TW201707703A - 軟膠囊劑 - Google Patents
軟膠囊劑 Download PDFInfo
- Publication number
- TW201707703A TW201707703A TW105117439A TW105117439A TW201707703A TW 201707703 A TW201707703 A TW 201707703A TW 105117439 A TW105117439 A TW 105117439A TW 105117439 A TW105117439 A TW 105117439A TW 201707703 A TW201707703 A TW 201707703A
- Authority
- TW
- Taiwan
- Prior art keywords
- mass
- soft capsule
- parts
- addition salt
- capsule
- Prior art date
Links
- 239000007901 soft capsule Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000002253 acid Substances 0.000 claims abstract description 21
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002775 capsule Substances 0.000 claims abstract description 18
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims abstract description 13
- 235000019345 sodium thiosulphate Nutrition 0.000 claims abstract description 13
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 10
- 239000000473 propyl gallate Substances 0.000 claims abstract description 9
- 235000010388 propyl gallate Nutrition 0.000 claims abstract description 9
- 229940075579 propyl gallate Drugs 0.000 claims abstract description 9
- 229930003935 flavonoid Natural products 0.000 claims description 2
- 150000002215 flavonoids Chemical class 0.000 claims description 2
- 235000017173 flavonoids Nutrition 0.000 claims description 2
- XGZZHZMWIXFATA-UEZBDDGYSA-N nalfurafine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@H]3N(C)C(=O)\C=C\C1=COC=C1)CN2CC1CC1 XGZZHZMWIXFATA-UEZBDDGYSA-N 0.000 abstract description 5
- 229960000441 nalfurafine Drugs 0.000 abstract description 5
- 239000011248 coating agent Substances 0.000 abstract 1
- 238000000576 coating method Methods 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 8
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- -1 Inorganic acid salts Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000004667 medium chain fatty acids Chemical class 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000004014 plasticizer Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 108010025899 gelatin film Proteins 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 238000004080 punching Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical class O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 1
