TWI574705B - Capsules - Google Patents
Capsules Download PDFInfo
- Publication number
- TWI574705B TWI574705B TW102113726A TW102113726A TWI574705B TW I574705 B TWI574705 B TW I574705B TW 102113726 A TW102113726 A TW 102113726A TW 102113726 A TW102113726 A TW 102113726A TW I574705 B TWI574705 B TW I574705B
- Authority
- TW
- Taiwan
- Prior art keywords
- capsule
- compound
- manufactured
- hypromellose
- gelatin
- Prior art date
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- 239000002775 capsule Substances 0.000 title claims description 184
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 30
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 29
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 29
- 229960003943 hypromellose Drugs 0.000 claims description 28
- -1 polytrisaccharide Polymers 0.000 claims description 17
- 239000000395 magnesium oxide Substances 0.000 claims description 14
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 14
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 14
- 239000000945 filler Substances 0.000 claims description 12
- 229920002472 Starch Polymers 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000008107 starch Substances 0.000 claims description 10
- 235000019698 starch Nutrition 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 6
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 6
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 description 70
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 44
- 238000004090 dissolution Methods 0.000 description 38
- 239000000203 mixture Substances 0.000 description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 29
- 238000003860 storage Methods 0.000 description 24
- 235000019359 magnesium stearate Nutrition 0.000 description 22
- 238000012360 testing method Methods 0.000 description 21
- 230000000052 comparative effect Effects 0.000 description 15
- 239000007903 gelatin capsule Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 description 15
- 230000011987 methylation Effects 0.000 description 15
- 238000007069 methylation reaction Methods 0.000 description 15
- 239000002585 base Substances 0.000 description 14
- 238000005469 granulation Methods 0.000 description 13
- 230000003179 granulation Effects 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 9
- 238000007922 dissolution test Methods 0.000 description 9
- 108010010803 Gelatin Proteins 0.000 description 8
