JP6258920B2 - Orally disintegrating film-coated tablets - Google Patents
Orally disintegrating film-coated tablets Download PDFInfo
- Publication number
- JP6258920B2 JP6258920B2 JP2015508567A JP2015508567A JP6258920B2 JP 6258920 B2 JP6258920 B2 JP 6258920B2 JP 2015508567 A JP2015508567 A JP 2015508567A JP 2015508567 A JP2015508567 A JP 2015508567A JP 6258920 B2 JP6258920 B2 JP 6258920B2
- Authority
- JP
- Japan
- Prior art keywords
- tablet
- orally disintegrating
- film
- manufactured
- disintegration
- 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.)
- Active
Links
- 239000007941 film coated tablet Substances 0.000 title description 45
- 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 33
- 239000007888 film coating Substances 0.000 claims description 27
- 238000009501 film coating Methods 0.000 claims description 27
- 235000003599 food sweetener Nutrition 0.000 claims description 27
- 238000004519 manufacturing process Methods 0.000 claims description 27
- 239000003765 sweetening agent Substances 0.000 claims description 27
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 20
- 210000000214 mouth Anatomy 0.000 claims description 18
- 239000004376 Sucralose Substances 0.000 claims description 17
- 235000019408 sucralose Nutrition 0.000 claims description 17
- 235000010355 mannitol Nutrition 0.000 claims description 16
- 239000011347 resin Substances 0.000 claims description 14
- 229920005989 resin Polymers 0.000 claims description 14
- 239000012461 cellulose resin Substances 0.000 claims description 12
- 229920000609 methyl cellulose Polymers 0.000 claims description 11
- 235000010981 methylcellulose Nutrition 0.000 claims description 11
- 239000001923 methylcellulose Substances 0.000 claims description 11
- 229960002900 methylcellulose Drugs 0.000 claims description 11
- 239000004386 Erythritol Substances 0.000 claims description 10
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 10
- 235000019414 erythritol Nutrition 0.000 claims description 10
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 10
- 229940009714 erythritol Drugs 0.000 claims description 10
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 claims description 9
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 9
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 9
- 229960003943 hypromellose Drugs 0.000 claims description 9
- 235000010449 maltitol Nutrition 0.000 claims description 7
- 239000000845 maltitol Substances 0.000 claims description 7
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 7
- 229940035436 maltitol Drugs 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 6
- 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 claims description 5
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 5
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 5
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 5
- 239000000832 lactitol Substances 0.000 claims description 5
- 235000010448 lactitol Nutrition 0.000 claims description 5
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 claims description 5
- 229960003451 lactitol Drugs 0.000 claims description 5
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 5
- 229940074410 trehalose Drugs 0.000 claims description 5
- 239000000811 xylitol Substances 0.000 claims description 5
- 235000010447 xylitol Nutrition 0.000 claims description 5
- 229960002675 xylitol Drugs 0.000 claims description 5
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 5
- 239000010410 layer Substances 0.000 claims description 4
- 230000007613 environmental effect Effects 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 59
- 239000006191 orally-disintegrating tablet Substances 0.000 description 40
- 239000011247 coating layer Substances 0.000 description 29
- 239000000126 substance Substances 0.000 description 23
- 238000012360 testing method Methods 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 17
- 238000000034 method Methods 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 14
- 239000004203 carnauba wax Substances 0.000 description 14
- 235000013869 carnauba wax Nutrition 0.000 description 14
- 239000011248 coating agent Substances 0.000 description 14
- 238000000576 coating method Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 10
- 239000000654 additive Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 238000001878 scanning electron micrograph Methods 0.000 description 10
- 239000004372 Polyvinyl alcohol Substances 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- 238000002156 mixing Methods 0.000 description 9
- 238000004806 packaging method and process Methods 0.000 description 9
- 229920002451 polyvinyl alcohol Polymers 0.000 description 9
- 230000000996 additive effect Effects 0.000 description 8
- 239000006185 dispersion Substances 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000001993 wax Substances 0.000 description 7
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 6
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 6
- 229930195725 Mannitol Natural products 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 5
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 5
- 239000000594 mannitol Substances 0.000 description 5
- 229960001855 mannitol Drugs 0.000 description 5
- 239000007935 oral tablet Substances 0.000 description 5
- 229940096978 oral tablet Drugs 0.000 description 5
- 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 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 4
- 108010011485 Aspartame Proteins 0.000 description 4
- 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 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229920002472 Starch Polymers 0.000 description 4
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 4
- 239000000605 aspartame Substances 0.000 description 4
- 235000010357 aspartame Nutrition 0.000 description 4
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 4
- 229960003438 aspartame Drugs 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 229960000913 crospovidone Drugs 0.000 description 4
- 239000003205 fragrance Substances 0.000 description 4
- 229920000578 graft copolymer Polymers 0.000 description 4
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 229960001375 lactose Drugs 0.000 description 4
- 239000004611 light stabiliser Substances 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- -1 naphthopidyl Chemical compound 0.000 description 4
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000004014 plasticizer Substances 0.000 description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000008199 coating composition Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000005498 polishing Methods 0.000 description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- PTKSEFOSCHHMPD-SNVBAGLBSA-N 2-amino-n-[(2s)-2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide Chemical compound COC1=CC=C(OC)C([C@H](O)CNC(=O)CN)=C1 PTKSEFOSCHHMPD-SNVBAGLBSA-N 0.000 description 2
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- UMSGKTJDUHERQW-UHFFFAOYSA-N Brotizolam Chemical compound C1=2C=C(Br)SC=2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl UMSGKTJDUHERQW-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 235000005979 Citrus limon Nutrition 0.000 description 2
- 244000131522 Citrus pyriformis Species 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 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 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000004378 Glycyrrhizin Substances 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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 description 2
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 2
- 244000246386 Mentha pulegium Species 0.000 description 2
- 235000016257 Mentha pulegium Nutrition 0.000 description 2
- 235000004357 Mentha x piperita Nutrition 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 239000004373 Pullulan Substances 0.000 description 2
- 229920001218 Pullulan Polymers 0.000 description 2
- 244000228451 Stevia rebaudiana Species 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 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 2
- 239000002253 acid Substances 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 229960000528 amlodipine Drugs 0.000 description 2
- 229960004005 amlodipine besylate Drugs 0.000 description 2
- 235000013871 bee wax Nutrition 0.000 description 2
- 239000012166 beeswax Substances 0.000 description 2
- 229960003051 brotizolam Drugs 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229960005069 calcium Drugs 0.000 description 2
- 235000013736 caramel Nutrition 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
- 150000001746 carotenes Chemical class 0.000 description 2
- 235000005473 carotenes Nutrition 0.000 description 2
- 229960002142 cefditoren pivoxil Drugs 0.000 description 2
- AFZFFLVORLEPPO-UVYJNCLZSA-N cefditoren pivoxil Chemical compound S([C@@H]1[C@@H](C(N1C=1C(=O)OCOC(=O)C(C)(C)C)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C AFZFFLVORLEPPO-UVYJNCLZSA-N 0.000 description 2
- 230000001055 chewing effect Effects 0.000 description 2
- 229930002875 chlorophyll Natural products 0.000 description 2
- 235000019804 chlorophyll Nutrition 0.000 description 2
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 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
- 239000013078 crystal Substances 0.000 description 2
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 description 2
- 229960001971 ebastine Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 2
- 229960004949 glycyrrhizic acid Drugs 0.000 description 2
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 2
- 235000019410 glycyrrhizin Nutrition 0.000 description 2
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 2
- 235000001050 hortel pimenta Nutrition 0.000 description 2
- 235000019223 lemon-lime Nutrition 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 150000002646 long chain fatty acid esters Chemical class 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 239000002932 luster Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 2
- 229940041616 menthol Drugs 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 229960001094 midodrine Drugs 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 235000019477 peppermint oil Nutrition 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 235000019423 pullulan Nutrition 0.000 description 2
- NTHPAPBPFQJABD-LLVKDONJSA-N ramosetron Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 NTHPAPBPFQJABD-LLVKDONJSA-N 0.000 description 2
- 229950001588 ramosetron Drugs 0.000 description 2
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 2
- 229960002477 riboflavin Drugs 0.000 description 2
- 235000019192 riboflavin Nutrition 0.000 description 2
- 239000002151 riboflavin Substances 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 2
- 229960003946 selegiline Drugs 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- ILJOYZVVZZFIKA-UHFFFAOYSA-M sodium;1,1-dioxo-1,2-benzothiazol-3-olate;hydrate Chemical compound O.[Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 ILJOYZVVZZFIKA-UHFFFAOYSA-M 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 230000003746 surface roughness Effects 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000892 thaumatin Substances 0.000 description 2
- 235000010436 thaumatin Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- 239000001069 triethyl citrate Substances 0.000 description 2
- 235000013769 triethyl citrate Nutrition 0.000 description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 2
- 229940052016 turmeric extract Drugs 0.000 description 2
- 235000020240 turmeric extract Nutrition 0.000 description 2
- 239000008513 turmeric extract Substances 0.000 description 2
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- ATCGGEJZONJOCL-UHFFFAOYSA-N 6-(2,5-dichlorophenyl)-1,3,5-triazine-2,4-diamine Chemical compound NC1=NC(N)=NC(C=2C(=CC=C(Cl)C=2)Cl)=N1 ATCGGEJZONJOCL-UHFFFAOYSA-N 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
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-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
- 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
- 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
- 239000004605 External Lubricant Substances 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229930091371 Fructose Natural products 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
- 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
- 239000004471 Glycine Substances 0.000 description 1
- KMZQAVXSMUKBPD-DJWKRKHSSA-N Lafutidine Chemical compound C=1C=COC=1C[S+]([O-])CC(=O)NC\C=C/COC(N=CC=1)=CC=1CN1CCCCC1 KMZQAVXSMUKBPD-DJWKRKHSSA-N 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 229960004998 acesulfame potassium Drugs 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- YWGDOWXRIALTES-NRFANRHFSA-N bepotastine Chemical compound C1CN(CCCC(=O)O)CCC1O[C@H](C=1N=CC=CC=1)C1=CC=C(Cl)C=C1 YWGDOWXRIALTES-NRFANRHFSA-N 0.000 description 1
- 229960002071 bepotastine Drugs 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 description 1
- 229960004588 cilostazol Drugs 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 description 1
- 229960001253 domperidone Drugs 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 229960001596 famotidine Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- SQKXYSGRELMAAU-UHFFFAOYSA-N imidafenacin Chemical compound CC1=NC=CN1CCC(C(N)=O)(C=1C=CC=CC=1)C1=CC=CC=C1 SQKXYSGRELMAAU-UHFFFAOYSA-N 0.000 description 1
- 229950005396 imidafenacin Drugs 0.000 description 1
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- 229950010984 irsogladine Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229960003303 lafutidine Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- 229960004114 olopatadine Drugs 0.000 description 1
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229950004693 polaprezinc Drugs 0.000 description 1
- 108700035912 polaprezinc Proteins 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 229960003855 solifenacin Drugs 0.000 description 1
- FBOUYBDGKBSUES-VXKWHMMOSA-N solifenacin Chemical compound C1([C@H]2C3=CC=CC=C3CCN2C(O[C@@H]2C3CCN(CC3)C2)=O)=CC=CC=C1 FBOUYBDGKBSUES-VXKWHMMOSA-N 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 229960003487 xylose Drugs 0.000 description 1
- IUWLTSZHVYHOHY-FJXQXJEOSA-L zinc;(2s)-2-(3-azanidylpropanoylazanidyl)-3-(1h-imidazol-5-yl)propanoate Chemical compound [Zn+2].[NH-]CCC(=O)[N-][C@H](C([O-])=O)CC1=CN=CN1 IUWLTSZHVYHOHY-FJXQXJEOSA-L 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
- 229960001475 zolpidem Drugs 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
- A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
Description
本発明は、経時的な外観変化の生じない口腔内崩壊性フィルムコーティング錠に関する。更に詳しくは、甘味料の少なくとも1種を含有するセルロース系樹脂のフィルムコーティングが施された、ごくわずかな経時的な外観の変化も認められない安定な口腔内崩壊性フィルムコーティング錠に関する。 The present invention relates to an orally disintegrating film-coated tablet that does not change its appearance over time. More specifically, the present invention relates to a stable orally disintegrating film-coated tablet which is subjected to a film coating of a cellulose-based resin containing at least one sweetener and in which no slight change in appearance over time is observed.