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 description 1
- UBVSIAHUTXHQTD-UHFFFAOYSA-N 2-n-(4-bromophenyl)-1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(NC=2C=CC(Br)=CC=2)=N1 UBVSIAHUTXHQTD-UHFFFAOYSA-N 0.000 description 1
- 229920000945 Amylopectin Polymers 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 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
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229940123054 Opioid kappa receptor agonist Drugs 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920002675 Polyoxyl Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 235000019484 Rapeseed oil Nutrition 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001139 anti-pruritic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 229940067596 butylparaben Drugs 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 235000012732 erythrosine Nutrition 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- TVQGDYNRXLTQAP-UHFFFAOYSA-N ethyl heptanoate Chemical compound CCCCCCC(=O)OCC TVQGDYNRXLTQAP-UHFFFAOYSA-N 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical class OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- SXQCTESRRZBPHJ-UHFFFAOYSA-M lissamine rhodamine Chemical compound [Na+].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S([O-])(=O)=O)C=C1S([O-])(=O)=O SXQCTESRRZBPHJ-UHFFFAOYSA-M 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
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003021 phthalic acid derivatives Chemical class 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- DGPCSURYVBYWAT-UHFFFAOYSA-N propane-1,2,3-triol;tetradecanoic acid Chemical compound OCC(O)CO.CCCCCCCCCCCCCC(O)=O DGPCSURYVBYWAT-UHFFFAOYSA-N 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- AZJPTIGZZTZIDR-UHFFFAOYSA-L rose bengal Chemical compound [K+].[K+].[O-]C(=O)C1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C([O-])=C(I)C=C21 AZJPTIGZZTZIDR-UHFFFAOYSA-L 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229950006451 sorbitan laurate Drugs 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 229950003429 sorbitan palmitate Drugs 0.000 description 1