- 239000008273 gelatin Substances 0.000 description 8
- 229920000159 gelatin Polymers 0.000 description 8
- 235000019322 gelatine Nutrition 0.000 description 8
- 235000011852 gelatine desserts Nutrition 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- 239000000654 additive Substances 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 7
- 239000001095 magnesium carbonate Substances 0.000 description 7
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 7
- 235000014380 magnesium carbonate Nutrition 0.000 description 7
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 229960004584 methylprednisolone Drugs 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 239000004475 Arginine Substances 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 5
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 5
- 239000000347 magnesium hydroxide Substances 0.000 description 5
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 239000010452 phosphate Substances 0.000 description 5
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 description 4
- 235000010216 calcium carbonate Nutrition 0.000 description 4
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 4
- 239000001354 calcium citrate Substances 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 235000013337 tricalcium citrate Nutrition 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 3
- 229940024545 aluminum hydroxide Drugs 0.000 description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 3
- 235000013539 calcium stearate Nutrition 0.000 description 3
- 239000008116 calcium stearate Substances 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 229940091250 magnesium supplement Drugs 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 3
- 235000010234 sodium benzoate Nutrition 0.000 description 3
- 239000004299 sodium benzoate Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 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 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-M L-lysinate Chemical compound NCCCC[C@H](N)C([O-])=O KDXKERNSBIXSRK-YFKPBYRVSA-M 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000011481 absorbance measurement Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- QVQLCTNNEUAWMS-UHFFFAOYSA-N barium oxide Chemical compound [Ba]=O QVQLCTNNEUAWMS-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 235000012730 carminic acid Nutrition 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229960003104 ornithine Drugs 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