フィルムコーティングとは、錠剤表面に薄い膜状の物質を形成させる処理の一つであり、外観の改善、耐水性の付与、摩損性の改善、光安定化、識別性の向上などの様々な機能を付与する目的で実施される。 Film coating is one of the processes to form a thin film-like substance on the tablet surface, and has various functions such as improving appearance, imparting water resistance, improving wear resistance, stabilizing light, and improving discrimination. It is carried out for the purpose of granting.
近年、疾患、加齢、唾液分泌量の低下など様々な原因から、嚥下機能の低下した患者に対して、服用しやすい剤形として、口腔内で迅速に崩壊する口腔内崩壊錠の開発が盛んに行われている。口腔内崩壊錠は、患者の服用性の観点から、一般的な錠剤と比較して求められる崩壊速度が圧倒的に速く、崩壊速度を追求した特殊剤形である。しかしながら、一般的に、速崩壊性と高い錠剤硬度は相反する特性であるため、口腔内崩壊錠は錠剤硬度不足や高い摩損性のために、ＰＴＰから錠剤を取り出す際に錠剤の欠け、割れを生じ、調剤現場でも自動分包機を使用する上で取り扱い面での課題が指摘されている。すなわち、錠剤は、自動分包前の分包機内では無包装形態で保存され、また分包後は簡易包装形態で保存されるため、光、温度、湿度などの保存環境の影響を受けやすい。例えば、光により分解するなど、外的環境に弱い活性成分に適用できないのは勿論のこと、吸湿により、口腔内崩壊錠自体の硬度が低下し、服用までの取り扱いに耐えられないなどの課題が指摘されている。これらの課題を解決する上で、フィルムコーティングの手法は有用であるが、コーティング層による崩壊遅延が懸念され、口腔内崩壊錠へのフィルムコーティングの適用は難しいのが現状である。 In recent years, the development of orally disintegrating tablets that rapidly disintegrate in the oral cavity has been actively developed as an easy-to-use dosage form for patients with reduced swallowing function due to various causes such as diseases, aging, and decreased salivary secretion. Has been done. The orally disintegrating tablet is a special dosage form that pursues the disintegration rate because the disintegration rate required is higher than that of a general tablet from the viewpoint of patient ingestion. In general, however, fast disintegrating properties and high tablet hardness are contradictory properties. Therefore, orally disintegrating tablets suffer from tablet chipping and cracking when taking out tablets from PTP due to insufficient tablet hardness and high friability. As a result, problems in handling have been pointed out when using an automatic packaging machine at the dispensing site. That is, the tablets are stored in a non-wrapping form in the pre-packaging machine and in a simple packaging form after the packaging, and thus are easily affected by storage environments such as light, temperature, and humidity. For example, it cannot be applied to active ingredients that are weak to the external environment, for example, it decomposes by light, but due to moisture absorption, the hardness of the orally disintegrating tablet itself decreases, and it cannot be handled until taking. It has been pointed out. In order to solve these problems, the film coating technique is useful, but the present situation is that it is difficult to apply the film coating to the orally disintegrating tablet due to concern about the delay of disintegration due to the coating layer.
一方で、コーティング層に水溶性物質を含有するポリビニルアルコール系樹脂を用いることで、口腔内での速崩壊性を確保しながら、口腔内崩壊錠が高湿度下において吸湿により膨潤した場合においても、被覆層に亀裂が生じることが無い安定な口腔内崩壊性被覆錠剤が開示されている（特許文献１）。しかしながら、亀裂以外の外観変化については、一切、報告されておらず、また、水溶性物質を配合していることから、高湿度での外観変化が予想される。 On the other hand, by using a polyvinyl alcohol-based resin containing a water-soluble substance in the coating layer, while ensuring fast disintegration in the oral cavity, even when the orally disintegrating tablet swells due to moisture absorption under high humidity, A stable orally disintegrating coated tablet that does not cause cracks in the coating layer is disclosed (Patent Document 1). However, no change in appearance other than cracks has been reported, and since a water-soluble substance is blended, a change in appearance at high humidity is expected.
さらに、ある一定以上の硬度を有した口腔内崩壊性の錠芯に水溶性高分子を含むフィルムコーティング層を施すことで、高い強度を付与した口腔内崩壊性フィルムコーティング錠が開示されているが（特許文献２）、前項同様に、破断以外の外観変化については、一切、報告されていない。 Furthermore, an orally disintegrating film-coated tablet imparted with high strength by applying a film coating layer containing a water-soluble polymer to an orally disintegrating tablet core having a certain hardness or more is disclosed. (Patent Document 2) As in the previous section, no change in appearance other than breakage has been reported.
一方で、フィルムコーティングによらない口腔内崩壊錠の被覆方法として、有核型速溶崩壊性錠剤が開示されている（特許文献３）。しかしながら、製造に特殊な装置を要することのほか、フィルムコーティング錠と比べて外周層が厚いため、錠剤径が大きくなる場合が多い。口腔内崩壊錠は口腔内で崩壊させて服用するだけでなく、通常の錠剤と同様に、水で服用する場合もあることから、錠剤径が大きくなることは好ましくない。 On the other hand, a nucleated fast-disintegrating tablet has been disclosed as a method for coating an orally disintegrating tablet that does not rely on film coating (Patent Document 3). However, in addition to requiring a special device for production, the outer diameter layer is thicker than that of film-coated tablets, so that the tablet diameter is often increased. An orally disintegrating tablet is not only disintegrated in the oral cavity but also taken, and since it may be taken with water in the same manner as a normal tablet, it is not preferable that the tablet diameter increases.
本発明は、口腔内での速崩壊性の機能を保持しつつ、高湿度下において吸湿により、コーティング層の亀裂のみならず、艶消失などのごくわずかな経時的な外観の変化も認められない安定な口腔内崩壊性フィルムコーティング錠を提供することを目的とする。 In the present invention, while maintaining the function of rapidly disintegrating in the oral cavity, not only cracks in the coating layer but also slight slight changes in appearance over time such as loss of gloss are not observed due to moisture absorption under high humidity. An object of the present invention is to provide a stable orally disintegrating film-coated tablet.
一般に、錠剤のフィルムコーティングは、外観の改善、耐水性の付与、摩損性の改善、光安定化、識別性の向上などを目的として実施される。この手法を口腔内崩壊錠に適用する場合、速崩壊性を要するという性質上、コーティング層に溶解性の優れるポリビニルアルコール系樹脂を用い、水溶性物質を配合する方法が有用である。一方で、これらの錠剤は、分包時および分包後においては、無包装および簡易包装形態で保存されるため、光、温度、湿度などの外的環境に晒されても、品質を維持することが要求されるが、ポリビニルアルコール系樹脂に水溶性物質を配合したコーティング層では、特に高湿度下での保存時に、艶の消失することが明らかとなった。このような外観変化は、患者に不安を与え、服薬コンプライアンスの低下を招く。 In general, the film coating of tablets is performed for the purpose of improving the appearance, imparting water resistance, improving friability, stabilizing the light, and improving discrimination. When this technique is applied to an orally disintegrating tablet, a method in which a water-soluble substance is blended using a polyvinyl alcohol resin having excellent solubility in the coating layer is useful because of its property of requiring rapid disintegration. On the other hand, since these tablets are stored in a non-wrapping and simple packaging form at the time of packaging and after packaging, the quality is maintained even when exposed to an external environment such as light, temperature, and humidity. However, it has been clarified that the coating layer in which the water-soluble substance is blended with the polyvinyl alcohol-based resin loses the gloss particularly when stored under high humidity. Such a change in appearance causes anxiety to the patient and leads to a decrease in compliance.
そこで、発明者らは、速崩壊性を有し、高湿度下でも外観変化の生じない口腔内崩壊性フィルムコーティング錠を開発すべく、鋭意検討を行った結果、セルロース系樹脂に甘味料を組み合わせることにより、速崩壊性の機能を保持しつつ、高湿度下においても、コーティング層の亀裂のみならず、艶消失などのごくわずかな経時的な外観変化の生じない口腔内崩壊性フィルムコーティング錠が得られることを見出し、本発明を完成するに至った。 Therefore, the inventors have conducted an extensive study to develop an orally disintegrating film-coated tablet that has rapid disintegration and does not change appearance even under high humidity. As a result, a sweetener is combined with a cellulosic resin. Therefore, an orally disintegrating film-coated tablet that retains its fast disintegrating function and does not cause slight changes in appearance over time such as loss of gloss as well as cracks in the coating layer even under high humidity. As a result, the present invention was completed.
