物。
- 糖アルコールが、マンニトールである、請求項7記載の薬学的錠剤組成物。
- 加工助剤がコロイド状二酸化ケイ素である、請求項3または4記載の薬学的錠剤組成物。
- 流動促進剤がステアリン酸マグネシウムである、請求項3または4記載の薬学的錠剤組成物。
- ・塩酸2−(3,5−ビス−トリフルオロメチルフェニル)−N−メチル−N−(6−モルホリン−4−イル−4−o−トリルピリジン−3−イル)イソブチルアミド
400.00mg、
・エチレンオキシドおよびプロピレンオキシドのブロック共重合体
133.35mg、
・微結晶質セルロース 162.65mg、
・マンニトール 30.00mg、
・クロスポビドン 16.00mg、
・コロイド状二酸化ケイ素 16.00mg、
・トウモロコシ澱粉 30.00mg、
・ステアリン酸マグネシウム 12.00mg、
・薄膜被覆剤 25.00mg、
・純水 131.25ml
を含む、請求項4記載の薬学的錠剤組成物。
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KR20150041174A (ko) | 2005-11-08 | 2015-04-15 | 버텍스 파마슈티칼스 인코포레이티드 | Atp 결합 카세트 수송체의 헤테로사이클릭 조정제 |
US7671221B2 (en) | 2005-12-28 | 2010-03-02 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-Binding Cassette transporters |
US7754739B2 (en) | 2007-05-09 | 2010-07-13 | Vertex Pharmaceuticals Incorporated | Modulators of CFTR |
AU2008251504B2 (en) | 2007-05-09 | 2013-07-18 | Vertex Pharmaceuticals Incorporated | Modulators of CFTR |
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