- 239000002831 pharmacologic agent Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- 229940038773 trisodium citrate Drugs 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 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
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-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
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-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
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 240000004670 Glycyrrhiza echinata Species 0.000 description 1
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 description 1
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Classifications
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- 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
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Description
本發明關於一種膠囊劑。詳言之,本發明關於一種包含磷酸甲酯化雷夫康唑(ravuconazole)的膠囊劑。
作為經口投與醫藥品的劑型,包含膠囊和被填充在該膠囊內之物(被填充物)的膠囊劑被廣泛地使用。最頻繁使用的用於形成膠囊的膠囊基料係明膠。然而,使用以明膠作為膠囊基料的膠囊(明膠膠囊)之製劑,在貯存過程中被填充物會與明膠進行相互作用,可能導致藥物從膠囊中溶出的延遲。
經口投與醫藥品服用後,藥物會從製劑溶出,由胃腸道吸收而發揮其藥理作用。因此,由於貯存導致溶出延遲的製劑,通常胃腸道對藥物的吸收減少,無法獲得充分的藥理效果。
作為通常與明膠進行相互作用的化合物,具羰基或醛基的化合物、還原糖以及在貯存過程中產生醛的化合物係已知的。它們的具體實例包括乳糖和聚乙二醇(polyethylene glycol;macrogol)。
但是,即使是在與明膠進行相互作用的化合物被填充在明膠膠囊中的情況下,亦未必引起會影響醫藥品之藥理效果的溶出延遲。例如,在明膠膠囊內填充有含乳糖或聚乙二醇的顆粒之醫藥品於市場上廣為流通。進而,亦有市售膠囊本身即添加有聚乙二醇的明膠膠囊,且使用該膠囊的藥品也流通於日本市場。
因此,難以預測在明膠膠囊中填充藥物的醫藥品是否會導致足
以影響藥理效果的溶出延遲。
雷夫康唑係具有抗真菌作用的三唑化合物,並對水的溶解度低。專利文獻1揭示一種磷酸甲酯化雷夫康唑作為雷夫康唑溶解度經改善的前藥。專利文獻2揭露了一包含磷酸甲酯化雷夫康唑的製劑。然而,專利文獻2沒有揭示從製劑中溶出的磷酸甲酯化雷夫康唑的溶出行為或由於貯存所引起的溶出延遲,並且沒有揭示膠囊基料。
專利文獻1:PCT申請號2003-520235的日語譯本
專利文獻2:WO 2007/097386
本案發明人已經發現:當藥物為磷酸甲酯化雷夫康唑時,若填充在一明膠膠囊中,在貯存之後磷酸甲酯化雷夫康唑從膠囊的溶出明顯延遲。本發明一目的係提供一膠囊劑,該膠囊劑包含磷酸甲酯化雷夫康唑,無論磷酸甲酯化雷夫康唑之填充量為多少,均可抑制由於貯存所造成之溶出延遲。
本發明係一種膠囊劑,使用不含明膠的膠囊作為填充磷酸甲酯化雷夫康唑的膠囊。
本發明如以下所述。
[1]一種膠囊劑,包含:被填充物,其包含{[(1R,2R)-2-[4-(4-氰基苯基)-1,3-噻唑-2-基]-1-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基甲基)丙基]氧基}甲基二氫磷酸酯(下文中亦稱“化合物1”)或其藥理學上可接受的鹽、或任何上述化合物的溶劑合物(在本說明書中亦統稱為“磷酸甲酯化雷夫康