すなわち本発明は、
［１］甘味料の少なくとも１種を含有するセルロース系樹脂のフィルムコーティングが施された口腔内崩壊性フィルムコーティング錠、
［２］当該セルロース系樹脂が、メチルセルロース、ヒプロメロース、ヒドロキシプロピルセルロースおよびヒプロメロース酢酸エステルコハク酸エステルから選択される少なくとも１種である、上記［１］記載の口腔内崩壊性フィルムコーティング錠、
［３］当該甘味料が、Ｄ−マンニトール、エリスリトール、キシリトール、マルチトール、乳糖、トレハロース、ラクチトールおよびスクラロースから選択される少なくとも１種である、上記［１］記載の口腔内崩壊性フィルムコーティング錠、
［４］３０℃、相対湿度８１％の環境下で１箇月保存するとき、錠剤表面の艶が消失することを特徴とするごくわずかな経時的な外観の変化も認められない安定な、上記［１］記載の口腔内崩壊性フィルムコーティング錠、
［５］３０℃、相対湿度８１％の環境下で１箇月保存するとき、８°グロス値が製造直後に対し８０％以上保持されている、上記［１］記載の口腔内崩壊性フィルムコーティング錠、
［６］フィルムコーティング層中のセルロース系樹脂と甘味料の比率が、セルロース系樹脂１重量部に対し、甘味料が０．１〜９重量部であることを特徴とする、上記［１］記載の口腔内崩壊性フィルムコーティング錠、
［７］甘味料の少なくとも１種およびセルロース系樹脂を含有する口腔内崩壊性錠剤フィルムコーティング用組成物、
［８］甘味料がＤ−マンニトール、エリスリトール、キシリトール、マルチトール、乳糖、トレハロース、ラクチトールおよびスクラロースから選択される少なくとも１種であり、セルロース系樹がメチルセルロース、ヒプロメロース、ヒドロキシプロピルセルロースおよびヒプロメロース酢酸エステルコハク酸エステルから選択される少なくとも１種である、上記［７］記載の組成物、
［９］セルロース系樹脂と甘味料の比率が、セルロース系樹脂１重量部に対し、甘味料が０．１〜９重量部であることを特徴とする、上記［７］に記載の組成物および
［１０］上記［７］〜［９］いずれか１項記載の組成物を用いて素錠をコーティングすることを特徴とする口腔内崩壊性錠剤のフィルムコーティング方法に関する。That is, the present invention
[1] An orally disintegrating film-coated tablet provided with a film coating of a cellulose resin containing at least one sweetener,
[2] The orally disintegrating film-coated tablet according to [1], wherein the cellulose resin is at least one selected from methylcellulose, hypromellose, hydroxypropylcellulose, and hypromellose acetate succinate.
[3] The orally disintegrating film-coated tablet according to the above [1], wherein the sweetener is at least one selected from D-mannitol, erythritol, xylitol, maltitol, lactose, trehalose, lactitol, and sucralose.
[4] The above stable, no slight change in appearance over time characterized by loss of gloss on the tablet surface when stored for 1 month in an environment of 30 ° C. and 81% relative humidity, 1] orally disintegrating film-coated tablets,
[5] The orally disintegrating film-coated tablet according to the above [1], wherein when stored for 1 month in an environment of 30 ° C. and relative humidity 81%, an 8 ° gloss value is maintained at 80% or more as compared to immediately after production. ,
[6] The above-mentioned [1], wherein the ratio of the cellulose resin and the sweetener in the film coating layer is 0.1 to 9 parts by weight of the sweetener relative to 1 part by weight of the cellulose resin. Orally disintegrating film-coated tablets,
[7] An orally disintegrating tablet film coating composition containing at least one sweetener and a cellulose resin,
[8] The sweetener is at least one selected from D-mannitol, erythritol, xylitol, maltitol, lactose, trehalose, lactitol and sucralose, and the cellulosic tree is methylcellulose, hypromellose, hydroxypropylcellulose and hypromellose acetate succinate The composition according to [7] above, which is at least one selected from acid esters,
[9] The composition according to [7] above, wherein the ratio of the cellulose resin and the sweetener is 0.1 to 9 parts by weight of the sweetener with respect to 1 part by weight of the cellulose resin. [10] A film coating method for orally disintegrating tablets, comprising coating an uncoated tablet with the composition according to any one of [7] to [9] above.
本発明によれば、口腔内での速崩壊性の機能を保持しつつ、高湿度下においても、コーティング層の亀裂のみならず、艶消失などのごくわずかな経時的な外観変化の生じない口腔内崩壊性フィルムコーティング錠を提供することができる。また、自動分包時および服用までの取り扱い上、十分な硬度を有し、光、温度、湿度などの外的環境に晒された場合であっても、硬度低下や光による活性成分の分解が改善された口腔内崩壊性フィルムコーティング錠を提供することができる。より詳細には、光に不安定な活性成分を含有する口腔内崩壊錠においては、コーティング層に光安定化剤を配合することで、活性成分の分解を抑制することもできる。また、フィルムコーティングすることで、錠剤硬度の向上が可能であることから、これまで硬度不足により自動分包できなかった口腔内崩壊錠の一包化包装を可能とし、また、高湿度下において、吸湿により硬度低下する口腔内崩壊錠であっても、取り扱い可能な錠剤強度を確保することができる。これらの効果により、患者の服薬コンプライアンスを改善し、治療効果を向上させることができる。 According to the present invention, while maintaining a function of rapidly disintegrating in the oral cavity, even under high humidity, not only cracks in the coating layer but also the oral cavity in which only slight temporal changes such as loss of gloss do not occur. An internally disintegrating film-coated tablet can be provided. In addition, it has sufficient hardness for automatic packaging and handling until taking, and even when exposed to an external environment such as light, temperature, and humidity, the hardness is reduced and the active ingredient is decomposed by light. An improved orally disintegrating film-coated tablet can be provided. More specifically, in an orally disintegrating tablet containing a light-labile active ingredient, decomposition of the active ingredient can be suppressed by blending a light stabilizer in the coating layer. In addition, since film hardness can be improved by film coating, it is possible to package orally disintegrating tablets that could not be automatically packaged due to insufficient hardness until now, and under high humidity, Even if it is an orally disintegrating tablet whose hardness is reduced by moisture absorption, it is possible to secure a handleable tablet strength. These effects can improve patient compliance and improve the therapeutic effect.
本発明の好適な実施形態について、以下に説明する。
本発明の口腔内崩壊性フィルムコーティング錠は、内核錠（素錠）である口腔内崩壊錠の表面に、甘味料等を含有するセルロース系樹脂のコーティング層で被覆を施した口腔内崩壊性のフィルムコーティング錠である。
本発明の口腔内崩壊性錠剤フィルムコーティング用組成物は、甘味料の少なくとも１種およびセルロース系樹脂を含有し、内核錠（素錠）である口腔内崩壊錠の表面のコーティングに用いられる成分の組合せである。組合せは各成分の粉末の混合物であってもよく、粉末を混合して適切な溶媒に溶解または懸濁した状態でもよく、粉末を単独で適切な溶媒に溶解または懸濁した複数の液の組合せでもよく、コーティング層としての被膜を形成する成分の組合せであればよい。
本発明に用いられる「甘味料」とは、速やかに水に溶解し、口腔内で好適な甘味を呈する物質を指し、これらの群より選択される少なくとも１種を含んでなる。薬学上許容される甘味料としては、例えば、乳糖、白糖、精製白糖、ブドウ糖、果糖、マンニトール、エリスリトール、キシリトール、マルチトール、ラクチトール、ソルビトール、トレハロース、キシロース、グリシン、グリセリン、スクラロース、アセスルファムカリウム、グリチルリチン酸二カリウム、アスパルテーム、サッカリンナトリウム、ステビア、ソーマチンなどが挙げられ、好ましくは、マンニトール、エリスリトール、乳糖、マルチトール、ラクチトール、トレハロース、キシリトールであり、さらに好ましくは、マンニトール、エリスリトールである。A preferred embodiment of the present invention will be described below.
The orally disintegrating film-coated tablet of the present invention is an orally disintegrating film in which the surface of an orally disintegrating tablet that is an inner core tablet (plain tablet) is coated with a coating layer of a cellulose resin containing a sweetener and the like. Film-coated tablet.
The composition for coating an orally disintegrating tablet film of the present invention comprises at least one sweetener and a cellulose resin, and is a component used for coating the surface of an orally disintegrating tablet that is an inner core tablet (plain tablet). It is a combination. The combination may be a mixture of powders of each component, may be in a state where the powder is mixed and dissolved or suspended in a suitable solvent, or a combination of a plurality of liquids in which the powder is dissolved or suspended alone in a suitable solvent However, it may be a combination of components that form a film as a coating layer.
The “sweetener” used in the present invention refers to a substance that dissolves quickly in water and exhibits a suitable sweetness in the oral cavity, and comprises at least one selected from these groups. Examples of the pharmaceutically acceptable sweetener include lactose, sucrose, purified sucrose, glucose, fructose, mannitol, erythritol, xylitol, maltitol, lactitol, sorbitol, trehalose, xylose, glycine, glycerin, sucralose, acesulfame potassium, glycyrrhizin Examples include dipotassium acid, aspartame, sodium saccharin, stevia, thaumatin, and the like, preferably mannitol, erythritol, lactose, maltitol, lactitol, trehalose, xylitol, and more preferably mannitol and erythritol.
本発明に用いられる「セルロース系樹脂」とは、薬学上許容されるセルロース系誘導体を指し、これらの群より、１種または２種以上を組み合わせて用いることができる。例えば、メチルセルロース、ヒプロメロース、ヒプロメロースフタル酸エステル、ヒプロメロース酢酸エステルコハク酸エステル、ヒドロキシプロピルセルロース、カルボキシメチルエチルセルロースなどが挙げられ、好ましくは、メチルセルロース、ヒプロメロース、ヒドロキシプロピルセルロース、ヒプロメロース酢酸エステルコハク酸エステルであり、さらに好ましくは、メチルセルロース、ヒプロメロースである。 The “cellulosic resin” used in the present invention refers to a pharmaceutically acceptable cellulose derivative and can be used alone or in combination of two or more from these groups. For example, methyl cellulose, hypromellose, hypromellose phthalate, hypromellose acetate succinate, hydroxypropylcellulose, carboxymethylethylcellulose, etc., preferably methylcellulose, hypromellose, hydroxypropylcellulose, hypromellose acetate succinate And methyl cellulose and hypromellose are more preferable.
本発明のコーティング層およびコーティング用組成物におけるセルロース系樹脂に対する甘味料の重量比は特に制限されないが、好ましくは、セルロース系樹脂１重量部に対し甘味料が約０．１〜約９重量部であり、さらに好ましくは、約０．３〜約１．１重量部である。この理由としては、甘味料の配合量が多い場合、成膜性が低下し、甘味料の配合量が少ない場合、速崩壊性を確保できないからである。 The weight ratio of the sweetener to the cellulosic resin in the coating layer and coating composition of the present invention is not particularly limited, but preferably the sweetener is about 0.1 to about 9 parts by weight with respect to 1 part by weight of the cellulosic resin. More preferably about 0.3 to about 1.1 parts by weight. The reason for this is that when the amount of the sweetener is large, the film formability is lowered, and when the amount of the sweetener is small, the rapid disintegration property cannot be secured.
本発明の「ごくわずかな経時的な外観の変化も認められない安定な口腔内崩壊性フィルムコーティング錠」とは、口腔内崩壊性フィルムコーティング錠が高湿度下に晒された場合においても、吸湿により、コーティング層の亀裂などの明らかな外観の変化のみならず、表面の艶消失など、肉眼で観察し得るごくわずかな外観の変化も生じないことを意味する。具体的には、口腔内崩壊性フィルムコーティング錠を３０℃、相対湿度８１％の雰囲気下に１箇月間保存し、コーティング層の外観を肉眼観察することで評価できる。 The “stable orally disintegrating film-coated tablet with no slight change in appearance over time” of the present invention refers to moisture absorption even when the orally disintegrating film-coated tablet is exposed to high humidity. This means that not only an apparent change in appearance such as a crack in the coating layer but also a slight change in appearance that can be observed with the naked eye such as loss of gloss on the surface does not occur. Specifically, it can be evaluated by storing the orally disintegrating film-coated tablet in an atmosphere of 30 ° C. and a relative humidity of 81% for one month, and visually observing the appearance of the coating layer.