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229940093609 tricaprylin Drugs 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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Abstract
本發明提供一種具有含量穩定性優異之納呋拉啡或其酸加成鹽之軟膠囊劑。膠囊內容物中含有納呋拉啡或其酸加成鹽、疏水性之油性基劑及沒食子酸丙酯，膠囊皮膜中含有硫代硫酸鈉。
Description
本發明係關於一種含有納呋拉啡或其酸加成鹽之軟膠囊劑。
納呋拉啡(Nalfurafine)作為選擇性類鴉片κ受體促效劑，對於類鴉片系統干預之中樞性之發癢顯示強力之止癢作用(專利文獻1)。並且，含有納呋拉啡鹽酸鹽之軟膠囊劑作為經口瘙癢症改善劑而上市。
然而，納呋拉啡對於熱、光、氧、水分有化學不穩定性，保存時必須採取低溫保存、遮光、惰性氣體置換等方法。
因此，含有納呋拉啡或其酸加成鹽之膠囊劑藉由向水及聚乙二醇中調配作為水溶性抗氧化劑之硫代硫酸鈉，而確保其穩定性(專利文獻2)。
然而，若將親水性之聚乙二醇用作基劑，則易於引起水分所致之軟膠囊劑彼此附著及凹陷。因此，需要軟膠囊劑之嚴密之水分管理，乾燥步驟容易變得繁雜。又，可認為因將親水性之聚乙二醇用作基劑，故而因聚乙二醇所含之水而納呋拉啡之含量穩定性降低及分解物生成。
[專利文獻1]日本專利第3531170號公報
[專利文獻2]日本專利第3743449號公報
本發明係關於提供一種具有含量穩定性優異之納呋拉啡或其酸加成鹽之軟膠囊劑。
本發明者等人對含有納呋拉啡或其酸加成鹽之軟膠囊劑反覆進行努力研究，結果發現膠囊之內容物中使用疏水性之油性基劑，並含有納呋拉啡或其酸加成鹽及沒食子酸丙酯，皮膜中含有硫代硫酸鈉之軟膠囊劑之納呋拉啡或其酸加成鹽之含量穩定性及其良好。
即，本發明係以下之1)~3)。
1)一種軟膠囊劑，其膠囊內容物中含有納呋拉啡或其酸加成鹽、疏水性之油性基劑及沒食子酸丙酯，膠囊皮膜中含有硫代硫酸鈉。
2)如1)之軟膠囊劑，其相對於納呋拉啡或其酸加成鹽1質量份含有疏水性之油性基劑400~200,000質量份、沒食子酸丙酯150~20,000質量份。
3)如1)或2)之軟膠囊劑，其相對於納呋拉啡或其鹽1質量份含有硫代硫酸鈉150~20,000質量份。
藉由使用本發明，可製造納呋拉啡或其酸加成鹽之含量穩定性優異及抑制特定之分解物之生成之含有穩定之納呋拉啡或其酸加成鹽之膠囊劑，又於膠囊之製造步驟中無需嚴密之水分管理，可簡化乾燥步驟。
於本發明中，「納呋拉啡」意指下述所表示之(2E)-N-[(5R,6R)-17-(環丙基甲基)-4,5-環氧-3,14-二羥基嗎啡-6-基]-3-(呋喃-3-基)-N-甲
基丙-2-烯胺鹽酸鹽)。
作為納呋拉啡之酸加成鹽，只要為藥理學上所容許之鹽則並無特別限定，例如可列舉鹽酸鹽、硫酸鹽、硝酸鹽、氫溴酸鹽、氫碘酸鹽、磷酸鹽等無機酸鹽、乙酸鹽、乳酸鹽、檸檬酸鹽、草酸鹽、戊二酸鹽、蘋果酸鹽、酒石酸鹽、富馬酸鹽、苦杏仁酸鹽、馬來酸鹽、苯甲酸鹽、苯二甲酸鹽等有機羧酸鹽、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽、樟腦磺酸鹽等有機磺酸鹽等，其中鹽酸鹽、氫溴酸鹽、磷酸鹽、酒石酸鹽、馬來酸鹽、甲磺酸鹽較佳。
上述含有納呋拉啡或其酸加成鹽之軟膠囊劑之內容物中使用疏水性之油性基劑作為基劑。
作為疏水性之油性基劑，例如可列舉中鏈脂肪酸三酸甘油酯、三辛精、己酸、辛酸、油酸、亞麻油酸、次亞麻油酸、植物油等。此處作為植物油，可列舉椰子油、橄欖油、菜籽油、花生油、玉米油、大豆油、棉籽油、葡萄油、紅花子油等。該等可為單獨亦可為2種以上之混合物。其中，較佳為碳數8~12之中鏈脂肪酸之甘油酯，適宜為三辛酸甘油酯、三(辛酸、癸酸)甘油酯等。
該疏水性之油性基劑之使用量相對於納呋拉啡或其酸加成鹽1質量份為400質量份以上，較佳為1,000質量份以上，更佳為10,000質量份以上，進而較佳為40,000質量份以上，較佳為200,000質量份以下，更佳為150,000質量份以下，進而較佳為120,000質量份以下。又，較
佳為400~200,000質量份，更佳為10,000~150,000質量份，若考慮膠囊尺寸，則進而較佳為40,000~120,000質量份。
於本發明中，沒食子酸丙酯係作為穩定劑而添加者，其添加量相對於納呋拉啡或其酸加成鹽1質量份較佳為150質量份以上，較佳為300質量份以上，更佳為500質量份以上，較佳為20,000質量份以下，更佳為2,000質量份以下，進而較佳為1,500質量份以下。又，較佳為150~20,000質量份，更佳為300~2,000質量份，進而較佳為500~1,500質量份。