唑”);和不含明膠的膠囊;[2]如前項[1]之膠囊劑,其中該膠囊係以包含澱粉、聚三葡萄糖(pullulan)、聚乙烯醇或羥丙甲纖維素之膠囊基料形成;[3]如前項[1]之膠囊劑,其中該膠囊用包含聚三葡萄糖或羥丙甲纖維素的膠囊基料形成;[4]如前項[1]之膠囊劑,其中該膠囊用包含羥丙甲纖維素的膠囊基料形成;[5]如前項[1]至[4]中任一項之膠囊劑,其中該磷酸甲酯化雷夫康唑係L-賴胺酸-{[(1R,2R)-2-[4-(4-氰基苯基)-1,3-噻唑-2-基]-1-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基甲基)丙基]氧基}甲基二氫磷酸酯-乙醇(1/1/1)(下文中亦稱“化合物2”);[6]如前項[1]至[5]中任一項之膠囊劑,其中該被填充物進一步包含氧化鎂;[7]如前項[1]至[6]中任一項之膠囊劑,其中該磷酸甲酯化雷夫康唑換算成該化合物2之質量後,對該膠囊的質量比係0.27以上;[8]如前項[1]至[6]中任一項之膠囊劑,其中該磷酸甲酯化雷夫康唑換算成該化合物2之質量後,對該膠囊的質量比係0.27~10;[9]如前項[7]或[8]之膠囊劑,其中該磷酸甲酯化雷夫康唑換算成該化合物2之質量後,每一膠囊的含量係17mg以上;[10]如前項[1]至[9]中任一項之膠囊劑,其在40℃和相對濕度75%的條件下以開封狀態貯存1個月之後,根據日本藥典第16版的溶出測試法,於測試開始60分鐘後,磷酸甲酯化雷夫康唑的平均溶出率係60%以上;以及[11]如前項[1]至[9]中任一項之膠囊劑,其在40℃和相對濕度75%的條件下以開封狀態貯存1個月之後,根據日本藥典第16版的溶
出測試法,於測試開始60分鐘後,磷酸甲酯化雷夫康唑的平均溶出率係85%以上。
根據本發明,可以提供一種膠囊劑,無論磷酸甲酯化雷夫康唑之填充量為多少,均可以抑制在貯存過程中可能發生的該磷酸甲酯化雷夫康唑之溶出延遲。
圖1係在貯存前的檢體之間,將藥物含量與測試開始60分鐘後的平均溶出率(60分鐘溶出率)之間的關係進行比較的圖,此於試驗例1的表1中亦有記載。
圖2係在40℃和相對濕度75%的條件下貯存1個月之後的檢體之間,將藥物含量與測試開始60分鐘後的平均溶出率(60分鐘溶出率)之間的關係進行比較的圖,此於試驗例1的表1中亦有記載。
圖3係在貯存前與在40℃和相對濕度75%的條件下貯存1個月之後,對藥物從明膠膠囊溶出的行為進行比較的圖,此於試驗例1的表2中亦有記載。
圖4係在貯存之前與在40℃和相對濕度75%的條件下貯存1個月之後,對藥物從以羥丙甲纖維素(羥丙基甲基纖維素)作為基料的膠囊(羥丙甲纖維素膠囊)溶出的行為進行比較的圖,此於試驗例1的表2中亦有記載。
以下實施形態係實施本發明之形態的例示。因此,本發明不限於以下實施形態。例如,由熟習相關技術者所更改的實施形態只要符合本發明要旨,均涵蓋在本發明之範圍內。
本發明係一種膠囊劑,包含被填充物和不含明膠的膠囊,該被
填充物包含磷酸甲酯化雷夫康唑。在本發明中,該磷酸甲酯化雷夫康唑被填充在該不含明膠的膠囊中。
在本發明中,磷酸甲酯化雷夫康唑係{[(1R,2R)-2-[4-(4-氰基苯基)-1,3-噻唑-2-基]-1-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基甲基)丙基]氧基}甲基二氫磷酸酯(化合物1;{[(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyl]oxy}methyl dihydrogen phosphate)或其藥理學上可接受的鹽。進而,磷酸甲酯化雷夫康唑還可以是化合物1或其藥理學上可接受的鹽之溶劑合物。該溶劑合物可列舉例如水合物、乙醇合物等。
化合物1的藥理學上可接受的鹽可列舉例如無機鹼鹽、有機鹼鹽以及鹼性胺基酸鹽等。
無機鹼鹽可列舉例如鈉鹽、鉀鹽等鹼金屬鹽;鈣鹽、鎂鹽等鹼土金屬鹽;以及銨鹽等。
有機鹼鹽可列舉例如三甲基胺鹽、三乙基胺鹽等烷基胺鹽;乙醇胺鹽、二乙醇胺鹽、三乙醇胺鹽等烷醇胺鹽;吡啶鹽、甲基吡啶鹽等雜環胺鹽;二環己胺鹽;以及N,N'-二苄基乙二胺鹽等。
鹼性胺基酸鹽可列舉例如賴胺酸(Lysine)、鳥胺酸、組胺酸或精胺酸之鹽等,較佳的是鹼性胺基酸的單鹽、二鹽、三鹽。
藥理學上可接受的鹽較佳的是賴胺酸鹽,更佳的是L-賴胺酸鹽,進而更佳的是一-L-賴胺酸鹽(L-賴胺酸鹽;單賴胺酸鹽)或二-L-賴胺酸鹽(二賴胺酸鹽)。
磷酸甲酯化雷夫康唑較佳的是其藥理學上可接受的鹽的溶劑合物。該溶劑合物較佳的是一-L-賴胺酸鹽的乙醇合物或二-L-賴胺酸鹽的乙醇合物,更佳的是L-賴胺酸-{[(1R,2R)-2-[4-(4-氰基苯基)-1,3-噻
唑-2-基]-1-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基甲基)丙基]氧基}甲基二氫磷酸酯-乙醇(1/1/1)(化合物2;L-Lysine-{[(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyl]oxy}methyl dihydrogen phosphate-ethanol(1/1/1))。
化合物1係由下述式1表示的化合物,化合物2係由下述式2表示的化合物:
涵蓋在磷酸甲酯化雷夫康唑中的化合物1和化合物2可以根據PCT申請號2003-520235的日語譯本(專利文獻1)和WO 2007/097386(專利文獻2)之描述來製造。
在本發明中,所謂“不含明膠的膠囊”意指作為膠囊主要構成成分之膠囊基料不含明膠的膠囊,。該膠囊可列舉包含例如羥丙甲纖維素、聚三葡萄糖、聚乙烯醇、澱粉等作為膠囊基料的膠囊,較佳的是包含羥丙甲纖維素或聚三葡萄糖作為膠囊基料的膠囊,進而更佳的是
包含羥丙甲纖維素作為膠囊基料的膠囊。除了如羥丙甲纖維素、聚三葡萄糖、聚乙烯醇、澱粉等膠囊基料之外,該膠囊還可以包含如卡拉膠(carrageenan)之類的膠凝劑,如氯化鉀之類的輔助膠凝劑,著色劑以及通常可以被添加至膠囊中的其他成分作為膠囊的構成成分。作為包含羥丙甲纖維素或聚三葡萄糖作為膠囊基料的膠囊,例如可使用市售品。包含聚乙烯醇作為膠囊基料的膠囊可以根據例如在專利公開號JP-A-2001-170137中所述方法製造,包含澱粉作為膠囊基料的膠囊可以根據例如在Ho J.Bae等人所撰"Film and pharmaceutical hard capsule formation properties of mungbean,water chestnut,and sweet potato starches",Food Chemistry,106(2008)第96-105頁中所述方法製造。