本発明の「外観の変化」の程度は４段階で評価し、製造直後と比較して変化がない場合を１（変化なし）、製造直後と３０℃、相対湿度８１％の雰囲気下に１箇月保存後の錠剤を並べて同時観察した時に、認識できる艶の消失があった場合を２（ごくわずかに変化あり）、製造直後と３０℃、相対湿度８１％の雰囲気下に１箇月保存後の錠剤を個々に観察した時に、認識できる艶の消失があった場合を３（わずかに変化あり）、３０℃、相対湿度８１％の雰囲気下に１箇月保存後の錠剤を単独で観察した時に、艶の消失に限らず、表面の荒れ、亀裂など、認識できる変化があった場合を４（変化あり）とし、本発明の「ごくわずかな経時的な外観の変化も認められない安定な口腔内崩壊性フィルムコーティング錠」とは、評価が１であった場合を指す。 The degree of “change in appearance” of the present invention is evaluated in four stages, 1 (no change) when there is no change compared with immediately after production, 1 month immediately after production and in an atmosphere of 30 ° C. and relative humidity 81%. When the stored tablets are lined up and observed at the same time, there is a loss of recognizable luster 2 (very slight change), and the tablet after storage for 1 month in an atmosphere of 30 ° C and 81% relative humidity When there was a loss of gloss that was recognizable when observed individually, 3 (slightly changed), when the tablet after storage for 1 month in an atmosphere of 30 ° C. and relative humidity of 81% was observed alone, Not only the disappearance of the skin, but also the case where there is a discernable change such as surface roughness, crack, etc., is 4 (there is a change), and “stable oral disintegration with no slight change in appearance over time” "Effective film-coated tablets" The point.
本発明の「８°グロス値」とは、ＪＩＳの６０°光沢計に近似するように設定された分光測色計で測定される数値であり、数値が大きいほど光沢度が高い、即ち、艶の程度が高いことを示す。錠剤は表面積が小さく光沢計は使用できないため、分光測色計を用いた。８°グロス値は、外観を肉眼観察した結果を客観的に示す数値であり、認識できる艶の消失がないことを示す観点では、製造直後に対し８０％以上保持されていることが好ましい。本発明に用いた分光測色計は、正反射光を含むＳＣＩ（Ｓｐｅｃｕｌａｒ Ｃｏｍｐｏｎｅｎｔ Ｉｎｃｌｕｄｅ）測定と正反射光を含まないＳＣＥ（Ｓｐｅｃｕｌａｒ Ｃｏｍｐｏｎｅｎｔ Ｅｘｃｌｕｄｅ）測定を同時に行うことが可能であり、これらの結果から８°グロス値を算出する機構となっている。 The “8 ° gloss value” of the present invention is a numerical value measured by a spectrocolorimeter set so as to approximate a JIS 60 ° gloss meter. Indicates a high degree. Since the tablet has a small surface area and a gloss meter cannot be used, a spectrocolorimeter was used. The 8 ° gloss value is a numerical value that objectively shows the result of visual observation of the appearance. From the viewpoint of indicating that there is no loss of recognizable gloss, it is preferably maintained at 80% or more immediately after production. The spectrocolorimeter used in the present invention can simultaneously perform SCI (special component include) measurement including specular reflection light and SCE (special component exclude) measurement not including specular reflection light. This is a mechanism for calculating an 8 ° gloss value.
本発明のコーティング層およびコーティング用組成物は、上述の成分のほか、必要に応じて光安定化剤を配合することが可能である。例えば、酸化チタン、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、タルク、およびカオリンなどが挙げられ、これらの具体例のうち１種または２種以上を組み合わせて用いることができる。光安定化剤の量は本発明に含まれる活性成分の量や光への感受性によっても異なるが、本発明の効果を損なわない観点からコーティング量の５０％以下であることが好ましい。これらは例示されたものであり、何ら限定するものではない。 In addition to the above-described components, the coating layer and coating composition of the present invention can contain a light stabilizer as necessary. Examples thereof include titanium oxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, talc, and kaolin. Among these specific examples, one kind or two or more kinds can be used in combination. The amount of the light stabilizer varies depending on the amount of the active ingredient contained in the present invention and the sensitivity to light, but is preferably 50% or less of the coating amount from the viewpoint of not impairing the effects of the present invention. These are merely examples and are not intended to be limiting.
本発明のコーティング層およびコーティング用組成物には、上述の成分のほか、必要に応じて薬学的に許容される添加剤を本発明の効果を損なわない範囲内で加えることが可能である。当該添加剤として例えば、賦形剤、崩壊剤、結合剤、可塑剤、矯昧剤、香料、着色剤または滑沢剤などが挙げられる。例えば賦形剤として、コーンスターチ、ポテトスターチなどのデンプン類、微結晶セルロース、軽質無水ケイ酸などを挙げることができる。例えば崩壊剤として、部分アルファー化デンプン、カルメロースカルシウム、クロスポビドン、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウムなどを挙げることができる。例えば結合剤として、ポリビニルピロリドン、アラビアゴム末、ゼラチン、プルラン、アミノアルキルメタルリレートコポリマーなどを挙げることができる。例えば可塑剤として、ポリエチレングリコール、プロピレングリコール、トリアセチン、クエン酸トリエチルなどを挙げることができる。例えば矯昧剤として、クエン酸などを挙げることができる。例えば香料として、メントール、ペパーミント、レモン、レモンライム、オレンジ、ハッカ油、各種フレーバーを挙げることができる。例えば着色剤として、タール系色素、ウコン抽出液、カラメル、カロチン液、s−カロテン、銅クロロフィル、リボフラビンなどを挙げることができる。例えば滑沢剤として、流動パラフィン、シリコーン、長鎖脂肪酸エステルなどの界面活性剤類、ミツロウ、カルナウバロウ、パラフィンなどのワックス類などが挙げられる。これら添加剤は例示されたものであり、何ら限定するものではない。また、本発明のコーティング層内のほか外表面に、当該添加剤を添加することも可能である。 In addition to the above-described components, a pharmaceutically acceptable additive can be added to the coating layer and coating composition of the present invention as necessary within a range that does not impair the effects of the present invention. Examples of the additive include an excipient, a disintegrant, a binder, a plasticizer, a corrigent, a fragrance, a coloring agent, and a lubricant. Examples of excipients include starches such as corn starch and potato starch, microcrystalline cellulose, and light anhydrous silicic acid. Examples of the disintegrating agent include partially pregelatinized starch, carmellose calcium, crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium and the like. For example, examples of the binder include polyvinyl pyrrolidone, gum arabic powder, gelatin, pullulan, aminoalkyl metal relate copolymer and the like. Examples of the plasticizer include polyethylene glycol, propylene glycol, triacetin, triethyl citrate and the like. For example, citric acid and the like can be mentioned as a flavoring agent. Examples of fragrances include menthol, peppermint, lemon, lemon lime, orange, peppermint oil, and various flavors. Examples of the colorant include tar dyes, turmeric extract, caramel, carotene solution, s-carotene, copper chlorophyll, and riboflavin. Examples of lubricants include surfactants such as liquid paraffin, silicone and long chain fatty acid esters, waxes such as beeswax, carnauba wax and paraffin. These additives are exemplified and are not limited at all. Moreover, it is also possible to add the said additive to an outer surface besides the inside of the coating layer of this invention.
本発明の口腔内崩壊性フィルムコーティング錠のコーティング操作は、当業者において周知の方法を用いることが可能である。例えば、コーティング液を錠剤の表面に噴霧、乾燥することによりコーティングする方法などが挙げられる。コーティング液は、本発明の甘味料とセルロース系樹脂のほか、必要に応じて配合される、薬学上許容される添加剤を、水またはエタノール、メタノールなどの溶媒に溶解もしくは懸濁して調製される。これらの溶媒は単独もしくは混合して用いることが可能である。口腔内崩壊錠の表面にコーティングする工程は、一般的に使用される装置が用いられ、例えばパンコーティング装置などを使用することができる。運転条件に特に制限はないが、摩損性が高い口腔内崩壊錠の場合は、パンの回転数は通常より低速に設定することで、錠剤のエッジ部分にも均一にコーティング層を形成することができる。コーティング量は、製剤の形状や大きさによって異なるが、口腔内崩壊錠の重量に対し０．１％以上あればよく、速崩壊性である観点から、上限は１０％以下であればよく、５％以下であることが好ましく、３％以下であることがさらに好ましい。 For the coating operation of the orally disintegrating film-coated tablet of the present invention, methods well known to those skilled in the art can be used. For example, the method of coating by spraying and drying a coating liquid on the surface of a tablet, etc. are mentioned. The coating liquid is prepared by dissolving or suspending, in addition to the sweetener of the present invention and the cellulosic resin, a pharmaceutically acceptable additive blended as necessary in water or a solvent such as ethanol or methanol. . These solvents can be used alone or in combination. For the step of coating the surface of the orally disintegrating tablet, a commonly used device is used, and for example, a pan coating device or the like can be used. There are no particular restrictions on the operating conditions, but in the case of orally disintegrating tablets with high friability, a coating layer can be uniformly formed on the edge of the tablet by setting the number of rotations of the pan to be lower than usual. it can. Although the coating amount varies depending on the shape and size of the preparation, it may be 0.1% or more with respect to the weight of the orally disintegrating tablet, and from the viewpoint of rapid disintegration, the upper limit may be 10% or less. % Or less, and more preferably 3% or less.
口腔内崩壊錠の口腔内崩壊時間は、健常成人の口腔内で、水を服用せず、錠剤を噛まずに唾液により錠剤が完全に崩壊するまでの時間を測定することで得られる。ここで、錠剤が完全に崩壊するとは、口腔内で異物感を感じなくなった時点を意味する。一般に、口腔内崩壊錠は、口腔内で水無しで６０秒以内に崩壊するように設計される。そのため、口腔内崩壊性フィルムコーティング錠の口腔内崩壊時間も、６０秒未満であることが好ましい。 The oral disintegration time of the orally disintegrating tablet is obtained by measuring the time until the tablet is completely disintegrated by saliva without chewing the tablet without taking water in the oral cavity of a healthy adult. Here, the fact that the tablet completely disintegrates means a point in time when no foreign body sensation is felt in the oral cavity. Generally, orally disintegrating tablets are designed to disintegrate within 60 seconds without water in the oral cavity. Therefore, the oral disintegration time of the orally disintegrating film-coated tablet is also preferably less than 60 seconds.