於本發明中，硫代硫酸鈉調配於膠囊皮膜中。藉由將硫代硫酸鈉調配於膠囊皮膜中，可抑制分解物之生成。
硫代硫酸鈉可為無水鹽，亦可為含水鹽，較佳為硫代硫酸鈉五水合物。
硫代硫酸鈉之含量相對於納呋拉啡或其酸加成鹽1質量份較佳為150質量份以上，較佳為300質量份以上，更佳為500質量份以上，較佳為20,000質量份以下，更佳為2,000質量份以下，進而較佳為1,500質量份以下。又，較佳為150~20,000質量份，更佳為300~2,000質量份，進而較佳為500~1,500質量份。
本發明之軟膠囊劑中，於不損及本發明之效果之範圍，除上述成分以外可於內容物中調配例如助溶劑、增溶劑、保存劑、界面活性劑、著色劑等，可於皮膜中調配例如皮膜基劑、塑化劑、著色劑、保存劑等。
此處作為助溶劑，例如可列舉乙醇、丙二醇、聚乙二醇、山梨醇酐倍半油酸酯、山梨醇酐月桂酸酯、山梨醇酐棕櫚酸酯、油酸甘油酯、肉豆蔻酸甘油酯、聚氧乙烯月桂醚、聚氧乙烯壬基苯醚、甘油等。
作為增溶劑，例如可列舉環糊精等。
作為保存劑，例如可列舉對羥苯甲酸甲酯、對羥苯甲酸乙酯、對羥苯甲酸丙酯、對羥苯甲酸丁酯、氯化苄烷銨等。
作為界面活性劑，例如可列舉聚山梨糖醇酯80、蓖麻油聚烴氧酯35等。
作為著色劑，例如可列舉氧化鈦、黃色三氧化二鐵、食用黃色4號、食用黃色5號、食用紅色3號、食用紅色102號、食用紅色105號、食用紅色106號、三氧化二鐵等。
作為皮膜基劑，例如可列舉明膠、琥珀醯明膠、澱粉、支鏈澱粉、聚乙烯醇共聚物、聚乙二醇等。
作為塑化劑，可列舉濃甘油、糖醇等。
本發明之軟膠囊劑之內容物例如可藉由使納呋拉啡或其酸加成鹽、及沒食子酸丙酯溶解於乙醇等助溶劑中，並將其調配於疏水性之油性基劑中，進行混合、攪拌而製造。
本發明之軟膠囊劑之皮膜例如可藉由使基劑、塑化劑及硫代硫酸鈉分散於水中，以60℃~90℃使其溶解後，進行真空消泡而製造。
本發明之軟膠囊劑可使用先前使用之軟膠囊之製法，例如使用旋轉式全自動軟膠囊成型機之沖裁法、於兩張明膠薄板間放入內容物並利用模具自兩面壓縮沖裁之平板法或使用雙重噴嘴之滴下法(無縫膠囊等)等，將內容物填充於皮膜中，並進行成型、乾燥而製造。
如此所獲得之上述軟膠囊劑如下述實施例所示，作為有效成分之納呋拉啡或其酸加成鹽之含量穩定性及其高，且抑制特定之分解物之生成。
[實施例]
藉由以下之實施例詳細地說明本發明，但本發明並不限定於此。
實施例1 軟膠囊劑之製備
使下述表1所示之特定量之納呋拉啡鹽酸鹽及沒食子酸丙酯溶解於特定量之乙醇中，使其混合於特定量之中鏈脂肪酸三酸甘油酯〔三(辛酸/癸酸)甘油酯(BASF公司製造)〕中並進行攪拌而製備膠囊填充組合物。進行攪拌使下述表1所示之特定量之明膠、琥珀醯明膠、濃甘油、D-山梨醇液、硫代硫酸鈉及氧化鈦分散於適量之純化水中，以60℃進行攪拌使其溶解後，進行真空消泡而製備明膠皮膜。使用上述之膠囊填充組合物及明膠皮膜，並藉由使用旋轉式全自動軟膠囊成型機之沖裁法而製備軟膠囊劑。
又，使用REMITCH膠囊2.5μg〔1顆膠囊中調配納呋拉啡鹽酸鹽2.5μg(東麗公司製造)〕作為比較品。將比較品之調配成分示於表2。
實施例2 穩定性試驗
將實施例1中所製備之軟膠囊劑放入玻璃瓶中，於栓緊狀態下以80℃保存1週。保存時間結束後利用HPLC(high performance liquid chromatography，高效液相層析法)法測定各軟膠囊劑中之納呋拉啡鹽酸鹽之含量及分解物。將測定結果示於表3及4。
根據表3可明確，本發明品與比較品相比納呋拉啡鹽酸鹽之殘存
率較高，顯示顯著之含量穩定性。又根據表4可明確，本發明品無比較品中可見之10α-OH體之增加，顯示對於作為納呋拉啡之分解物之10α-OH體之顯著之抑制效果。
實施例3 軟膠囊劑之製備
以下述表5所示之特定量並藉由與實施例1相同之方法而製備軟膠囊劑。
又，與實施例1相同使用REMITCH膠囊2.5μg〔1顆膠囊中調配納呋拉啡鹽酸鹽2.5μg(東麗公司製造)〕作為比較品。
實施例4 穩定性試驗
對實施例3中所製備之軟膠囊劑進行PTP(Press Through Packaging，泡罩包裝)/枕形包裝，以40℃ 75%RH保存6個月。1個月後、3個月後、保存時間結束後，利用HPLC法測定各軟膠囊劑中之納呋拉啡鹽酸鹽之含量及分解物。將測定結果示於表6及7。
根據表6可明確，本發明品與比較品相比納呋拉啡鹽酸鹽之殘存率較高，顯示顯著之含量穩定性。又根據表7可明確，本發明品無比較品中可見之分解物之增加，顯示對於納呋拉啡之分解物之顯著之抑制效果。
Claims (3)
- 一種軟膠囊劑，其膠囊內容物中含有納呋拉啡或其酸加成鹽、疏水性之油性基劑及沒食子酸丙酯，膠囊皮膜中含有硫代硫酸鈉。
- 如請求項1之軟膠囊劑，其相對於納呋拉啡或其酸加成鹽1質量份含有疏水性之油性基劑400~200,000質量份、沒食子酸丙酯150~20,000質量份。
- 如請求項1或2之軟膠囊劑，其相對於納呋拉啡或其鹽1質量份含有硫代硫酸鈉150~20,000質量份。
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