在本發明中,所謂“被填充物”意指在成為膠囊劑的狀態下,存在於膠囊之內側(內部)的內容物,而非膠囊本身亦非其構成物。
被填充物只要包含磷酸甲酯化雷夫康唑,即無特別限定,亦可含有包含磷酸甲酯化雷夫康唑的組合物作為被填充物。
作為該包含磷酸甲酯化雷夫康唑的組合物,可列舉例一種組合物,其包含磷酸甲酯化雷夫康唑及視需要包含穩定劑、賦形劑、粘合劑、崩解劑、潤滑劑、抗氧化劑、調味劑、著色劑、香料等其他藥理學上可接受的添加劑。作為該組合物,可列舉例如藉由將磷酸甲酯化雷夫康唑與上述視需要添加的添加劑相混合而獲得的組合物;藉由在磷酸甲酯化雷夫康唑中添加上述視需要添加的添加劑並經攪拌造粒、擠出造粒、滾筒造粒、流化床造粒、噴霧造粒等任何造粒作用而製造的顆粒狀組合物(在該組合物的情況下,以上添加劑亦可包含溶劑);以及於上述顆粒中視需要混合有上述添加劑的的組合物等。
在本發明中,較佳的是被填充物不含明膠。
作為穩定劑,可列舉WO 2007/097386(專利文獻2)中揭示的各
種鹼性物質。該鹼性物質亦可組合使用兩種以上。
鹼性物質可以是1%水溶液或懸濁液之pH呈7以上的物質,較佳的是1%水溶液或懸濁液之pH呈8以上的物質,更佳的是1%水溶液或懸濁液之pH呈10以上的物質。鹼性物質可列舉例如無機鹼、有機鹼、鹼性胺基酸、鹼性聚合物等。
無機鹼可列舉例如鹼式碳酸鎂、碳酸氫鉀、碳酸氫鈉、碳酸鉀、碳酸鈉、碳酸鎂、碳酸鈣、碳酸鋇、重質碳酸鎂、沈澱碳酸鈣、氫氧化鋰、氫氧化鉀、氫氧化鈉、氫氧化鎂、氫氧化鈣、鎂鋁氫氧化物、乾燥氫氧化鋁凝膠、氧化鎂、氧化鈣、氧化鋇、矽酸鈣、矽酸鎂、鎂鋁矽酸鹽、鋁酸鎂、偏矽酸鋁酸鎂(magnesium metasilicate-aluminate)、磷酸氫鈉、磷酸二氫鈉、合成水滑石、氫氧化鋁和氫氧化鎂的共沈澱物、氫氧化鋁與碳酸鎂與碳酸鈣的共沈澱物以及氫氧化鋁和碳酸氫鈉的共沈澱物,較佳的是鹼式碳酸鎂、氧化鎂、氫氧化鎂、碳酸鈉、碳酸鈣、碳酸氫鈉、矽酸鈣,更佳的是鹼式碳酸鎂、氫氧化鎂、氧化鎂、碳酸氫鈉。
有機鹼可列舉例如硬脂酸鈣、硬脂酸鎂、硬脂酸鈉、硬脂醯醇富馬酸鈉、檸檬酸三鈉、苯甲酸鈉、單乙醇胺、二乙醇胺、三乙醇胺、三丁胺、二環己基甲基胺、N-甲基吡咯烷酮等,較佳的是硬脂酸鈣、檸檬酸三鈉、苯甲酸鈉,更佳的是苯甲酸鈉。
鹼性胺基酸可列舉例如賴胺酸、鳥胺酸、組胺酸、精胺酸等,較佳的是賴胺酸、精胺酸,更佳的是精胺酸。
鹼性聚合物可列舉例如甲基丙烯酸胺烷基酯共聚物E、聚乙烯乙縮醛二乙胺基乙酯、乙基纖維素等。
鹼性物質較佳的是鹼式碳酸鎂、氫氧化鎂、氧化鎂、碳酸氫鈉、精胺酸,更佳的是氧化鎂。
賦形劑可列舉例如乳糖、蔗糖、葡萄糖、果糖、澱粉、馬鈴薯
澱粉、玉米澱粉、小麥澱粉、水稻澱粉、結晶纖維素、微晶纖維素、甘草粉、甘露糖醇、赤蘚糖醇、麥芽糖醇、山梨糖醇、海藻糖、無水矽酸、矽酸鈣、碳酸氫鈉、磷酸鈣、無水磷酸鈣、硫酸鈣等。
粘合劑可列舉例如澱粉、阿拉伯膠、黃芪膠、羧甲基纖維素、羥丙基纖維素、羥丙基甲基纖維素、聚乙烯吡咯烷酮、甲基纖維素、部分α化澱粉、α化澱粉、聚乙烯醇、海藻酸鈉、聚三葡萄糖、甘油等。
崩解劑可列舉例如胺基酸、澱粉、玉米澱粉、碳酸鈣、羧甲纖維素、羧甲纖維素鈣、交聯羧甲纖維素鈉、低取代羥丙基纖維素、羥丙基澱粉、交聚維酮等。
潤滑劑可列舉例如硬脂酸鎂、硬脂酸、硬脂酸鈣、硬脂醯醇富馬酸鈉、滑石、聚乙二醇(macrogol)等。
抗氧化劑可列舉例如抗壞血酸鈉、L-半胱胺酸、亞硫酸鈉、生育酚、大豆卵磷脂等。
調味劑可列舉例如檸檬酸、抗壞血酸、酒石酸、蘋果酸、阿斯巴甜、乙醯胺基磺酸鉀、索馬甜、三氯蔗糖、糖精鈉、甘草酸二鉀、穀胺酸鈉、5'-肌苷酸鈉、5'-鳥苷酸鈉等。
著色劑可列舉例如氧化鈦、三氧化二鐵、黃色三氧化二鐵、胭脂蟲紅(cochineal)、胭脂紅、核黃素、食用黃色5號、食用藍色2號等。
香料可列舉例如檸檬油、橙油、薄荷醇、薄荷油、冰片、香草香精等。
在本發明的膠囊劑中,磷酸甲酯化雷夫康唑對膠囊的質量比(磷酸甲酯化雷夫康唑/膠囊)以換算成化合物2的質量來計算時,通常是0.10以上、較佳的是0.27以上、更佳的是0.53以上、進而更佳的是1.3以上。所謂“換算成化合物2的質量”,係藉由使用化合物2的分
子量與填充的磷酸甲酯化雷夫康唑的分子量之比,將填充的磷酸甲酯化雷夫康唑的質量換算成等莫耳的化合物2的質量而獲得的值。
磷酸甲酯化雷夫康唑對膠囊的質量比的上限,係根據該膠囊的質量和內容積來決定。當磷酸甲酯化雷夫康唑對膠囊的質量比係基於換算成化合物2的質量來計算時,通常是10以下、較佳的是5.0以下、更佳的是4.5以下,進而更佳的是4.0以下。
磷酸甲酯化雷夫康唑對膠囊的質量比(基於換算成化合物2的質量來計算時;以下於本段中同)通常是0.10至10、較佳的是0.27至10、更佳的是0.53至10、進而更佳的是1.3至10;當磷酸甲酯化雷夫康唑對膠囊的質量比的上限係5.0時,通常是0.10至5.0、較佳的是0.27至5.0、更佳的是0.53至5.0、進而更佳的是1.3至5.0。
在本發明膠囊劑中,每一膠囊的磷酸甲酯化雷夫康唑的含量,換算成化合物2的質量後,通常是5mg以上、較佳的是17mg以上、更佳的是34mg以上、進而更佳的是85mg以上。所謂“換算成化合物2的質量”,係藉由使用化合物2的分子量與填充的磷酸甲酯化雷夫康唑的分子量之比、將填充的磷酸甲酯化雷夫康唑的質量換算成等莫耳的化合物2的質量而獲得的值。
在本發明膠囊劑中,通常磷酸甲酯化雷夫康唑對膠囊的質量比(換算成化合物2的質量;以下於本段中同)係0.10至10且每一膠囊的磷酸甲酯化雷夫康唑之含量係5mg以上;較佳的是磷酸甲酯化雷夫康唑對膠囊的質量比係0.27至10且每一膠囊的磷酸甲酯化雷夫康唑之含量係17mg以上;更佳的是磷酸甲酯化雷夫康唑對膠囊的質量比係0.53至10且每一個膠囊的磷酸甲酯化雷夫康唑之含量係34mg以上;進而更佳的是磷酸甲酯化雷夫康唑對膠囊的質量比係1.3至10且每一膠囊的磷酸甲酯化雷夫康唑之含量係85mg以上。
每一膠囊的磷酸甲酯化雷夫康唑含量之上限雖視發揮所謀求之
藥理作用所需劑量而定,但通常根據使用之膠囊的內容積而決定。每一膠囊的磷酸甲酯化雷夫康唑的含量相對於膠囊之內容積,通常是1.5g/mL以下、較佳的是0.8g/mL以下、更佳的是0.7g/mL以下。
在本發明中,被填充物中的磷酸甲酯化雷夫康唑的含有率雖未特別限定,但因含有率愈高製劑愈能小型化,就服用性的觀點而言較佳。本發明之膠囊劑即使磷酸甲酯化雷夫康唑的含有率高,貯存之後進行溶解測試60分鐘後,就平均溶出率而言,通常仍可釋放磷酸甲酯化雷夫康唑60%以上、較佳的是85%以上。在本發明中,磷酸甲酯化雷夫康唑相對於被填充物質量之含有率通常是50%以上、較佳的是75%以上、更佳的是90%以上、進而更佳的是95%以上。
本發明膠囊劑可以根據已知方法來製造,例如在日本藥典第16版之製劑總則乙節的“1.2膠囊劑(10頁)”中所記載的方法等。作為製造膠囊劑的方法,可列舉例如:僅將磷酸甲酯化雷夫康唑填充在膠囊中的方法;將磷酸甲酯化雷夫康唑與視需要添加之賦形劑、粘合劑、崩解劑、潤滑劑等添加劑混合而成的組合物填充在膠囊中的方法;將於磷酸甲酯化雷夫康唑中視需要加入賦形劑、粘合劑、崩解劑、溶劑等添加劑而進行攪拌造粒、擠出造粒、滾筒造粒、流化床造粒、噴霧造粒等任何造粒作用所製造之顆粒填充入膠囊中的方法;或將於上述顆粒中視需要添加賦形劑、粘合劑、崩解劑、潤滑劑等添加劑混合而成之組合物填充於膠囊中的方法。
本發明之膠囊劑可以治療動物、尤其是哺乳類、更具體而言是人的疾病為目的進行投與。本發明之膠囊劑的適應症並無特別限定,只要係磷酸甲酯化雷夫康唑可適用的疾病即可。本發明之膠囊劑可用於念珠菌病、甲癬等真菌感染症的治療。藥理活性成分磷酸甲酯化雷
夫康唑的投與量可根據藥理活性成分的活性、患者症狀、年齡、體重等各種條件而改變。經口投與的投與量大致為10至2000毫克/天,較佳的是50至1000毫克/天。
本發明的膠囊劑即使於例如以開封狀態於40℃及相對濕度75%的條件下貯存1個月後,在實施例中所述日本藥典第16版中“6.10溶出測試法(117至121頁)”乙節的溶出測試中,測試開始60分鐘後,以平均溶出率而言,通常可以釋放磷酸甲酯化雷夫康唑60%以上、較佳的是75%以上、更佳的是85%以上、進而更佳的是90%以上、特佳的是95%以上。
本發明係將包含磷酸甲酯化雷夫康唑的被填充物填充在不含明膠的膠囊中,藉此無論磷酸甲酯化雷夫康唑之填充量為何,均能抑制所得膠囊劑因貯存所致磷酸甲酯化雷夫康唑從膠囊劑溶出延遲之方法。該貯存條件可列舉例如在40℃和相對濕度75%的條件下以開封狀態貯存1個月等。
根據本發明之該抑制方法,例如在貯存之後,磷酸甲酯化雷夫康唑從膠囊劑溶出的平均溶出率通常可以達60%以上、較佳的是75%以上、更佳的是85%以上、進而更佳的是90%以上、特佳的是95%以上。
以下列舉實施例和比較例詳述本發明之實施形態及功效。該等實施例係實施形態之例示,本發明尚涵蓋以下所示實施例以外之實施形態。熟習相關技術者可對以下實施例作出各種修改而採用其等作為本發明之實施形態,並且該等修改的實施形態只要與本發明之意旨相符,也涵蓋在本發明範圍內。
將19.88g的化合物2(磷酸甲酯化雷夫康唑)與0.12g的硬脂酸鎂(萬靈科(Mallinckrodt)公司製)在一小瓶中進行混合。將生成的混合物稱取8.55mg置於一種羥丙甲纖維素膠囊(VcapsPlus®,2號大小,由CAPSUGEL公司製)中,獲得每一膠囊包含8.5mg化合物2的膠囊劑。
將19.88g的化合物2(磷酸甲酯化雷夫康唑)與0.12g的硬脂酸鎂(萬靈科公司製)在一小瓶中進行混合。將生成的混合物稱取17.1mg置於一種羥丙甲纖維素膠囊(VcapsPlus®,2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含17mg化合物2的膠囊劑。
將19.88g的化合物2(磷酸甲酯化雷夫康唑)與0.12g的硬脂酸鎂(萬靈科公司製)在一小瓶中進行混合。將生成的混合物稱取34.2mg置於一種羥丙甲纖維素膠囊(VcapsPlus®,2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含34mg化合物2的膠囊劑。
將19.88g的化合物2(磷酸甲酯化雷夫康唑)與0.12g的硬脂酸鎂(萬靈科公司製)在一小瓶中進行混合。將生成的混合物稱取85.5mg置於一種羥丙甲纖維素膠囊(VcapsPlus®,2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含85mg化合物2的膠囊劑。
將19.88g的化合物2(磷酸甲酯化雷夫康唑)與0.12g的硬脂酸鎂(萬靈科公司製)在一小瓶中進行混合。將生成的混合物稱取171.0mg置於一種羥丙甲纖維素膠囊(VcapsPlus®,2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含170mg化合物2的膠囊劑。
將19.88g的化合物2(磷酸甲酯化雷夫康唑)與0.12g的硬脂酸鎂(萬靈科公司製)在一小瓶中進行混合。將生成的混合物稱取342.1mg置於一種羥丙甲纖維素膠囊(VcapsPlus®,0號大小,CAPSUGEL公司製)中,獲得每一膠囊包含340mg化合物2的膠囊劑。
將19.88g的化合物2(磷酸甲酯化雷夫康唑)與0.12g的硬脂酸鎂(萬靈科公司製)在一小瓶中進行混合。將生成的混合物稱取85.5mg置於一聚三葡萄糖膠囊(NPcaps®,2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含85mg化合物2的膠囊劑。
將19.88g的化合物2(磷酸甲酯化雷夫康唑)與0.12g的硬脂酸鎂(萬靈科公司製)在一小瓶中進行混合。將生成的混合物稱取8.55mg置於一種明膠膠囊(2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含8.5mg化合物2的膠囊劑。
將19.88g的化合物2(磷酸甲酯化雷夫康唑)與0.12g的硬脂酸鎂(萬靈科公司製)在一小瓶中進行混合。將生成的混合物稱取17.1mg置於一種明膠膠囊(2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含17mg化合物2的膠囊劑。
將19.88g的化合物2(磷酸甲酯化雷夫康唑)與0.12g的硬脂酸鎂(萬靈科公司製)在一小瓶中進行混合。將生成的混合物稱取34.2mg置於一種明膠膠囊(2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含34mg化合物2的膠囊劑。
將19.88g的化合物2(磷酸甲酯化雷夫康唑)與0.12g的硬脂酸鎂(萬靈科公司製)在一小瓶中進行混合。將生成的混合物稱取85.5mg置於一種明膠膠囊(2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含85mg化合物2的膠囊劑。
將19.88g的化合物2(磷酸甲酯化雷夫康唑)與0.12g的硬脂酸鎂(萬靈科公司製)在一小瓶中進行混合。將生成的混合物稱取171.0mg置於一種明膠膠囊(2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含170mg化合物2的膠囊劑。
將19.88g的化合物2(磷酸甲酯化雷夫康唑)與0.12g的硬脂酸鎂(萬靈科公司製)在一小瓶中進行混合。將生成的混合物稱取342.1mg置於一種明膠膠囊(0號大小,CAPSUGEL公司製)中,獲得每一膠囊包含340mg化合物2的膠囊劑。
在一研缽中,將5.0g的化合物2(磷酸甲酯化雷夫康唑)、0.3g的聚維酮(ISP公司製)、1.5g的交聯羧甲纖維素鈉(峰文國際公司(FMC International)製)、0.3g的氧化鎂(協和化學工業股份有限公司(Kyowa Chemical Industry Co.,Ltd.)製)以及1.55g的甘露糖醇(三菱商事食品科技股份有限公司(Mitsubishi Shoji Foodtech Co.,Ltd.)製)進行混合。向生成的混合物中添加乙醇:水=7:1(w/w)的混合液,並且進行造粒。使用恒溫槽將所得造粒物乾燥,接著通過具有1mm篩孔的篩來調整粒徑(整粒)。於所得整粒物中添加1.2g的羧甲纖維素(日輪化學工業有限公司(Nichirin Chemical Industries,Ltd.)製)、0.05g的矽酸鈣(由德山曹達公司(Tokuyama
Corporation)製)以及0.1g的硬脂酸鎂(萬靈科公司製)進行混合。將生成的混合物稱取170mg後,材料測試機(Autograph®,島津公司(Shimadzu Corporation)製)上壓縮,獲得包含85mg化合物2且直徑為7.5mm的錠劑。
將實施例1至7和比較例1至7所獲得的膠囊劑或錠劑用作樣品。將各樣品置入小瓶中,在40℃和相對濕度75%的條件下以開封狀態貯存1個月。針對貯存前後的樣品,評估其在pH 6.8的磷酸緩衝液中之溶出行為。
溶出測試根據下述在日本藥典第16版中的“6.10溶出測試法”進行。於指定的容器中裝入900mL之pH 6.8的磷酸緩衝液作為溶出測試液,並安裝至一裝置上,且用溫度計確認測試液維持在37±0.5℃之後,將溫度計移除。膠囊劑置於日本藥典第16版的圖6.10-2a(第118頁)中所示描繪的沈降片(sinker)中,然後小心地投入各容器俾不使樣品表面附著氣泡。錠劑則直接投入各容器,並小心不要使樣品表面附著氣泡。樣品投入後,立即用50rpm的漿轉速使裝置運轉,並於預定時間從測試液上表面與旋轉葉片上表面的中間離容器壁10mm以上之位置採取測試液。使用0.45μm孔徑的過濾器過濾所採取之測試液,並且將濾液用於在後述吸光度測量。溶出測試液係藉由向136.1g的無水磷酸二氫鉀和224mL的2mol/L氫氧化鈉水溶液中添加純水至20L來進行製備。
化合物2的溶出率,係藉由測定上述在預定時間採取並經過濾後的測試液(濾液)之吸光度,並與另行製備的標準溶液的吸光度比較而算出。吸光度測定係使用光徑10mm的小容器(cell)來進行。測定各樣品所使用的測定波長和參考波長的組合如下所示。又,以下組合中還記載化合物2的含量小於7mg和化合物2的含量為380mg以上的
樣品的測定條件作為參考資訊。
包含小於7mg的化合物2的樣品:測定波長285nm/參考波長350nm
包含7mg以上且小於40mg的化合物2的樣品:測定波長302nm/參考波長350nm
包含40mg以上且小於200mg的化合物2的樣品:測定波長315nm/參考波長350nm
包含200mg以上且小於380mg的化合物2的樣品:測定波長318nm/參考波長350nm
包含380mg以上且小於800mg的化合物2的樣品:測定波長322nm/參考波長350nm
包含800mg以上的化合物2的樣品:測定波長325nm/參考波長350nm
實施例1至7和比較例1至7的各樣品在測試開始60分鐘後的平均溶出率(60分鐘溶出率)示於表1、圖1和圖2。實施例6和比較例6的各樣品在測試開始5分鐘後至60分鐘後的溶出率變動示於表2、圖3和圖4中。圖表中所示各實施例和各比較例的溶出率係三個樣品之平均溶出率。
關於貯存之後的形狀變化,觀察到實施例7的樣品(聚三葡萄糖膠囊)軟化並且變形,比較例7的樣品(錠劑)則有膨脹。使用羥丙甲纖維素膠囊和明膠膠囊的各樣品,則沒有觀察到膠囊軟化及變形。
貯存在40℃的實施例1至7的樣品的平均溶解率與初始值相較並無下降。尤其是實施例1至6的各樣品(羥丙甲纖維素膠囊),無論化合物2的填充量為何,即使在40℃貯存之後,測試開始60分鐘後仍然迅速溶出化合物2含量的85%以上。實施例7的樣品(聚三葡萄糖膠囊)相較於使用羥丙甲纖維素膠囊時,在樣品間的平均溶出率波動較大。
40℃貯存後之比較例1至7的樣品則平均溶出率下降,當化合物2含量愈高,平均溶出率的下降程度愈顯著。尤其是化合物2的含量為85mg以上的比較例4至7的樣品,測試開始60分鐘後的平均溶出率甚
至小於10%。
將796g的化合物2(磷酸甲酯化雷夫康唑)和4g的硬脂酸鎂(萬靈科公司製)進行混合。將生成的混合物172mg填充於一種羥丙甲纖維素膠囊(VcapsPlus®,2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含171mg化合物2的膠囊劑。
將794.4g的化合物2(磷酸甲酯化雷夫康唑)、1.6g的氧化鎂(協和化學工業股份有限公司製)以及4g的硬脂酸鎂(萬靈科公司製)進行混合。將生成的混合物172mg填充於一種羥丙甲纖維素膠囊(VcapsPlus®,2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含171mg化合物2的膠囊劑。
將792g的化合物2(磷酸甲酯化雷夫康唑)、4g的氧化鎂(協和化學工業股份有限公司製)以及4g的硬脂酸鎂(萬靈科公司製)進行混合。將生成的混合物173mg填充於一種羥丙甲纖維素膠囊(VcapsPlus®,2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含171mg化合物2的膠囊劑。
將788g的化合物2(磷酸甲酯化雷夫康唑)、8g的氧化鎂(協和化學工業股份有限公司製)以及4g的硬脂酸鎂(萬靈科公司製)進行混合。將生成的混合物174mg填充於一種羥丙甲纖維素膠囊(VcapsPlus®,2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含171mg化合物2的膠囊劑。
將148.05g的化合物2(磷酸甲酯化雷夫康唑)、0.75g的氧化鎂
(協和化學工業股份有限公司製)以及1.2g的硬脂酸鎂(萬靈科公司製)進行混合。將生成的混合物173mg填充於一種羥丙甲纖維素膠囊(VcapsPlus®,3號大小,CAPSUGEL公司製)中,獲得每一膠囊包含171mg化合物2的膠囊劑。
將147.75g的化合物2(磷酸甲酯化雷夫康唑)、0.75g的氧化鎂(協和化學工業股份有限公司製)以及1.5g的硬脂酸鎂(萬靈科公司製)進行混合。將生成的混合物174mg填充於一種羥丙甲纖維素膠囊(VcapsPlus®,2號大小,CAPSUGEL公司製)中,獲得每一膠囊包含171mg化合物2的膠囊劑。
將實施例12中獲得的羥丙甲纖維素膠囊用作樣品。以與試驗例1相同的方式將樣品以開封狀態貯存,並且評估貯存前後的樣品在pH 6.8的磷酸緩衝液中溶出行為。
貯存前後的樣品在測試開始60分鐘後的平均溶出率(60分鐘溶出率)示於表3。在表中所示溶出率係三個樣品之平均溶出率。
貯存在40℃的實施例12的樣品之平均溶出率與初始值相較沒有下降。
根據本發明,可以製造包含磷酸甲酯化雷夫康唑之膠囊劑。本發明之膠囊劑無論磷酸甲酯化雷夫康唑的填充量為何,均可抑制因貯存所致之溶出延遲,在醫療領域中具有產業利用性。
Claims (6)
- 一種膠囊劑,包含:被填充物,其含有{[(1R,2R)-2-[4-(4-氰基苯基)-1,3-噻唑-2-基]-1-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基甲基)丙基]氧基}甲基二氫磷酸酯或其藥理學上可接受之鹽、或其等任何之水合物或乙醇合物;及不含明膠之膠囊。
- 如請求項1之膠囊劑,其中該膠囊係由含有澱粉、聚三葡萄糖、聚乙烯醇或羥丙甲纖維素之膠囊基料形成。
- 如請求項1之膠囊劑,其中該膠囊係由含有聚三葡萄糖或羥丙甲纖維素之膠囊基料形成。
- 如請求項1之膠囊劑,其中該膠囊係由含有羥丙甲纖維素之膠囊基料形成。
- 如請求項1至4中任一項之膠囊劑,其中該{[(1R,2R)-2-[4-(4-氰基苯基)-1,3-噻唑-2-基]-1-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基甲基)丙基]氧基}甲基二氫磷酸酯或其藥理學上可接受之鹽、或其等任何之水合物或乙醇合物係L-賴胺酸鹽-{[(1R,2R)-2-[4-(4-氰基苯基)-1,3-噻唑-2-基]-1-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基甲基)丙基]氧基}甲基二氫磷酸酯-乙醇(1/1/1)。
- 如請求項1之膠囊劑,其中該被填充物材料進一步包含氧化鎂。
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