コーティング層の口腔内溶解時間は、健常成人が、水を服用せずに錠剤を口に含んだ時、噛まずに唾液によりコーティング層が溶解し、内核錠が露出したことを感じるまでの時間を測定することで得られる。口腔内崩壊性フィルムコーティング錠の口腔内崩壊時間を６０秒未満とするためには、内核錠の口腔内崩壊時間にもよるが、コーティング層の口腔内溶解時間は、２０秒未満であることが好ましく、１５秒未満であることがさらに好ましい。なお、本発明の口腔内崩壊性フィルムコーティング錠は、水なしで服用することを限定したものではなく、水とともに服用してもよい。 The dissolution time of the coating layer in the oral cavity is the time it takes for a healthy adult to feel that the coating layer is dissolved by saliva without chewing and the inner core tablet is exposed when the tablet is taken in the mouth without taking water. It is obtained by measuring. In order to reduce the oral disintegration time of the orally disintegrating film-coated tablet to less than 60 seconds, the dissolution time of the coating layer in the oral cavity may be less than 20 seconds, depending on the oral disintegration time of the core tablet. Preferably, the time is less than 15 seconds. The orally disintegrating film-coated tablet of the present invention is not limited to being taken without water, and may be taken with water.
本発明における口腔内崩壊錠である内核錠は、口腔内での崩壊時間が６０秒未満程度であれば、製法、組成に関して特に制限はされない。例えば、直接打錠法、間接打錠法、鋳型成形法など製剤分野における常法により製造されるものを用いることができる。このような製法として、例えば湿潤した粒子を打錠して多孔性錠剤を得る製法や、糖類の結晶化など物理化学的性質を利用する製法、凍結乾燥技術を用いた製法、クロスポビドンなどの崩壊剤を利用した製法、外部滑沢剤法を用いた製法などが挙げられる。 The inner core tablet which is an orally disintegrating tablet in the present invention is not particularly limited with respect to the production method and composition as long as the disintegration time in the oral cavity is less than about 60 seconds. For example, those produced by conventional methods in the pharmaceutical field such as direct tableting method, indirect tableting method, and molding method can be used. Such production methods include, for example, a method in which wet particles are tableted to obtain a porous tablet, a method using physicochemical properties such as crystallization of sugars, a method using freeze-drying technology, and a disintegration of crospovidone. And a production method using an external agent and a production method using an external lubricant method.
本発明における口腔内崩壊性フィルムコーティング錠が含有する活性成分は、コーティング層、内核錠またはこれらの両者のいずれに含有されていてもよく、該活性成分としては特に限定する必要はなく、生理活性を有する活性成分であれば制限されない。例えば、アカルボース、アムロジピン、アリピプラゾール、イミダフェナシン、イルソグラジン、エバスチン、オランザピン、オロパタジン、オンダンセトロン、ガランタミン、グリメピリド、シロスタゾール、セチリジン、セフジトレン ピボキシル、セレギリン、ソリフェナシン、ゾルピデム、タムスロシン、タルチレリン、沈降炭酸カルシウム、デスモプレシン、ドキシドパ、ドネペジル、ドンペリドン、ナフトピジル、パロキセチン、ピオグリタゾン、ファモチジン、フェキソフェナジン、ブロチゾラム、ベポタスチン、ボグリボース、ポラプレジンク、ミドドリン、ラフチジン、ラモセトロン、ランソプラゾール、リザトリフタン、リスペリドン、レバミピド、ロラタジンならびにその薬理学的に許容される塩および溶媒和物（たとえば水和物）およびビタミン類等のサプリメントの少なくとも１種を活性成分として含有することができる。なかでも、アムロジピン、エバスチン、セフジトレン ピボキシル、セレギリン、ブロチゾラム、ミドドリンおよびラモセトロン、ならびにその薬理学的に許容される塩および溶媒和物の少なくとも１種を活性成分として含有する場合、これらの活性成分は光に対して不安定であるので本コーティング層に光安定化剤を添加することが好ましい。
また、内核錠である口腔内崩壊錠には、上述の活性成分のほか、必要に応じて薬学的に許容される添加剤を本発明の効果を損なわない範囲内で加えることが可能である。当該添加剤としては、例えば、賦形剤、崩壊剤、結合剤、可塑剤、矯昧剤、香料、着色剤または滑沢剤などが挙げられる。例えば賦形剤として、コーンスターチ、ポテトスターチなどのデンプン類、微結晶セルロース、軽質無水ケイ酸などを挙げることができる。例えば崩壊剤として、部分アルファー化デンプン、カルメロースカルシウム、クロスポビドン、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウムなどを挙げることができる。例えば結合剤として、ポリビニルピロリドン、ヒプロメロース、ヒドロキシプロピルセルロース、アラビアゴム末、ゼラチン、プルラン、カルメロースナトリウム、エチルセルロース、アミノアルキルメタルリレートコポリマーなどを挙げることができる。例えば可塑剤として、ポリエチレングリコール、プロピレングリコール、トリアセチン、クエン酸トリエチルなどを挙げることができる。例えば矯昧剤として、アスパルテーム、スクラロース、サッカリンナトリウム、グリチルリチン二カリウム、ステビア、ソーマチン、クエン酸などを挙げることができる。例えば香料として、メントール、ペパーミント、レモン、レモンライム、オレンジ、ハッカ油、各種フレーバーを挙げることができる。例えば着色剤として、タール系色素、ウコン抽出液、カラメル、カロチン液、s−カロテン、銅クロロフィル、リボフラビンなどを挙げることができる。例えば滑沢剤として、ポリエチレングリコール、流動パラフィン、シリコーン、長鎖脂肪酸エステルなどの界面活性剤類、ミツロウ、カルナウバロウ、パラフィンなどのワックス類などが挙げられる。これら添加剤は例示されたものであり、何ら限定するものではない。The active ingredient contained in the orally disintegrating film-coated tablet in the present invention may be contained in any of the coating layer, the inner core tablet, or both of them, and the active ingredient is not particularly limited, and is physiologically active. If it is an active ingredient which has, it will not restrict | limit. For example, acarbose, amlodipine, aripiprazole, imidafenacin, irsogladine, ebastine, olanzapine, olopatadine, ondansetron, galantamine, glimepiride, cilostazol, cetirizine, cefditoren pivoxil, selegiline, solifenacin, zolpidem tyrosmodine, , Donepezil, domperidone, naphthopidyl, paroxetine, pioglitazone, famotidine, fexofenadine, brotizolam, bepotastine, voglibose, polaprezinc, midodrine, lafutidine, ramosetron, lansoprazole, rizatriftan, risperidone, pharmacologically, ralamipide Salts and solvates For example, hydrates) and supplements such as vitamins can be contained as active ingredients. In particular, when the active ingredient contains at least one of amlodipine, ebastine, cefditoren pivoxil, selegiline, brotizolam, midodrine and ramosetron, and pharmacologically acceptable salts and solvates thereof, these active ingredients are light. Therefore, it is preferable to add a light stabilizer to the coating layer.
Moreover, in addition to the above-mentioned active ingredient, a pharmaceutically acceptable additive can be added to the orally disintegrating tablet, which is an inner core tablet, as necessary within a range that does not impair the effects of the present invention. Examples of the additive include an excipient, a disintegrant, a binder, a plasticizer, a corrigent, a fragrance, a coloring agent, and a lubricant. Examples of excipients include starches such as corn starch and potato starch, microcrystalline cellulose, and light anhydrous silicic acid. Examples of the disintegrating agent include partially pregelatinized starch, carmellose calcium, crospovidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium and the like. Examples of the binder include polyvinyl pyrrolidone, hypromellose, hydroxypropyl cellulose, gum arabic powder, gelatin, pullulan, carmellose sodium, ethyl cellulose, aminoalkyl metal relate copolymer and the like. Examples of the plasticizer include polyethylene glycol, propylene glycol, triacetin, triethyl citrate and the like. For example, as a parting agent, aspartame, sucralose, sodium saccharin, dipotassium glycyrrhizin, stevia, thaumatin, citric acid and the like can be mentioned. Examples of fragrances include menthol, peppermint, lemon, lemon lime, orange, peppermint oil, and various flavors. Examples of the colorant include tar dyes, turmeric extract, caramel, carotene solution, s-carotene, copper chlorophyll, and riboflavin. For example, examples of the lubricant include surfactants such as polyethylene glycol, liquid paraffin, silicone, and long chain fatty acid ester, and waxes such as beeswax, carnauba wax, and paraffin. These additives are exemplified and are not limited at all.
以下に実施例および試験例をもって、本発明を具体的に説明するが、本発明はこれらの例に限定されるものではない。 The present invention will be specifically described below with reference to examples and test examples, but the present invention is not limited to these examples.
参考例１〜３
表１に示す配合比率で、内添部の添加剤を乾式造粒機（ローラーコンパクターＴＦ−ＭＩＮＩ：フロイント産業またはローラーコンパクターＦＲ１２５×４０：フロイント・ターボ）で圧縮した後、整粒機（ロールグラニュレーター（登録商標）ＧＲＮ−Ｔ−５４Ｓ：日本グラニュレーター）で整粒し、顆粒を得た。これに外添部の添加剤を混合した後、打錠機（コレクト６ＨＵＫまたは１２ＨＵＫ：菊水製作所）を用いて圧縮成形し、直径９ｍｍの口腔内崩壊錠を得た。なお、Ｄ−マンニトールは三菱商事フードテック製マンニットＱ、クロスポビドンはＩＳＰ製ポリプラスドンＩＮＦ−１０、アスパルテームは味の素製味の素ＫＫアスパルテーム、ショ糖脂肪酸エステルは第一製薬工業製ＤＫエステル（登録商標）ＳＳ、結晶セルロースは旭化成ケミカルズ製セオラスステアリン酸マグネシウムは日油製ステアリン酸マグネシウムＧＶ、Ｍａｌｌｉｎｃｋｒｏｄｔ製または太平化学産業製、結晶セルロースは旭化成ケミカルズ製セオラス（登録商標）ＫＧ−１０００、軽質無水ケイ酸はフロイント産業製アドソリダー（登録商標）−１０１を用いた。
After adding the additive in the internal part with a dry granulator (Roller Compactor TF-MINI: Freund Industries or Roller Compactor FR125 × 40: Freund Turbo) at the blending ratio shown in Table 1, the granulator (roll granulator) Granules were obtained by sizing with a lator (registered trademark) GRN-T-54S (Japan granulator). After adding the additive of an external addition part to this, it compression-molded using the tableting machine (Collect 6HUK or 12HUK: Kikusui Seisakusho), and obtained the orally disintegrating tablet of diameter 9mm. D-mannitol is manufactured by Mitsubishi Foodtech's Mannit Q, crospovidone is ISP polyplastidone INF-10, aspartame is Ajinomoto Ajinomoto KK Aspartame, sucrose fatty acid ester is DK Ester (registered trademark) manufactured by Daiichi Pharmaceutical ) SS, crystalline cellulose is manufactured by Asahi Kasei Chemicals Magnesium stearate, NOF Magnesium stearate GV, manufactured by Mallinckrodt or Taihei Chemical Industry, crystalline cellulose is manufactured by Asahi Kasei Chemicals, SEORUS (registered trademark) KG-1000, light anhydrous silicic acid is Freund Sangyo Ad Solider (registered trademark) -101 was used.
比較例１〜４
比較例１〜３は参考例１、比較例４は参考例２の口腔内崩壊錠に、表２に示す配合比率で水分散液を調製し、フィルムコーティング機（ハイコーター（登録商標）ＨＣＴ−３０：フロイント産業）を用いてフィルムコーティングを施した後、微量のカルナウバロウでコーティングし、口腔内崩壊性フィルムコーティング錠を得た。なお、ポリビニルアルコール・ポリエチレングリコール・グラフトコポリマー（ＰＶＡ−ＰＥＧグラフトコポリマー）はＢＡＳＦ製Ｋｏｌｌｉｃｏａｔ（登録商標）ＩＲ、マルチトールは林原生物化学研究所製結晶マビット（登録商標）微粉、乳糖水和物はＤＭＶ製Ｐｈａｒｍａｔｏｓｅ（登録商標）ＤＣＬ−１１、Ｄ−マンニトールは三菱商事フードテック製マンニットＰ、スクラロースは三栄源エフ・エフ・アイ製スクラロースＰ、酸化チタンは和光純薬工業製、黄色三二酸化鉄は癸巳化成製、カルナウバロウはフロイント産業製ポリシングワックス−１０３を用いた。
Comparative Examples 1 to 3 were prepared in Reference Example 1 and Comparative Example 4 was prepared in the orally disintegrating tablet of Reference Example 2 in an aqueous dispersion at the blending ratio shown in Table 2, and the film coating machine (HiCoater (registered trademark) HCT- 30: Freund Sangyo Co., Ltd.) and then coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet. Polyvinyl alcohol / polyethylene glycol graft copolymer (PVA-PEG graft copolymer) is BASF Kollicoat (registered trademark) IR, maltitol is Hayashibara Biochemical Laboratory Crystal Mabit (registered trademark) fine powder, lactose hydrate is DMV Pharmatose (registered trademark) DCL-11 and D-mannitol are manufactured by Mitsubishi Foodtech's Mannitol P, sucralose is sucralose P manufactured by Saneigen FFI, titanium oxide is manufactured by Wako Pure Chemical Industries, and yellow iron sesquioxide is The polishing wax-103 manufactured by Freund Sangyo Co., Ltd. was used as a product made by Kasei Chemical.
試験例１
比較例１〜４の口腔内崩壊性フィルムコーティング錠を３０℃、相対湿度８１％に１箇月間保存した後、外観を肉眼で製造直後と比較した。なお、変化の程度は、以下の４段階評価とした。結果を表３に示す。いずれの組成も、艶が消失し、ポリビニルアルコール系樹脂に水溶性物質を配合したコーティング層は、高湿度下において、外観変化の著しいことが判明した。
１：変化なし
２：ごくわずかに変化あり（並べて同時観察した時に認識できる艶の消失があった場合）
３：わずかに変化あり（個々に観察した時に認識できる艶の消失があった場合）
４：変化あり（３０℃、相対湿度８１％に１箇月間保存後の錠剤を単独で観察した時に、艶の消失に限らず、表面の荒れ、亀裂など、認識できる変化があった場合）
さらに、参考までに走査型電子顕微鏡（無蒸着、３０ＭＰａ、加速電圧５ｋＶ、反射電子像、１０００倍）で表面状態を観察した。結果を図１〜８に示す。いずれの組成もコーティング層表面に結晶状もしくは結晶が積層した析出物を認め、これが外観変化となって表れたものと考えられた。
After the orally disintegrating film-coated tablets of Comparative Examples 1 to 4 were stored at 30 ° C. and a relative humidity of 81% for 1 month, the appearance was compared with the naked eye immediately after production. The degree of change was evaluated according to the following four levels. The results are shown in Table 3. In any composition, the luster disappears, and it has been found that the coating layer in which the water-soluble substance is blended with the polyvinyl alcohol-based resin undergoes a remarkable change in appearance under high humidity.
1: No change 2: Very slight change (when there is a loss of gloss that can be recognized when observed side by side)
3: There is a slight change (when there is a loss of gloss that can be recognized when observed individually)
4: There is a change (when observing a tablet alone at 30 ° C. and 81% relative humidity for 1 month alone, not only the loss of gloss, but also a change that can be recognized, such as surface roughness and cracks)
Further, for reference, the surface state was observed with a scanning electron microscope (no evaporation, 30 MPa, acceleration voltage 5 kV, reflected electron image, 1000 times). The results are shown in FIGS. In any composition, it was considered that a precipitate in which a crystal or crystal was laminated on the surface of the coating layer was observed, and this appeared as an appearance change.
実施例１および２
参考例１の口腔内崩壊錠に、表４に示す配合比率で水分散液を調製し、フィルムコーティング機（ハイコーター（登録商標）ＨＣＴ−３０：フロイント産業）を用いてフィルムコーティングを施した後、微量のカルナウバロウでコーティングし、口腔内崩壊性フィルムコーティング錠を得た。なお、メチルセルロースは信越化学工業製メトローズ（登録商標）ＳＭ−４、Ｄ−マンニトールは三菱商事フードテック製マンニットＰ、エリスリトールは物産フードサイエンス製エリスリトール１００Ｍ、スクラロースは三栄源エフ・エフ・アイ製スクラロースＰ、ＰＥＧ４００は日興製薬製、酸化チタンは和光純薬工業製、黄色三二酸化鉄は癸巳化成製、カルナウバロウはフロイント産業製ポリシングワックス−１０３を用いた。
After preparing an aqueous dispersion at the blending ratio shown in Table 4 on the orally disintegrating tablet of Reference Example 1 and applying film coating using a film coating machine (HiCoater (registered trademark) HCT-30: Freund Sangyo) And coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet. In addition, Shin-Etsu Chemical Co., Ltd. Metros (registered trademark) SM-4, D-mannitol is manufactured by Mitsubishi Foodtech's Mannit K, Erythritol is erythritol 100M manufactured by Food Science Co., Ltd., and sucralose is sucralose manufactured by Saneigen FFI. P and PEG400 were manufactured by Nikko Pharmaceutical, titanium oxide was manufactured by Wako Pure Chemical Industries, yellow ferric oxide was manufactured by Kasei Kasei, and carnauba wax was polished wax 103 manufactured by Freund Corporation.
試験例２
比較例１〜４、実施例１および２の製造直後の崩壊性と、実施例１および２の外観変化を評価し、試験例１の結果と合わせて比較した。崩壊性は、第１６改正日本薬局方の崩壊試験法（水、補助盤あり）による崩壊時間の測定と、健常成人２名による口腔内膜溶解時間および口腔内錠剤崩壊時間の測定を行い、評価した。水を服用せずに錠剤を口に含み、口腔内膜溶解時間は、コーティング層が溶解し、内核錠が露出したことを感じるまでの時間を、口腔内錠剤崩壊時間は、錠剤が完全に崩壊するまでの時間を測定した。また、外観変化は、口腔内崩壊性フィルムコーティング錠を３０℃、相対湿度８１％に１箇月間保存した後、外観を肉眼で製造直後と比較した。なお、変化の程度は、試験例１と同様に４段階評価とした。結果を表５に示す。ポリビニルアルコール系樹脂に水溶性物質を配合してコーティングした口腔内崩壊錠は、良好な崩壊性を示す一方で、試験例１で既述のとおり、高湿度下における外観変化が顕著であった。一方、本発明の口腔内崩壊性フィルムコーティング錠は、ポリビニルアルコール系樹脂に水溶性物質を配合してコーティングした口腔内崩壊錠と同等以上の崩壊性を示し、且つ、高湿度下においても、亀裂は勿論のこと、艶の消失といった外観変化を全く認めなかった。
さらに、参考までに実施例１については、走査型電子顕微鏡（無蒸着、３０ＭＰａ、加速電圧５ｋＶ、反射電子像、１０００倍）で表面状態も観察した。結果を図９〜１０に示す。製造直後（図９）と３０℃、相対湿度８１％、１箇月後（図１０）を比較した結果、コーティング層の表面状態に変化は認められなかった。
このように、ごくわずかな経時的な外観の変化を生じないといった点で、本発明の優位性が示された。
The disintegration immediately after manufacture of Comparative Examples 1 to 4 and Examples 1 and 2 and the appearance change of Examples 1 and 2 were evaluated and compared with the results of Test Example 1. Disintegration was evaluated by measuring the disintegration time according to the 16th revised Japanese Pharmacopoeia disintegration test method (with water and an auxiliary board), and measuring the oral intimal dissolution time and oral tablet disintegration time by two healthy adults. did. The tablet is taken in the mouth without taking water, the dissolution time of the oral membrane is the time until the coating layer dissolves and the core tablet is exposed, the oral tablet disintegration time is the tablet completely disintegrates The time to do was measured. In addition, after changing the orally disintegrating film-coated tablet at 30 ° C. and relative humidity of 81% for 1 month, the appearance was compared with the naked eye immediately after production. Note that the degree of change was evaluated in a four-step manner as in Test Example 1. The results are shown in Table 5. While the orally disintegrating tablet coated with a water-soluble substance blended with a polyvinyl alcohol resin showed good disintegration properties, as described above in Test Example 1, the appearance change under high humidity was remarkable. On the other hand, the orally disintegrating film-coated tablet of the present invention exhibits a disintegration equivalent to or better than that of an orally disintegrating tablet coated with a water-soluble substance blended with a polyvinyl alcohol resin, and is cracked even under high humidity. Of course, no change in appearance such as loss of gloss was observed.
For reference, the surface state of Example 1 was also observed with a scanning electron microscope (no evaporation, 30 MPa, acceleration voltage 5 kV, reflected electron image, 1000 times). The results are shown in FIGS. As a result of comparing immediately after production (FIG. 9) with 30 ° C., 81% relative humidity and one month later (FIG. 10), no change was observed in the surface state of the coating layer.
Thus, the superiority of the present invention was shown in that no slight change in appearance over time occurred.
実施例３〜５
参考例１の口腔内崩壊錠に、表６に示す配合比率で水分散液を調製し、フィルムコーティング機（ハイコーター（登録商標）ＨＣＴ−３０：フロイント産業）を用いてフィルムコーティングを施した後、微量のカルナウバロウでコーティングし、口腔内崩壊性フィルムコーティング錠を得た。なお、メチルセルロースは信越化学工業製メトローズ（登録商標）ＳＭ−４、Ｄ−マンニトールは三菱商事フードテック製マンニットＰ、スクラロースは三栄源エフ・エフ・アイ製スクラロースＰ、ＰＥＧ４００は日興製薬製、酸化チタンは和光純薬工業製、黄色三二酸化鉄は癸巳化成製、カルナウバロウはフロイント産業製ポリシングワックス−１０３を用いた。
After preparing an aqueous dispersion at the mixing ratio shown in Table 6 on the orally disintegrating tablet of Reference Example 1 and applying film coating using a film coating machine (HiCoater (registered trademark) HCT-30: Freund Sangyo) And coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet. Note that methylcellulose is manufactured by Shin-Etsu Chemical Co., Ltd., Metros (registered trademark) SM-4, D-mannitol is manufactured by Mitsubishi Corporation Foodtech Mannit P, sucralose is sucralose P manufactured by Saneigen FFI, and PEG400 is manufactured by Nikko Pharmaceutical. Titanium was manufactured by Wako Pure Chemical Industries, yellow ferric oxide was manufactured by Kasei Kasei, and carnauba wax was polished wax 103 manufactured by Freund Corporation.
試験例３
実施例１および３〜５の口腔内崩壊性フィルムコーティング錠につき、製造直後の崩壊性および外観変化を評価した。崩壊性は、第１６改正日本薬局方の崩壊試験法（水、補助盤あり）による崩壊時間の測定と、健常成人２名による口腔内膜溶解時間および口腔内錠剤崩壊時間の測定を、試験例２と同様の基準で行い、評価した。また、外観変化は、口腔内崩壊性フィルムコーティング錠を３０℃、相対湿度８１％に１箇月間保存した後、外観を肉眼で製造直後と比較した。なお、変化の程度は、試験例１と同様に４段階評価とした。結果を表７に示す。甘味料の増加に伴って崩壊性は向上し、いずれも口腔内崩壊錠として好ましい速崩壊性を示した。一方、高湿度下において、いずれも外観変化を認めず、本発明が、速崩壊性の機能を保持しつつ、ごくわずかな経時的な外観の変化を生じないことが示された。
The orally disintegrating film-coated tablets of Examples 1 and 3 to 5 were evaluated for disintegration and appearance changes immediately after production. Disintegration is a test example by measuring the disintegration time according to the 16th revised Japanese Pharmacopoeia disintegration test method (with water and an auxiliary board), and measuring the oral intimal dissolution time and oral tablet disintegration time by two healthy adults. The evaluation was performed based on the same criteria as in No. 2. In addition, after changing the orally disintegrating film-coated tablet at 30 ° C. and relative humidity of 81% for 1 month, the appearance was compared with the naked eye immediately after production. Note that the degree of change was evaluated in a four-step manner as in Test Example 1. The results are shown in Table 7. As the sweetener increased, the disintegration property was improved, and all showed fast disintegration properties preferable as an orally disintegrating tablet. On the other hand, no change in appearance was observed under high humidity, indicating that the present invention did not cause a slight change in appearance over time while maintaining a rapidly disintegrating function.
比較例５、実施例６および７
参考例１の口腔内崩壊錠に、表８に示す配合比率で水分散液を調製し、フィルムコーティング機（ハイコーター（登録商標）ＨＣＴ−３０：フロイント産業）を用いてフィルムコーティングを施した後、微量のカルナウバロウでコーティングし、口腔内崩壊性フィルムコーティング錠を得た。なお、メチルセルロースは信越化学工業製メトローズ（登録商標）ＳＭ−４、Ｄ−マンニトールは三菱商事フードテック製マンニットＰ、ＰＥＧ４００は日興製薬製、酸化チタンは和光純薬工業製、黄色三二酸化鉄は癸巳化成製、カルナウバロウはフロイント産業製ポリシングワックス−１０３を用いた。
After preparing an aqueous dispersion at the blending ratio shown in Table 8 on the orally disintegrating tablet of Reference Example 1 and applying film coating using a film coating machine (HiCoater (registered trademark) HCT-30: Freund Sangyo) And coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet. In addition, methyl cellulose is manufactured by Shin-Etsu Chemical Co., Ltd., Metros (registered trademark) SM-4, D-mannitol is manufactured by Mitsubishi Corporation Foodtech Mannit P, PEG400 is manufactured by Nikko Pharmaceutical, titanium oxide is manufactured by Wako Pure Chemical Industries, and yellow ferric oxide is The polishing wax-103 manufactured by Freund Sangyo Co., Ltd. was used as a product made by Kasei Chemical.
試験例４
比較例５、実施例１、３、６および７の口腔内崩壊性フィルムコーティング錠につき、製造直後の崩壊性と外観変化および８°グロス値を評価した。崩壊性は、第１６改正日本薬局方の崩壊試験法（水、補助盤あり）による崩壊時間の測定と、健常成人２名による口腔内膜溶解時間および口腔内錠剤崩壊時間の測定を、試験例２と同様の基準で行い、評価した。また、口腔内崩壊性フィルムコーティング錠を３０℃、相対湿度８１％に１箇月間保存した後、外観変化は、試験例１と同様の４段階評価で、外観を肉眼で製造直後と比較して評価し、８°グロス値は分光測色計（ＣＭ−７００ｄ：コニカミノルタ、孔径３ｍｍのターゲットマスク装着、Ｃ光源、２°視野）を用いて測定した。結果を表９に示す。甘味料を全く配合しない場合は、口腔内膜溶解時間および口腔内錠剤崩壊時間が長く、口腔内崩壊錠としては好ましくないことが示された。また、甘味料が１種であっても、崩壊性は良好であり、且つ、高湿度下において外観変化および８°グロス値の低下を認めなかったことから、必要とされる甘味料は少なくとも１種で良いことが示された。
The orally disintegrating film-coated tablets of Comparative Example 5, Examples 1, 3, 6 and 7 were evaluated for disintegration and appearance change immediately after production and 8 ° gloss value. Disintegration is a test example by measuring the disintegration time according to the 16th revised Japanese Pharmacopoeia disintegration test method (with water and an auxiliary board), and measuring the oral intimal dissolution time and oral tablet disintegration time by two healthy adults. The evaluation was performed based on the same criteria as in No. 2. In addition, after storing the orally disintegrating film-coated tablet at 30 ° C. and relative humidity of 81% for 1 month, the change in appearance is the same four-stage evaluation as in Test Example 1, and the appearance is compared with the naked eye immediately after production. The 8 ° gloss value was measured using a spectrocolorimeter (CM-700d: Konica Minolta, wearing a target mask with a hole diameter of 3 mm, C light source, 2 ° field of view). The results are shown in Table 9. In the case where no sweetener was blended at all, it was shown that the oral intimal dissolution time and the oral tablet disintegration time were long, which is not preferable as an orally disintegrating tablet. Moreover, even if there is only one kind of sweetener, the disintegration is good, and since no change in appearance and no decrease in 8 ° gloss value were observed under high humidity, at least one sweetener is required. It was shown that seeds are good.
比較例６〜９および実施例８
参考例３の口腔内崩壊錠に、表１０に示す配合比率で水分散液を調製し、フィルムコーティング機（ハイコーター（登録商標）ＨＣＴ−３０：フロイント産業）を用いてフィルムコーティングを施した後、微量のカルナウバロウでコーティングし、口腔内崩壊性フィルムコーティング錠を得た。なお、ポリビニルアルコール・ポリエチレングリコール・グラフトコポリマー（ＰＶＡ−ＰＥＧグラフトコポリマー）はＢＡＳＦ製Ｋｏｌｌｉｃｏａｔ（登録商標）ＩＲ、メチルセルロースは信越化学工業製メトローズ（登録商標）ＳＭ−４、マルチトールは林原生物化学研究所製結晶マビット（登録商標）微粉、乳糖水和物はＤＭＶ製Ｐｈａｒｍａｔｏｓｅ（登録商標）ＤＣＬ−１１、Ｄ−マンニトールは三菱商事フードテック製マンニットＰ、スクラロースは三栄源エフ・エフ・アイ製スクラロースＰ、ＰＥＧ４００は日興製薬製、酸化チタンは和光純薬工業製、黄色三二酸化鉄は癸巳化成製、カルナウバロウはフロイント産業製ポリシングワックス−１０３を用いた。
After preparing an aqueous dispersion at the blending ratio shown in Table 10 on the orally disintegrating tablet of Reference Example 3 and applying film coating using a film coating machine (HiCoater (registered trademark) HCT-30: Freund Sangyo) And coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet. Polyvinyl alcohol / polyethylene glycol graft copolymer (PVA-PEG graft copolymer) is BASF Kollicoat (registered trademark) IR, methylcellulose is Shin-Etsu Chemical Co., Ltd. Metros (registered trademark) SM-4, and maltitol is Hayashibara Biochemical Research Institute. Crystal Mabit (registered trademark) fine powder, lactose hydrate is Pharmatose (registered trademark) DCL-11 manufactured by DMV, D-mannitol is Mannit P manufactured by Mitsubishi Foodtech, and sucralose is Sucralose P manufactured by Saneigen FFI PEG400 was manufactured by Nikko Pharmaceutical, titanium oxide was manufactured by Wako Pure Chemical Industries, yellow iron sesquioxide was manufactured by Kasei Kasei, and carnauba wax was polished wax 103 manufactured by Freund Sangyo.
試験例５
比較例１〜４および６〜９と実施例５および８の口腔内崩壊性フィルムコーティング錠につき、試験例４と同様の方法で、製造直後の崩壊性と外観変化および８°グロス値を評価した。結果を表１１に示す。内核錠が実薬錠であっても、プラセボ錠であっても、崩壊性、高湿度下における外観変化および８°グロス値に顕著な差は認められず、試験例２で示された特性、即ち、ポリビニルアルコール系樹脂に水溶性物質を配合してコーティングした口腔内崩壊錠は、良好な崩壊性を示す一方で、高湿度下における外観変化が顕著であるのに対し、本発明の口腔内崩壊性フィルムコーティング錠は、良好な崩壊性を示し、且つ、高湿度下においても外観変化を全く認めなかったという特性は、コーティング層の組成によるものであることが示された。
For the orally disintegrating film-coated tablets of Comparative Examples 1-4 and 6-9 and Examples 5 and 8, disintegration and appearance change immediately after production and 8 ° gloss value were evaluated in the same manner as in Test Example 4. . The results are shown in Table 11. Regardless of whether the inner core tablet is an actual drug tablet or a placebo tablet, no significant difference was observed in disintegration, appearance change under high humidity, and 8 ° gloss value, the characteristics shown in Test Example 2, That is, the orally disintegrating tablet coated with a water-soluble substance blended with a polyvinyl alcohol resin exhibits good disintegration, while the appearance change under high humidity is remarkable, whereas the oral cavity of the present invention The disintegrating film-coated tablet showed good disintegration, and the property that no change in appearance was observed even under high humidity was shown to be due to the composition of the coating layer.
実施例９〜１１
参考例３の口腔内崩壊錠に、表１２に示す配合比率で水分散液を調製し、フィルムコーティング機（ハイコーター（登録商標）ＨＣＴ−３０：フロイント産業）を用いてフィルムコーティングを施した後、微量のカルナウバロウでコーティングし、口腔内崩壊性フィルムコーティング錠を得た。なお、メチルセルロースは信越化学工業製メトローズ（登録商標）ＳＭ−４、ヒプロメロースは信越化学工業製ＴＣ−５（登録商標）Ｅ、ヒプロメロース酢酸エステルコハク酸エステルは信越化学工業製Ｓｈｉｎ−Ｅｔｓｕ ＡＱＯＡＴ（登録商標）、Ｄ−マンニトールは三菱商事フードテック製マンニットＰ、エリスリトールは物産フードサイエンス製エリスリトール１００Ｍ、スクラロースは三栄源エフ・エフ・アイ製スクラロースＰ、ＰＥＧ４００は日興製薬製、酸化チタンは和光純薬工業製、黄色三二酸化鉄は癸巳化成製、カルナウバロウはフロイント産業製ポリシングワックス−１０３を用いた。
After preparing an aqueous dispersion at the blending ratio shown in Table 12 on the orally disintegrating tablet of Reference Example 3 and applying film coating using a film coating machine (HiCoater (registered trademark) HCT-30: Freund Sangyo) And coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet. In addition, Shin-Etsu AQOAT (registered trademark) is manufactured by Shin-Etsu AQOAT (manufactured by Shin-Etsu Chemical Co., Ltd.), methylcellulose is Shin-Etsu Chemical Co., Ltd. Metros (registered trademark) SM-4, hypromellose is Shin-Etsu Chemical TC-5 (registered trademark) E, and hypromellose acetate succinate. ), D-mannitol is Mannitol P manufactured by Mitsubishi Corporation Foodtech, Erythritol is Erythritol 100M manufactured by Food Science, sucralose is sucralose P manufactured by Saneigen FFI, PEG400 is manufactured by Nikko Pharmaceutical, and titanium oxide is manufactured by Wako Pure Chemical Industries. The yellow iron sesquioxide used was Kasei Kasei Co., Ltd., and Carnauba wax used Polishing Wax 103 made by Freund Corporation.
試験例６
実施例８〜１１の口腔内崩壊性フィルムコーティング錠につき、試験例４と同様の方法で、製造直後の崩壊性と外観変化および８°グロス値を評価した。結果を表１３に示す。セルロース系樹脂および甘味料の種類を変化させた場合であっても、本発明が、速崩壊性の機能を保持しつつ、ごくわずかな経時的な外観の変化を生じないことが示された。
The orally disintegrating film-coated tablets of Examples 8 to 11 were evaluated for disintegration and appearance change immediately after production and 8 ° gloss value in the same manner as in Test Example 4. The results are shown in Table 13. Even when the types of the cellulose resin and the sweetener were changed, it was shown that the present invention does not cause a slight change in appearance over time while maintaining a fast disintegrating function.
実施例１２
表１４に示す配合比率で水分散液を調製し、アムロジピンベシル酸塩を含有する大日本住友製薬製アムロジン（商標登録）ＯＤ錠２．５ｍｇに、フィルムコーティング機（ハイコーター（登録商標）ＨＣＴ−３０：フロイント産業）を用いてフィルムコーティングを施した後、微量のカルナウバロウでコーティングし、口腔内崩壊性フィルムコーティング錠を得た。なお、メチルセルロースは信越化学工業製メトローズ（登録商標）ＳＭ−４、Ｄ−マンニトールは三菱商事フードテック製マンニットＰ、スクラロースは三栄源エフ・エフ・アイ製スクラロースＰ、ＰＥＧ４００は日興製薬製、酸化チタンは和光純薬工業製、黄色三二酸化鉄は癸巳化成製、カルナウバロウはフロイント産業製ポリシングワックス−１０３を用いた。
An aqueous dispersion was prepared at a blending ratio shown in Table 14, and Amlodipine Besylate-containing Amurogin (registered trademark) OD tablet 2.5 mg manufactured by Sumitomo Dainippon Pharma Co., Ltd. was added to a film coating machine (Hicoater (registered trademark) HCT- 30: Freund Sangyo Co., Ltd.) and then coated with a small amount of carnauba wax to obtain an orally disintegrating film-coated tablet. Note that methylcellulose is manufactured by Shin-Etsu Chemical Co., Ltd., Metros (registered trademark) SM-4, D-mannitol is manufactured by Mitsubishi Corporation Foodtech Mannit P, sucralose is sucralose P manufactured by Saneigen FFI, and PEG400 is manufactured by Nikko Pharmaceutical. Titanium was manufactured by Wako Pure Chemical Industries, yellow ferric oxide was manufactured by Kasei Kasei, and carnauba wax was polished wax 103 manufactured by Freund Corporation.
試験例７
実施例１２およびその内核錠であるアムロジン（商標登録）ＯＤ錠２．５ｍｇにつき、製造直後の崩壊性と外観変化、８°グロス値および硬度を評価した。崩壊性、外観変化および８°グロス値は試験例４と同様の方法で、硬度は錠剤硬度計（８Ｍ：シュロイニゲル）を用いて評価した。結果を表１５に示す。含有される活性成分をアムロジピンベシル酸塩とした場合であっても、本発明が、速崩壊性の機能を保持しつつ、ごくわずかな経時的な外観の変化を生じないことが示された。また、本発明のコーティングを施すことで製造直後の絶対硬度は向上し、高湿度下における絶対硬度は、コーティングを施さない場合よりも高く保持されることが示された。
With respect to Example 12 and 2.5 mg of Amrodin (registered trademark) OD tablet which is an inner core tablet thereof, disintegration and appearance change immediately after production, 8 ° gloss value and hardness were evaluated. The disintegration, appearance change, and 8 ° gloss value were evaluated in the same manner as in Test Example 4, and the hardness was evaluated using a tablet hardness tester (8M: Schleunigel). The results are shown in Table 15. Even when the active ingredient contained is amlodipine besylate, it has been shown that the present invention does not cause a slight change in appearance over time while maintaining a rapidly disintegrating function. In addition, it was shown that the absolute hardness immediately after the production was improved by applying the coating of the present invention, and the absolute hardness under high humidity was kept higher than that without the coating.
本発明によれば、口腔内での速崩壊性の機能を保持しつつ、高湿度下においても、コーティング層の亀裂のみならず、艶消失などのごくわずかな経時的な外観の変化が生じない口腔内崩壊性フィルムコーティング錠を提供することができる。また、これまで適用できなかった、光に不安定な活性成分であっても、口腔内崩壊錠とすることができる。さらに、フィルムコーティングすることで、錠剤硬度の向上が可能であることから、これまで硬度不足により自動分包できなかった口腔内崩壊錠の一包化包装を可能とし、また、高湿度下において、吸湿により硬度低下する口腔内崩壊錠であっても、取り扱い可能な錠剤強度を確保することができる。これらの効果により、患者の服薬コンプライアンスを改善し、治療効果を向上させることができる。
According to the present invention, while maintaining a function of rapidly disintegrating in the oral cavity, not only the crack of the coating layer but also a slight change in appearance over time such as loss of gloss does not occur even under high humidity. An orally disintegrating film-coated tablet can be provided. Moreover, even an active ingredient unstable to light, which has not been applied so far, can be made into an orally disintegrating tablet. Furthermore, since film hardness can be improved by film coating, it enables the packaging of orally disintegrating tablets that could not be automatically packaged due to insufficient hardness until now, and under high humidity, Even if it is an orally disintegrating tablet whose hardness is reduced by moisture absorption, it is possible to secure a handleable tablet strength. These effects can improve patient compliance and improve the therapeutic effect.
Claims (4)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2013065382 | 2013-03-27 | ||
| JP2013065382 | 2013-03-27 | ||
| PCT/JP2014/058395 WO2014157264A1 (en) | 2013-03-27 | 2014-03-26 | Film-coated orally disintegrating tablet |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPWO2014157264A1 JPWO2014157264A1 (en) | 2017-02-16 |
| JP6258920B2 true JP6258920B2 (en) | 2018-01-10 |
Family
ID=51624230
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2015508567A Active JP6258920B2 (en) | 2013-03-27 | 2014-03-26 | Orally disintegrating film-coated tablets |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JP6258920B2 (en) |
| WO (1) | WO2014157264A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3106152B1 (en) | 2014-02-12 | 2021-02-17 | Sawai Pharmaceutical Co., Ltd. | Orally disintegrating tablet coated with film |
| JP7202898B2 (en) * | 2018-01-11 | 2023-01-12 | 沢井製薬株式会社 | Film-coated orally disintegrating tablet |
| FR3089756B1 (en) * | 2018-12-17 | 2021-02-19 | Roquette Freres | Sugar coated solid forms with improved stability |
| JP7219979B2 (en) * | 2020-02-26 | 2023-02-09 | 日新製薬株式会社 | Orally disintegrating tablet having a coating layer |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6328994B1 (en) * | 1998-05-18 | 2001-12-11 | Takeda Chemical Industries, Ltd. | Orally disintegrable tablets |
| JP2000302672A (en) * | 1999-04-16 | 2000-10-31 | Taisho Pharmaceut Co Ltd | Chewable coated tablet |
| JP4044709B2 (en) * | 1999-11-19 | 2008-02-06 | 信越化学工業株式会社 | Water-based film coating agent and oral solid preparation |
| JP2001139495A (en) * | 1999-11-19 | 2001-05-22 | Shin Etsu Chem Co Ltd | Film-coating agent and oral solid preparation |
| TWI455733B (en) * | 2009-03-30 | 2014-10-11 | Toray Industries | A coating tablet collapsible in the oral cavity |
| JP2010248106A (en) * | 2009-04-14 | 2010-11-04 | Dainippon Sumitomo Pharma Co Ltd | Film-coated tablet |
| PL2508206T3 (en) * | 2009-11-30 | 2014-12-31 | Toray Industries | Film coating agent for solid preparation, and solid preparation using same |
| WO2012147873A1 (en) * | 2011-04-28 | 2012-11-01 | 持田製薬株式会社 | Coating composition with superior oral disintegration characteristics |
| US20130177646A1 (en) * | 2012-01-05 | 2013-07-11 | Mcneil Ab | Solid Nicotine-Comprising Dosage Form with Reduced Organoleptic Disturbance |
-
2014
- 2014-03-26 WO PCT/JP2014/058395 patent/WO2014157264A1/en active Application Filing
- 2014-03-26 JP JP2015508567A patent/JP6258920B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| WO2014157264A1 (en) | 2014-10-02 |
| JPWO2014157264A1 (en) | 2017-02-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5549586B2 (en) | Orally disintegrating coated tablets | |
| US10588856B2 (en) | Orally disintegrating tablet coated with film | |
| JP2010248106A (en) | Film-coated tablet | |
| JP2019534887A (en) | Oral tablet composition of lenalidomide | |
| KR102092002B1 (en) | Tablets with coating and the production thereof | |
| JP6258920B2 (en) | Orally disintegrating film-coated tablets | |
| JP5907516B2 (en) | Coating composition excellent in disintegration in the oral cavity | |
| RU2018137590A (en) | PHARMACEUTICAL COMPOSITIONS FOR N-PROPARGYLAMINE DERIVATIVE | |
| JP5818219B2 (en) | Preparation containing 6,7-unsaturated-7-carbamoylmorphinan derivative | |
| JP7219979B2 (en) | Orally disintegrating tablet having a coating layer | |
| JP5700367B2 (en) | Paroxetine-containing oral film coating | |
| JP2018030840A (en) | Tablet, coated tablet, method for producing tablet and method for producing coated tablet | |
| JP7012492B2 (en) | Tablets and their manufacturing methods | |
| JP6895856B2 (en) | Method for manufacturing solid preparations and tablets | |
| JP2019123707A (en) | Film-coated intraoral disintegrable tablet | |
| JP2018039801A (en) | Tablet and coated tablet and method for producing them | |
| JP2014172854A (en) | Rapidly disintegrating tablet in oral cavity | |
| JP2011213606A (en) | Method for producing solid preparation containing donepezil |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20170106 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170824 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170920 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20171003 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20171122 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20171204 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20171207 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6258920 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |