JP2019182859A - Orally disintegrating tablet - Google Patents
Orally disintegrating tablet Download PDFInfo
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- JP2019182859A JP2019182859A JP2019074279A JP2019074279A JP2019182859A JP 2019182859 A JP2019182859 A JP 2019182859A JP 2019074279 A JP2019074279 A JP 2019074279A JP 2019074279 A JP2019074279 A JP 2019074279A JP 2019182859 A JP2019182859 A JP 2019182859A
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- JP
- Japan
- Prior art keywords
- tablet
- orally disintegrating
- lubricant
- disintegrating tablet
- tableting
- 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.)
- Granted
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- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 86
- 239000003826 tablet Substances 0.000 claims abstract description 131
- 239000000314 lubricant Substances 0.000 claims abstract description 51
- 229910017569 La2(CO3)3 Inorganic materials 0.000 claims abstract description 37
- 229960001633 lanthanum carbonate Drugs 0.000 claims abstract description 37
- 239000004480 active ingredient Substances 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- NZPIUJUFIFZSPW-UHFFFAOYSA-H lanthanum carbonate Chemical compound [La+3].[La+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O NZPIUJUFIFZSPW-UHFFFAOYSA-H 0.000 claims abstract 3
- 238000000034 method Methods 0.000 claims description 66
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 58
- 229910052751 metal Inorganic materials 0.000 claims description 34
- 239000002184 metal Substances 0.000 claims description 34
- 235000019359 magnesium stearate Nutrition 0.000 claims description 29
- 239000004605 External Lubricant Substances 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 16
- AFCUGQOTNCVYSW-UHFFFAOYSA-H lanthanum(3+);tricarbonate;hydrate Chemical compound O.[La+3].[La+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O AFCUGQOTNCVYSW-UHFFFAOYSA-H 0.000 claims description 6
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 5
- PKOQIYFBOVTYOH-UHFFFAOYSA-H lanthanum(3+);tricarbonate;tetrahydrate Chemical compound O.O.O.O.[La+3].[La+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O PKOQIYFBOVTYOH-UHFFFAOYSA-H 0.000 description 39
- 238000011156 evaluation Methods 0.000 description 28
- 230000000052 comparative effect Effects 0.000 description 26
- 238000005461 lubrication Methods 0.000 description 24
- 239000000203 mixture Substances 0.000 description 22
- 230000037303 wrinkles Effects 0.000 description 20
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 15
- 229960000913 crospovidone Drugs 0.000 description 13
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 13
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 13
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 13
- 108010011485 Aspartame Proteins 0.000 description 11
- 239000000605 aspartame Substances 0.000 description 11
- 235000010357 aspartame Nutrition 0.000 description 11
- 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 11
- 229960003438 aspartame Drugs 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 8
- 238000009472 formulation Methods 0.000 description 7
- 229920002261 Corn starch Polymers 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229960002413 ferric citrate Drugs 0.000 description 6
- NPFOYSMITVOQOS-UHFFFAOYSA-K iron(III) citrate Chemical compound [Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NPFOYSMITVOQOS-UHFFFAOYSA-K 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000005507 spraying Methods 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 201000005991 hyperphosphatemia Diseases 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 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
- 239000011248 coating agent Substances 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 210000000744 eyelid Anatomy 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- GAYSPCNXZCAPHX-UHFFFAOYSA-H lanthanum(3+);tricarbonate;octahydrate Chemical compound O.O.O.O.O.O.O.O.[La+3].[La+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O GAYSPCNXZCAPHX-UHFFFAOYSA-H 0.000 description 3
- 239000000395 magnesium oxide Substances 0.000 description 3
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 3
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 3
- 239000004570 mortar (masonry) Substances 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 239000008109 sodium starch glycolate Substances 0.000 description 3
- 229920003109 sodium starch glycolate Polymers 0.000 description 3
- 229940079832 sodium starch glycolate Drugs 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- -1 sucrose fatty acid ester Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 206010026749 Mania Diseases 0.000 description 2
- 238000004497 NIR spectroscopy Methods 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 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
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 229940024546 aluminum hydroxide gel Drugs 0.000 description 2
- SMYKVLBUSSNXMV-UHFFFAOYSA-K aluminum;trihydroxide;hydrate Chemical compound O.[OH-].[OH-].[OH-].[Al+3] SMYKVLBUSSNXMV-UHFFFAOYSA-K 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- 229940057948 magnesium stearate Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 239000004071 soot Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 229910001631 strontium chloride Inorganic materials 0.000 description 2
- AHBGXTDRMVNFER-UHFFFAOYSA-L strontium dichloride Chemical compound [Cl-].[Cl-].[Sr+2] AHBGXTDRMVNFER-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000004246 zinc acetate Substances 0.000 description 2
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241001489705 Aquarius Species 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
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 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
- 208000002972 Hepatolenticular Degeneration Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010021148 Hypozincaemia Diseases 0.000 description 1
- 239000004610 Internal Lubricant Substances 0.000 description 1
- 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 1
- 241000408529 Libra Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- 208000018839 Wilson disease Diseases 0.000 description 1
- CUPCBVUMRUSXIU-UHFFFAOYSA-N [Fe].OOO Chemical compound [Fe].OOO CUPCBVUMRUSXIU-UHFFFAOYSA-N 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 238000005299 abrasion Methods 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
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 229910021417 amorphous silicon Inorganic materials 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 230000001458 anti-acid effect Effects 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
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000005530 etching Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000010884 ion-beam technique Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229910021519 iron(III) oxide-hydroxide Inorganic materials 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 229940125722 laxative agent Drugs 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- ZADYMNAVLSWLEQ-UHFFFAOYSA-N magnesium;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[Mg+2].[Si+4] ZADYMNAVLSWLEQ-UHFFFAOYSA-N 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- 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 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
Abstract
Description
本発明は、口腔内崩壊錠に関する。より具体的には、金属系の医薬有効成分（例えば、炭酸ランタン等）を含む口腔内崩壊錠に関する。本発明はまた、前記口腔内崩壊錠の製造方法に関する。 The present invention relates to an orally disintegrating tablet. More specifically, the present invention relates to an orally disintegrating tablet containing a metal-based active pharmaceutical ingredient (for example, lanthanum carbonate). The present invention also relates to a method for producing the orally disintegrating tablet.
金属系の医薬有効成分である炭酸ランタンは、慢性腎臓病患者の高リン血症の治療において高い有効性が示されており、それを含む医薬が国内外で販売されている。 Lanthanum carbonate, a metal-based pharmaceutical active ingredient, has been shown to be highly effective in the treatment of hyperphosphatemia in patients with chronic kidney disease, and pharmaceuticals containing it have been sold both in Japan and overseas.
炭酸ランタンの製剤としては、顆粒製剤、チュアブル製剤、口腔内崩壊製剤（「Orally Disintegrating Preparation：ＯＤ錠」または「口腔内崩壊錠」ともいう。）等が開発されている。なかでも、口腔内崩壊錠は、水なしで容易に服用できるために、特に、咀嚼や嚥下が困難な患者において有用である。 As preparations of lanthanum carbonate, granular preparations, chewable preparations, orally disintegrating preparations (also referred to as “Orally Disintegrating Preparation: OD tablets” or “orally disintegrating tablets”) and the like have been developed. Especially, since an orally disintegrating tablet can be easily taken without water, it is particularly useful for patients who are difficult to chew or swallow.
炭酸ランタンを含む口腔内崩壊錠として、例えば、特許文献１には、炭酸ランタンまたはその薬学的に許容される塩を７０〜９０質量％含有する口腔内崩壊用の医薬組成物が記載されている。また、特許文献２には、炭酸ランタン水和物、一定量のタルクおよび一定量の脂肪酸および／または脂肪酸誘導体を含有する口腔内崩壊錠が記載されている。 As an orally disintegrating tablet containing lanthanum carbonate, for example, Patent Document 1 describes a pharmaceutical composition for oral disintegration containing 70 to 90% by mass of lanthanum carbonate or a pharmaceutically acceptable salt thereof. . Patent Document 2 describes an orally disintegrating tablet containing lanthanum carbonate hydrate, a certain amount of talc, and a certain amount of fatty acid and / or fatty acid derivative.
ところで、口腔内崩壊錠等の錠剤を製造する際に、錠剤用の粉末を圧縮する際に打錠機杵臼と錠剤間の摩擦を緩和し、スティッキング等の打錠障害を防ぐために、ステアリン酸マグネシウム等の滑沢剤が錠剤処方の添加剤として用いられている。かかる滑沢剤は、通常、打錠工程前に打錠用の粉末に混合して用いられる（内部滑沢法）。 By the way, when manufacturing tablets such as orally disintegrating tablets, magnesium stearate is used to reduce friction between the tableting die and the tablets when compressing the powder for tablets and prevent tableting troubles such as sticking. Are used as additives for tablet formulations. Such a lubricant is usually used by mixing with a tableting powder before the tableting process (internal lubrication method).
しかし、特許文献１に記載されている口腔内崩壊錠は、内部滑沢法で製造されているため、打錠用の粉末に一定量の滑沢剤が含まれている。ステアリン酸マグネシウム等の滑沢剤が錠剤の内部に過剰に含まれると、錠剤に含まれる粉末間の接着力が弱くなるために、錠剤の硬度が低下してしまうという問題が生じる場合があった。さらに、特許文献１に記載されている口腔内崩壊錠は、有効成分である炭酸ランタン水和物の含有量が９０質量％を超えると、摩損度の上昇、すなわち、割れ・欠けの発生率が特に増加するという問題があった。 However, since the orally disintegrating tablet described in Patent Document 1 is produced by the internal lubricant method, a certain amount of lubricant is contained in the powder for tableting. When a lubricant such as magnesium stearate is excessively contained in the tablet, the adhesive strength between the powders contained in the tablet is weakened, which may cause a problem that the hardness of the tablet decreases. . Furthermore, when the content of the lanthanum carbonate hydrate as an active ingredient exceeds 90% by mass, the orally disintegrating tablet described in Patent Document 1 has an increased friability, that is, the occurrence rate of cracks and chips. There was a problem of increasing in particular.
特許文献２に記載されている技術は、添加剤としてステアリン酸マグネシウムとタルクとを併用して、口腔内崩壊錠の問題点の一つである、貯蔵による経時的な溶出低下の問題点を解決しようとする技術であるが、内部滑沢法により上記添加剤が添加されているため、得られた錠剤が摩損し易いという問題があった。 The technique described in Patent Document 2 uses magnesium stearate and talc as additives to solve one of the problems of orally disintegrating tablets. Although it is the technique which it is going to be, since the said additive was added by the internal lubrication method, there existed a problem that the obtained tablet was easy to be worn out.
そこで、本発明の一態様は、打錠障害等の製造性の問題が改善されるとともに、速やかな崩壊性を有する新規の、金属系の医薬有効成分（例えば、炭酸ランタン等）を含む口腔内崩壊錠を実現することを目的とする。 Thus, one embodiment of the present invention is an oral cavity containing a novel metal-based pharmaceutical active ingredient (for example, lanthanum carbonate, etc.) having improved disintegration and improved manufacturability problems such as tableting troubles. The purpose is to realize a disintegrating tablet.
本発明者らは、上記課題を解決するために鋭意検討を重ねた結果、金属系の医薬有効成分（例えば、炭酸ランタン等）を含む口腔内崩壊錠の製造工程において、外部滑沢法により滑沢剤を添加することにより、製造性が改善されるとともに、速やかな崩壊性を有する口腔内崩壊錠を得ることができることを初めて見出した。 As a result of intensive studies in order to solve the above problems, the present inventors have found that an external lubricant method is used in the production process of orally disintegrating tablets containing a metal-based active pharmaceutical ingredient (eg, lanthanum carbonate). It has been found for the first time that an orally disintegrating tablet having rapid disintegration can be obtained by adding a bulking agent as well as improving productivity.
また、本発明者らは、口腔内崩壊錠中の金属系の医薬有効成分（例えば、炭酸ランタン等）の含有量が９０質量％を超える極めて高い場合であっても、外部滑沢法を採用することにより、上記と同様の効果を得ることができることを見出した。そして、これらの知見を基に、本発明を完成するに至った。すなわち、本発明の一実施形態は以下の構成を包含する。
＜１＞金属系の医薬有効成分または薬学的に許容されるその塩、および滑沢剤を含む口腔内崩壊錠であり、前記滑沢剤が錠剤の表面に偏在することを特徴とする、口腔内崩壊錠。
＜２＞金属系の医薬有効成分または薬学的に許容されるその塩、および滑沢剤を含む口腔内崩壊錠であり、前記滑沢剤が外部滑沢法により添加されていることを特徴とする、口腔内崩壊錠。
＜３＞前記金属系の医薬有効成分が、炭酸ランタンである、＜１＞または＜２＞に記載の口腔内崩壊錠。
＜４＞前記炭酸ランタンが、以下の式（１）で表される炭酸ランタン水和物であることを特徴とする、＜３＞に記載の口腔内崩壊錠。
In addition, the present inventors adopt an external lubrication method even when the content of a metal-based pharmaceutical active ingredient (for example, lanthanum carbonate) in the orally disintegrating tablet is extremely high exceeding 90% by mass. As a result, it was found that the same effect as described above can be obtained. And based on these knowledge, it came to complete this invention. That is, one embodiment of the present invention includes the following configuration.
<1> An orally disintegrating tablet containing a metal-based active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof and a lubricant, wherein the lubricant is unevenly distributed on the surface of the tablet. Inner disintegrating tablet.
<2> An orally disintegrating tablet comprising a metal-based pharmaceutically active ingredient or a pharmaceutically acceptable salt thereof and a lubricant, wherein the lubricant is added by an external lubricant method Orally disintegrating tablets.
<3> The orally disintegrating tablet according to <1> or <2>, wherein the metal-based pharmaceutical active ingredient is lanthanum carbonate.
<4> The orally disintegrating tablet according to <3>, wherein the lanthanum carbonate is a lanthanum carbonate hydrate represented by the following formula (1).
Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ ・・・（１）
（式中、ｘは、３〜９である。）
＜５＞前記金属系の医薬有効成分の含有率が９０質量％を超えることを特徴とする、＜１＞〜＜４＞のいずれかに記載の口腔内崩壊錠。
＜６＞前記滑沢剤が、ステアリン酸マグネシウムであることを特徴とする、＜１＞〜＜５＞のいずれかに記載の口腔内崩壊錠。
＜７＞＜１＞または＜３＞〜＜６＞のいずれかに記載の口腔内崩壊錠を製造する方法であり、滑沢剤が外部滑沢法により添加される工程を含むことを特徴とする、方法。
＜８＞金属系の医薬有効成分または薬学的に許容されるその塩を含む口腔内崩壊錠において、前記口腔内崩壊錠の崩壊性を改善する、および／または前記口腔内崩壊錠の製造工程における打錠障害を改善する方法であり、
前記口腔内崩壊錠に外部滑沢法により滑沢剤を含ませることを特徴とする、方法。
La 2 (CO 3 ) 3 · xH 2 O (1)
(In the formula, x is 3 to 9.)
<5> The orally disintegrating tablet according to any one of <1> to <4>, wherein the content of the metal-based pharmaceutical active ingredient exceeds 90% by mass.
<6> The orally disintegrating tablet according to any one of <1> to <5>, wherein the lubricant is magnesium stearate.
<7> A method for producing an orally disintegrating tablet according to any one of <1> or <3> to <6>, comprising a step in which a lubricant is added by an external lubricant method how to.
<8> An orally disintegrating tablet containing a metal-based pharmaceutically active ingredient or a pharmaceutically acceptable salt thereof, improving the disintegration property of the orally disintegrating tablet, and / or in the production process of the orally disintegrating tablet Is a method of improving tableting disorders,
A method comprising incorporating a lubricant into the orally disintegrating tablet by an external lubricant method.
本発明の一態様によれば、製造性が改善され、かつ、速やかな崩壊性を有する新規の、金属系の医薬有効成分（例えば、炭酸ランタン等）を含む口腔内崩壊錠を提供することができる。 According to one aspect of the present invention, it is possible to provide a novel orally disintegrating tablet comprising a metal-based pharmaceutical active ingredient (for example, lanthanum carbonate) having improved manufacturability and rapid disintegration. it can.
本発明の一実施形態に関して以下に説明するが、本発明はこれに限定されるものではない。本発明は、以下に説明する各構成に限定されるものではなく、特許請求の範囲に示した範囲で種々の変更が可能であり、異なる実施形態にそれぞれ開示された技術的手段を適宜組み合わせて得られる実施形態に関しても本発明の技術的範囲に含まれる。なお、本明細書において特記しない限り、数値範囲を表す「Ａ〜Ｂ」は、「Ａ以上、Ｂ以下」を意味する。 An embodiment of the present invention will be described below, but the present invention is not limited to this. The present invention is not limited to each configuration described below, and various modifications are possible within the scope shown in the claims, and various technical means disclosed in different embodiments are appropriately combined. The obtained embodiments are also included in the technical scope of the present invention. Unless otherwise specified in this specification, “A to B” indicating a numerical range means “A or more and B or less”.
〔１．口腔内崩壊錠〕
本発明の一実施形態に係る口腔内崩壊錠（以下、「本発明の口腔内崩壊錠」と称する。）は、金属系の医薬有効成分（例えば、炭酸ランタン等）または薬学的に許容されるその塩、および滑沢剤を含む口腔内崩壊錠であり、前記滑沢剤が錠剤の表面に偏在する、口腔内崩壊錠である。また、本発明の口腔内崩壊錠は、金属系の医薬有効成分（例えば、炭酸ランタン等）または薬学的に許容されるその塩、および滑沢剤を含む口腔内崩壊錠であり、前記滑沢剤が外部滑沢法により添加されている、口腔内崩壊錠とも表現される。
[1. (Orally disintegrating tablets)
The orally disintegrating tablet according to an embodiment of the present invention (hereinafter referred to as “orally disintegrating tablet of the present invention”) is a metal-based pharmaceutical active ingredient (eg, lanthanum carbonate) or pharmaceutically acceptable. An orally disintegrating tablet containing the salt and a lubricant, wherein the lubricant is unevenly distributed on the surface of the tablet. The orally disintegrating tablet of the present invention is an orally disintegrating tablet containing a metal-based pharmaceutical active ingredient (eg, lanthanum carbonate) or a pharmaceutically acceptable salt thereof, and a lubricant. It is also expressed as an orally disintegrating tablet to which an agent is added by an external lubrication method.
本明細書において「金属系の医薬有効成分」とは、金属原子を含む物質であり、かつ、医薬用途において効果を示し得る物質を意味する。本発明の一実施形態における金属系の医薬有効成分は、例えば、酸化マグネシウム、炭酸リチウム、塩化ストロンチウム、酢酸亜鉛、炭酸ランタン、クエン酸第二鉄、スクロオキシ水酸化鉄等であり得る。また、本発明の一実施形態における金属系の医薬有効成分は、好ましくは、金属系のリン吸着成分であり得る。金属系のリン吸着成分は、上記「金属系の医薬有効成分」の定義に該当し、かつ、リン吸着機能を有する物質であれば特に限定されないが、例えば、炭酸ランタン、クエン酸第二鉄、スクロオキシ水酸化鉄等であり得る。本発明の一実施形態における金属系の医薬有効成分は、好ましくは、炭酸ランタンである。 In the present specification, the “metal-based pharmaceutically active ingredient” means a substance containing a metal atom and capable of showing an effect in pharmaceutical use. In one embodiment of the present invention, the metal-based pharmaceutically active ingredient may be, for example, magnesium oxide, lithium carbonate, strontium chloride, zinc acetate, lanthanum carbonate, ferric citrate, iron oxyhydrate. In addition, the metal-based pharmaceutically active ingredient in one embodiment of the present invention may preferably be a metal-based phosphorus adsorption component. The metal-based phosphorus-adsorbing component is not particularly limited as long as it falls within the definition of the above-mentioned “metal-based pharmaceutical active ingredient” and has a phosphorus-adsorbing function. For example, lanthanum carbonate, ferric citrate, It may be iron oxyhydroxide. The metal-based pharmaceutically active ingredient in one embodiment of the present invention is preferably lanthanum carbonate.
なお、上記金属系のリン吸着成分は、高リン血症の治療等において有用である。また、上記酸化マグネシウムは、制酸・緩下剤として、炭酸リチウムは、躁病・躁状態治療剤として、塩化ストロンチウムは、放射性医薬品または骨転移疼痛緩和剤として、酢酸亜鉛は、ウィルソン病治療剤（銅吸収阻害剤）または低亜鉛血症治療剤として、有用である。 The metal-based phosphorus adsorption component is useful in the treatment of hyperphosphatemia and the like. Magnesium oxide is used as an antacid / laxative agent, lithium carbonate is used as a treatment for mania and mania, strontium chloride is used as a radiopharmaceutical or bone metastasis pain relieving agent, and zinc acetate is used as a Wilson's disease treatment Inhibitors) or as therapeutic agents for hypozincemia.
本明細書において「口腔内崩壊錠」とは、唾液または少量の水により口腔内で崩壊するように調製された製剤を意味する。 As used herein, “orally disintegrating tablet” means a preparation prepared to disintegrate in the oral cavity with saliva or a small amount of water.
以下、金属系の医薬有効成分の一例として、炭酸ランタンを用いて説明する。すなわち、炭酸ランタンについての説明は、炭酸ランタン以外の金属系の医薬有効成分の説明として援用される。 Hereinafter, lanthanum carbonate will be described as an example of a metal-based pharmaceutical active ingredient. That is, the description of lanthanum carbonate is incorporated as an explanation of metal-based pharmaceutical active ingredients other than lanthanum carbonate.
本発明者らは、炭酸ランタンを含む口腔内崩壊錠について詳細に検討を行った結果、以下の知見を得ることに成功した。
・外部滑沢法により滑沢剤を添加することにより、打錠障害を回避できる。
・前記で得られた錠剤は、速やかな崩壊性を有する。
・前記で得られた錠剤は、従来品と比較して、同程度もしくは優れた硬度を示す。
・前記で得られた錠剤は、摩損等の問題を生じない。特に、炭酸ランタンの含有率が９０質量％を超える場合でも、摩損等の問題を生じない。
As a result of detailed studies on orally disintegrating tablets containing lanthanum carbonate, the present inventors have succeeded in obtaining the following findings.
-Tableting troubles can be avoided by adding a lubricant by the external lubricant method.
-The tablet obtained above has quick disintegration.
-The tablet obtained above shows comparable or superior hardness as compared with the conventional product.
-The tablets obtained above do not cause problems such as wear. In particular, even when the content of lanthanum carbonate exceeds 90% by mass, problems such as abrasion do not occur.
すなわち、炭酸ランタンを含む口腔内崩壊錠の従来品では、上述した通り、製造性の問題、摩損度の上昇（割れ・欠けの発生率の増加）の問題等があった。また、金属系の医薬有効成分（例えば、炭酸ランタン等）の打錠は、打錠障害が問題になることが多く、さらに多くの崩壊剤を加えなければ崩壊性に乏しいために、一般に困難であることが当該技術分野での技術常識であった。 That is, in the conventional orally disintegrating tablet containing lanthanum carbonate, as described above, there are problems of manufacturability, problems of increased friability (increased incidence of cracking and chipping), and the like. In addition, tableting of metal-based pharmaceutical active ingredients (for example, lanthanum carbonate, etc.) is generally difficult because tableting troubles are often a problem, and the disintegrability is poor unless more disintegrating agents are added. There was technical common sense in the technical field.
したがって、本発明者らが見出した上記の知見、すなわち、金属系の医薬有効成分である炭酸ランタンに、外部滑沢法により滑沢剤を添加して、製造性が改善されるとともに、速やかな崩壊性および優れた硬度を有し、かつ、摩損が生じない（摩損が生じにくい）、口腔内崩壊錠を製造できることは驚くべきことであった。 Therefore, the above-mentioned findings found by the present inventors, that is, the addition of a lubricant by an external lubricant method to lanthanum carbonate, which is a metal-based pharmaceutical active ingredient, improves the productivity, and promptly. It was surprising to be able to produce an orally disintegrating tablet that has disintegration and excellent hardness and does not wear (i.e., does not easily wear).
本発明の口腔内崩壊錠は、上記の知見に基づく効果を奏することから、極めて有用な新規の炭酸ランタンを含む口腔内崩壊錠を提供することができる。 Since the orally disintegrating tablet of the present invention has an effect based on the above findings, an orally disintegrating tablet containing a very useful novel lanthanum carbonate can be provided.
本発明の口腔内崩壊錠は、滑沢剤が外部滑沢法により添加される工程を含む、方法により製造される。 The orally disintegrating tablet of the present invention is produced by a method including a step in which a lubricant is added by an external lubricant method.
外部滑沢法は、打錠用混合物を調製する際には滑沢剤を添加せずに、滑沢剤を打錠機の上下杵および臼に噴霧（塗布）して添加する方法である。滑沢剤を上下杵および臼へ直接噴霧することで、滑沢剤の皮膜を粉末との接触面に形成することができる。本発明の口腔内崩壊錠を、外部滑沢法により滑沢剤を添加する工程を含む方法により製造することにより、上述の本発明の効果を達成できる。また、滑沢剤を打錠機の杵臼に噴霧（塗布）することは、従来の公知の方法に基づき、あるいは市販の機械を用いて行うことができる。 The external lubrication method is a method in which a lubricant is sprayed (applied) onto the upper and lower punches and a die of a tableting machine without adding a lubricant when preparing a tableting mixture. By directly spraying the lubricant on the upper and lower punches and the die, a lubricant film can be formed on the contact surface with the powder. By producing the orally disintegrating tablet of the present invention by a method including a step of adding a lubricant by an external lubricant method, the above-described effects of the present invention can be achieved. Moreover, spraying (application | coating) a lubricant agent to the die of a tableting machine can be performed based on the conventionally well-known method, or using a commercially available machine.
本発明の口腔内崩壊錠を製造する際に使用される打錠装置としては、例えば、単発打錠機、ロータリー式打錠機等が挙げられる。ロータリー式打錠機としては、例えば、ＡＱＵＡＲＩＵＳ Ｇ／ＬＩＢＲＡ ２／ＶＩＲＧＯ（菊水製作所）、ＣＯＭＰＲＩＭＡ（ＩＭＡ）等が使用され得る。 Examples of the tableting device used when producing the orally disintegrating tablet of the present invention include a single tableting machine and a rotary tableting machine. As the rotary tableting machine, for example, AQUARIUS G / LIBRA 2 / VIRGO (Kikusui Seisakusho), COMPRIMA (IMA) and the like can be used.
本発明の一実施形態における滑沢剤は、特に限定されないが、例えば、カルナウバロウ、含水二酸化ケイ素、含水無晶形酸化ケイ素、乾燥水酸化アルミニウムゲル、ケイ酸マグネシウム、軽質無水ケイ酸、合成ケイ酸アルミニウム、酸化マグネシウム、重質無水ケイ酸、ショ糖脂肪酸エステル、水酸化アルミニウムゲル、ステアリルアルコール、ステアリン酸、ステアリン酸カルシウム、ステアリン酸マグネシウム、セタノール、炭酸マグネシウム、沈降炭酸カルシウム、フマル酸ステアリルナトリウム、タルク、無水ケイ酸水加物、メタケイ酸アルミン酸マグネシウム等であり得る。本発明の一実施形態における滑沢剤は、打錠障害軽減の観点から、好ましくは、ステアリン酸マグネシウムである。 The lubricant in one embodiment of the present invention is not particularly limited. For example, carnauba wax, hydrous silicon dioxide, hydrous amorphous silicon oxide, dry aluminum hydroxide gel, magnesium silicate, light anhydrous silicic acid, and synthetic aluminum silicate. , Magnesium oxide, heavy anhydrous silicic acid, sucrose fatty acid ester, aluminum hydroxide gel, stearyl alcohol, stearic acid, calcium stearate, magnesium stearate, cetanol, magnesium carbonate, precipitated calcium carbonate, sodium stearyl fumarate, talc, anhydrous It can be silicate hydrate, magnesium aluminate metasilicate and the like. The lubricant in one embodiment of the present invention is preferably magnesium stearate from the viewpoint of reducing tableting trouble.
本発明の一実施形態において、外部滑沢法によって口腔内崩壊錠に添加される滑沢剤の量は、口腔内崩壊錠の質量を基準として、例えば、１質量％未満であり、好ましくは、０．５質量％以下であり、より好ましくは、０．１質量％以下である。滑沢剤の添加量が上記好ましい範囲であると、得られた口腔内崩壊錠の崩壊時間が短くなるという利点を有する。 In one embodiment of the present invention, the amount of lubricant added to the orally disintegrating tablet by the external lubricant method is, for example, less than 1% by mass, preferably based on the mass of the orally disintegrating tablet, It is 0.5 mass% or less, More preferably, it is 0.1 mass% or less. When the addition amount of the lubricant is within the above preferable range, there is an advantage that the disintegration time of the obtained orally disintegrating tablet is shortened.
本発明の口腔内崩壊錠は、滑沢剤が錠剤の表面に偏在している。本明細書において「滑沢剤が錠剤の表面に偏在している」とは、錠剤の表層部および／またはその近傍に滑沢剤が偏って存在していることを意味する。本発明の一実施形態において、滑沢剤の錠剤表面への偏在は、錠剤の表面に滑沢剤の全含有量の半分を超える量が偏って存在していればよい。滑沢剤が錠剤の表面に偏在しているか否かについては、高精度で表面のエッチング処理が可能である集束イオンビーム法を用いて調製した錠剤断面サンプルを走査型電子顕微鏡（ＳＥＭ）で観察することや、近赤外分光法（ＮＩＲ）イメージング法を用いて錠剤表面と錠剤断面の滑沢剤の分布を比較することにより評価することができる。 In the orally disintegrating tablet of the present invention, the lubricant is unevenly distributed on the surface of the tablet. In the present specification, “the lubricant is unevenly distributed on the surface of the tablet” means that the lubricant is unevenly present on the surface layer of the tablet and / or in the vicinity thereof. In one embodiment of the present invention, the lubricant is unevenly distributed on the tablet surface as long as more than half of the total content of the lubricant is unevenly present on the surface of the tablet. Whether or not the lubricant is unevenly distributed on the surface of the tablet is observed with a scanning electron microscope (SEM) using a focused ion beam method that enables high-precision surface etching. It can be evaluated by comparing the distribution of lubricants on the tablet surface and tablet cross section using near infrared spectroscopy (NIR) imaging.
本発明の口腔内崩壊錠において、滑沢剤が錠剤の表面に偏在する理由としては、本発明の口腔内崩壊錠の製造が、上述の通り、外部滑沢法により滑沢剤が添加されることによる。すなわち、外部滑沢法では、打錠する前の打錠用混合物には滑沢剤は含まれておらず、打錠機の杵臼の表面に付着した滑沢剤が、打錠の際に錠剤の表面に付着することになる。このため、必然的に、錠剤内部に比して、錠剤表面により多くの滑沢剤が偏在するといえる。すなわち、外部滑沢法で製造された口腔内崩壊剤は、上記のＳＥＭ観察を行うまでもなく、滑沢剤が錠剤の表面に偏在しているといえる。 In the orally disintegrating tablet of the present invention, the reason why the lubricant is unevenly distributed on the surface of the tablet is that the preparation of the orally disintegrating tablet of the present invention is added by the external lubricant method as described above. It depends. That is, in the external lubrication method, the tableting mixture before tableting does not contain a lubricant, and the lubricant adhering to the surface of the die of the tableting machine is converted into a tablet during tableting. Will adhere to the surface of the. Therefore, inevitably, it can be said that more lubricant is unevenly distributed on the tablet surface than in the tablet interior. That is, it can be said that the oral disintegrant produced by the external lubricant method is unevenly distributed on the surface of the tablet without performing the above SEM observation.
本発明の一実施形態における炭酸ランタンは、以下の式（１）で表される炭酸ランタン水和物である。 The lanthanum carbonate in one embodiment of the present invention is a lanthanum carbonate hydrate represented by the following formula (1).
Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ ・・・（１）
（式中、ｘは、３〜９である。）
前記式（１）で表される炭酸ランタン水和物は、物理的性質、化学的性質および生物学的性質が公知であるため、本発明の口腔内崩壊錠に含まれる炭酸ランタンとして好ましい。
La 2 (CO 3 ) 3 · xH 2 O (1)
(In the formula, x is 3 to 9.)
The lanthanum carbonate hydrate represented by the formula (1) is known as a lanthanum carbonate contained in the orally disintegrating tablet of the present invention because its physical properties, chemical properties and biological properties are known.
本発明の一実施形態における炭酸ランタンは、上記式（１）中のｘが、３〜９である。 As for the lanthanum carbonate in one Embodiment of this invention, x in the said Formula (1) is 3-9.
本発明の一実施形態における炭酸ランタンまたは薬学的に許容されるその塩の含有率は、特に限定されないが、好ましくは、５０質量％以上であり、より好ましくは、７０質量％以上であり、とりわけ好ましくは、７５質量％以上であり、特に好ましくは、８０質量％以上であり、さらに好ましくは、９０質量％を超える量である。炭酸ランタンまたは薬学的に許容されるその塩の含有率が７０質量％以上であると、一度に多量の炭酸ランタンを服用することが可能となり、患者の負担が軽減されるという利点を有する。また、本発明の口腔内崩壊錠は、９０質量％を超える極めて多量の炭酸ランタンまたは薬学的に許容されるその塩を含有することができるため、９０質量％を超える含有率では錠剤の摩損度等に問題が生じていた従来品と比べて、極めて有利である。 The content of lanthanum carbonate or a pharmaceutically acceptable salt thereof in one embodiment of the present invention is not particularly limited, but is preferably 50% by mass or more, more preferably 70% by mass or more, The amount is preferably 75% by mass or more, particularly preferably 80% by mass or more, and further preferably an amount exceeding 90% by mass. When the content of lanthanum carbonate or a pharmaceutically acceptable salt thereof is 70% by mass or more, it is possible to take a large amount of lanthanum carbonate at a time, which has an advantage of reducing the burden on the patient. Further, since the orally disintegrating tablet of the present invention can contain a very large amount of lanthanum carbonate exceeding 90% by mass or a pharmaceutically acceptable salt thereof, the friability of the tablet is exceeded at a content exceeding 90% by mass. This is extremely advantageous as compared with the conventional product in which problems have occurred.
本発明の口腔内崩壊錠の硬度は、特に限定されないが、後述する実施例に記載の方法に基づき評価した場合に、例えば、８０Ｎ以上であり、好ましくは、１００Ｎ以上である。口腔内崩壊錠の硬度が８０Ｎ以上であれば、輸送時等における物理的破損を回避できるという利点を有する。 Although the hardness of the orally disintegrating tablet of this invention is not specifically limited, When evaluated based on the method as described in the Example mentioned later, it is 80N or more, for example, Preferably, it is 100N or more. If the hardness of the orally disintegrating tablet is 80 N or more, there is an advantage that physical breakage during transportation can be avoided.
本発明の口腔内崩壊錠の崩壊時間は、特に限定されないが、後述する実施例に記載の方法に基づき評価した場合に、例えば、３０秒以下であり、好ましくは、１５秒以下である。口腔内崩壊錠の崩壊時間が３０秒以下であれば、口腔内崩壊錠として適した崩壊性（崩壊速度）を有するという利点を有する。 Although the disintegration time of the orally disintegrating tablet of the present invention is not particularly limited, it is, for example, 30 seconds or less, preferably 15 seconds or less, when evaluated based on the method described in Examples described later. If the disintegration time of the orally disintegrating tablet is 30 seconds or less, it has an advantage of having disintegration property (disintegration rate) suitable as an orally disintegrating tablet.
本発明の口腔内崩壊錠は、前記滑沢剤に加えて、さらに他の添加剤を含み得る。そのような添加剤としては、特に限定されないが、例えば、結合剤（例えば、アルファー化デンプン、ポリビニルピロリドン、ゼラチン、カンテン等）、賦形剤（例えば、Ｄ−マンニトール、乳糖、白糖、コーンスターチ（トウモロコシデンプン）、リン酸カルシウム、ソルビット、結晶セルロース等）、崩壊剤（例えば、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、デンプングリコール酸ナトリウム、クロスカルメロースナトリウム、バレイショデンプン等）、コーティング剤（例えば、ヒドロキシプロピルセルロース、ヒプロメロース、エチルセルロース等）、甘味剤（アスパルテーム、果糖、サッカリン、スクラロース、白糖、Ｄ−ソルビトール、ブドウ糖、アセスルファムカリウム等）等が挙げられる。 The orally disintegrating tablet of the present invention may further contain other additives in addition to the lubricant. Examples of such additives include, but are not limited to, binders (for example, pregelatinized starch, polyvinylpyrrolidone, gelatin, agar), excipients (for example, D-mannitol, lactose, sucrose, corn starch (corn) Starch), calcium phosphate, sorbit, crystalline cellulose, etc.), disintegrating agents (eg, crospovidone, low-substituted hydroxypropylcellulose, sodium starch glycolate, croscarmellose sodium, potato starch, etc.), coating agents (eg, hydroxypropylcellulose) , Hypromellose, ethyl cellulose, etc.), sweeteners (aspartame, fructose, saccharin, sucralose, sucrose, D-sorbitol, glucose, acesulfame potassium, etc.).
前記添加剤の含有率は、特に限定されることなく、従来公知の技術に基づいて、適宜設定され得る。例えば、崩壊剤の含有率は、例えば、３〜１０質量％であり、好ましくは、４〜７質量％であり、より好ましくは、５〜６質量％である。崩壊剤の含有率が３質量％以下であると、崩壊剤としての効果が得られず、１０質量％以上であると有効成分を高含量含む製剤とすることができない。 The content rate of the additive is not particularly limited and can be appropriately set based on a conventionally known technique. For example, the content rate of a disintegrating agent is 3-10 mass%, for example, Preferably, it is 4-7 mass%, More preferably, it is 5-6 mass%. When the content of the disintegrant is 3% by mass or less, an effect as a disintegrant cannot be obtained, and when it is 10% by mass or more, a preparation containing a high content of active ingredients cannot be obtained.
本発明の口腔内崩壊錠の成形は、特に限定されることなく、どのような形状も採用することができる。本発明の口腔内崩壊錠は、例えば、円形、楕円形、球形、棒状型、ドーナツ型の形状等であり得る。また、本発明の口腔内崩壊錠は、積層錠、有核錠等であってもよく、錠剤の表面がコーティング剤により被膜されていてもよい。 The shape of the orally disintegrating tablet of the present invention is not particularly limited, and any shape can be adopted. The orally disintegrating tablet of the present invention can be, for example, circular, elliptical, spherical, rod-shaped, donut-shaped or the like. The orally disintegrating tablet of the present invention may be a laminated tablet, a dry-coated tablet, or the like, and the surface of the tablet may be coated with a coating agent.
本発明の口腔内崩壊錠は、高リン血症治療剤として、とりわけ、慢性腎臓病患者における高リン血症治療剤として、使用することができる。 The orally disintegrating tablet of the present invention can be used as a therapeutic agent for hyperphosphatemia, particularly as a therapeutic agent for hyperphosphatemia in patients with chronic kidney disease.
本発明の口腔内崩壊錠の投与量は、患者の状態や体重等によっても異なるが、口腔内崩壊錠に含まれるランタンの量を基準として、成人１日当たり、例えば、約１００ｍｇ〜１０ｇ、好ましくは、約５００ｍｇ〜５ｇ、より好ましくは、約７５０ｍｇ〜２．２５ｇであり得る。また、本発明の口腔内崩壊錠の投与回数は、例えば、１日１〜数回、好ましくは、１日３回であり得る。 The dose of the orally disintegrating tablet of the present invention varies depending on the patient's condition, weight, etc., but based on the amount of lanthanum contained in the orally disintegrating tablet, for example, about 100 mg to 10 g per day, preferably About 500 mg to 5 g, more preferably about 750 mg to 2.25 g. Moreover, the frequency | count of administration of the orally disintegrating tablet of this invention may be 1 to several times a day, for example, Preferably, it may be 3 times a day.
また、本発明の一実施形態において、金属系の医薬有効成分または薬学的に許容されるその塩を含む口腔内崩壊錠において、前記口腔内崩壊錠の崩壊性を改善する、および／または前記口腔内崩壊錠の製造工程における打錠障害を改善する方法であり、前記口腔内崩壊錠に外部滑沢法により滑沢剤を含ませることを特徴とする、方法を提供する。 In one embodiment of the present invention, an orally disintegrating tablet comprising a metal-based pharmaceutically active ingredient or a pharmaceutically acceptable salt thereof improves the disintegration property of the orally disintegrating tablet, and / or the oral cavity. There is provided a method for improving a tableting trouble in a production process of an internally disintegrating tablet, wherein a lubricant is contained in the orally disintegrating tablet by an external lubricant method.
〔２．製造方法〕
本発明の一実施形態に係る口腔内崩壊錠の製造方法（以下、「本発明の製造方法」と称する。）は、前記１．に記載の口腔内崩壊錠を製造する方法であり、滑沢剤が外部滑沢法により添加される工程を含む、方法である。
[2. Production method〕
The method for producing an orally disintegrating tablet according to an embodiment of the present invention (hereinafter referred to as “the production method of the present invention”) is as described in 1. It is a method of manufacturing the orally disintegrating tablet as described in above, and including the process in which a lubricant is added by the external lubrication method.
本発明の製造方法は、外部滑沢法により滑沢剤を添加する工程を含んでいれば、その他の工程は特に限定されない。前記その他の工程としては、従来公知の任意の方法が使用され得る。 If the manufacturing method of this invention includes the process of adding a lubricant by the external lubrication method, other processes will not be specifically limited. As the other steps, any conventionally known method can be used.
本発明の一実施形態において、外部滑沢法による滑沢剤の添加工程は、前記１．に記載の外部滑沢法による添加工程であり得る。 In one embodiment of the present invention, the step of adding a lubricant by an external lubricant method includes the steps described in 1. The addition step by the external lubrication method described in the above.
また、本発明の口腔内崩壊錠は、前記本発明の製造方法により製造された口腔内崩壊錠であり得る。 The orally disintegrating tablet of the present invention may be an orally disintegrating tablet produced by the production method of the present invention.
本発明は上述した各実施形態に限定されるものではなく、請求項に示した範囲で種々の変更が可能であり、異なる実施形態にそれぞれ開示された技術的手段を適宜組み合わせて得られる実施形態についても本発明の技術的範囲に含まれる。 The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope shown in the claims, and embodiments obtained by appropriately combining technical means disclosed in different embodiments. Is also included in the technical scope of the present invention.
本発明の一実施例について以下に説明する。 One embodiment of the present invention will be described below.
［測定および評価方法］
実施例および比較例における各評価を、以下の方法で行った。
[Measurement and evaluation method]
Each evaluation in an Example and a comparative example was performed with the following method.
（１．杵／杵臼の状態の評価）
杵１本あたり２００錠の打錠を行った。杵の状態の評価では、打錠後に、杵の表面を目視にて観察した。評価は、上杵および下杵の各々について行った。打錠前と比較して、杵が曇ったり、杵への錠剤の付着が認められたりした場合を「×」と評価した。一方、打錠前後で変化がない場合を「○」と評価した。また、杵臼の状態の評価では、上杵、下杵および臼について評価を行った。打錠前と比較して、杵が曇ったり、杵臼への錠剤の付着が認められたりした場合を「×」と評価した。一方、打錠前後で変化がない場合を「○」と評価した。
(1. Evaluation of the state of heel / rear)
200 tablets were punched per bottle. In the evaluation of the state of the heel, the surface of the heel was visually observed after tableting. Evaluation was performed for each of the upper and lower eyelids. The case where the wrinkles were clouded or the tablets were attached to the wrinkles was evaluated as “x” as compared with before tableting. On the other hand, the case where there was no change before and after tableting was evaluated as “◯”. In the evaluation of the state of the mortar, the upper heel, lower heel and mortar were evaluated. The case where the wrinkles were clouded or the tablets were attached to the mortar was evaluated as “x” compared to before tableting. On the other hand, the case where there was no change before and after tableting was evaluated as “◯”.
（２．錠剤の状態の評価）
杵１本あたり２００錠の打錠を行った。打錠後に、錠剤表面を目視にて観察した。評価は、錠剤上面および錠剤下面の各々について行った。また、比較例６、７および実施例６、７では、前記に加えて、錠剤の帯についても評価を行った。錠剤表面または錠剤の帯に光沢がない場合を「×」と評価した。一方、錠剤表面または錠剤の帯に光沢がある場合を「○」と評価した。なお、本評価は、（１．杵の状態の評価）と同様、定性的なスティッキングの評価である。スティッキングが発生すると、錠剤表面の粉が杵に付着することで、反対に錠剤の表面の光沢がなくなるため、本評価により、スティッキングの有無を評価できる。
(2. Evaluation of tablet condition)
200 tablets were punched per bottle. After tableting, the tablet surface was visually observed. Evaluation was performed for each of the upper surface and the lower surface of the tablet. Further, in Comparative Examples 6 and 7 and Examples 6 and 7, in addition to the above, evaluation was also performed for the band of tablets. A case where the tablet surface or tablet band was not glossy was evaluated as “x”. On the other hand, the case where the tablet surface or tablet band was glossy was evaluated as “◯”. This evaluation is a qualitative sticking evaluation as in (1. Evaluation of the state of wrinkles). When sticking occurs, the powder on the surface of the tablet adheres to the wrinkles, and on the contrary, the gloss of the surface of the tablet disappears. Therefore, the presence or absence of sticking can be evaluated by this evaluation.
（３．錠剤硬度）
錠剤硬度計ＴＢＨ４２５（ERWEKA社製）を用いて、錠剤硬度を測定した。錠剤硬度の測定は、製造直後、２５℃／相対湿度７５％／室温で５日間保管後、４０℃／相対湿度７５％／室温で５日間保管後、および６０℃（湿度および温度は制御なし）で５日間保管後について行った。硬度の測定は、Ｎ＝３で行い、その平均値を錠剤硬度とした。
(3. Tablet hardness)
Tablet hardness was measured using a tablet hardness meter TBH425 (manufactured by ERWEKA). Tablet hardness is measured immediately after production, after storage for 5 days at 25 ° C./75% relative humidity / room temperature, after storage for 5 days at 40 ° C./75% relative humidity / room temperature, and 60 ° C. (humidity and temperature are not controlled) And after storage for 5 days. The hardness was measured at N = 3, and the average value was defined as tablet hardness.
（４．崩壊試験）
第１６改正日本薬局方に記載されている崩壊試験法にしたがい試験を行った。試験液として水を用いた場合の崩壊時間（秒）を測定することにより、錠剤の崩壊性を評価した。崩壊時間の測定は、製造直後、２５℃／相対湿度７５％／室温で５日間保管後、４０℃／相対湿度７５％／室温で５日間保管後、および６０℃（湿度および温度は制御なし）で５日間保管後について行った。崩壊試験は、Ｎ＝３で行い、その平均値を崩壊時間とした。
(4. Disintegration test)
The test was conducted according to the disintegration test method described in the 16th revision Japanese Pharmacopoeia. The disintegration property of the tablet was evaluated by measuring the disintegration time (seconds) when water was used as the test solution. Disintegration time was measured immediately after production, after storage for 5 days at 25 ° C./75% relative humidity / room temperature, after storage for 5 days at 40 ° C./75% relative humidity / room temperature, and 60 ° C. (humidity and temperature are not controlled) And after storage for 5 days. The disintegration test was performed at N = 3, and the average value was defined as the disintegration time.
［比較例１］
炭酸ランタン８水和物、クロスポビドン、トウモロコシデンプンおよびアスパルテームを、表１に記載の量で袋内に投入し、混合した。続いて、前記袋内にステアリン酸マグネシウムを、表１に記載の量で投入し、混合した。その後、直径１０ｍｍの杵に前記混合物（打錠用混合物）を投入し、ロータリー式打錠機（ＶＩＲＧＯ、菊水製作所社製）を用いて、１２ｋＮの打錠圧で打錠を行い、錠剤を得た。なお、表１中、比較例１の「微量」は、０．１質量％以下の量を、内部滑沢法で添加したことを示す。すなわち、前記打錠用混合物中に、０．１質量％以下の量のステアリン酸マグネシウムが含まれていることを示す。
[Comparative Example 1]
Lanthanum carbonate octahydrate, crospovidone, corn starch and aspartame were charged into the bags in the amounts shown in Table 1 and mixed. Subsequently, magnesium stearate was added in the amount shown in Table 1 and mixed in the bag. Thereafter, the mixture (mixture for tableting) is put into a punch having a diameter of 10 mm, and tableting is performed using a rotary tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 12 kN. It was. In Table 1, “trace amount” in Comparative Example 1 indicates that an amount of 0.1% by mass or less was added by the internal lubrication method. That is, it shows that 0.1 mass% or less of magnesium stearate is contained in the tableting mixture.
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表２に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 2.
［比較例２］
ステアリン酸マグネシウムの量を「５．９ｍｇ」に変更し、トウモロコシデンプンの量を「３．５４ｍｇ」に変更した以外は、比較例１と同様の方法により、錠剤を得た。
[Comparative Example 2]
A tablet was obtained in the same manner as in Comparative Example 1 except that the amount of magnesium stearate was changed to “5.9 mg” and the amount of corn starch was changed to “3.54 mg”.
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表２に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 2.
［比較例３］
クロスポビドンをデンプングリコール酸ナトリウムに変更した以外は、比較例２と同様の方法により、錠剤を得た。
[Comparative Example 3]
A tablet was obtained in the same manner as in Comparative Example 2 except that crospovidone was changed to sodium starch glycolate.
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表２に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 2.
［実施例１］
炭酸ランタン８水和物、クロスポビドン、トウモロコシデンプンおよびアスパルテームを、表１に記載の量で袋内に投入し、混合した。その後、直径１０ｍｍの杵に前記混合物（打錠用混合物）を投入し、ロータリー式打錠機を用いて、微量のステアリン酸マグネシウムを噴霧しながら、１２ｋＮの打錠圧で打錠を行い、錠剤を得た。なお、表１中、実施例１の「微量」は、０．１質量％以下の量を、外部滑沢法で添加したこと（杵に噴霧したこと）を示す。以下、実施例２〜４において同様である。
[Example 1]
Lanthanum carbonate octahydrate, crospovidone, corn starch and aspartame were charged into the bags in the amounts shown in Table 1 and mixed. Thereafter, the mixture (mixing for tableting) is put into a punch having a diameter of 10 mm, and tableting is performed at a tableting pressure of 12 kN while spraying a small amount of magnesium stearate using a rotary tableting machine. Got. In Table 1, “trace amount” of Example 1 indicates that an amount of 0.1% by mass or less was added by the external lubrication method (sprayed on the candy). The same applies to Examples 2 to 4 below.
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表２に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 2.
［実施例２］
クロスポビドンを低置換度ヒドロキシプロピルセルロースに変更した以外は、実施例１と同様の方法により、錠剤を得た。
[Example 2]
A tablet was obtained in the same manner as in Example 1 except that crospovidone was changed to low-substituted hydroxypropylcellulose.
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表２に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 2.
［実施例３］
クロスポビドンをデンプングリコール酸ナトリウムに変更した以外は、実施例１と同様の方法により、錠剤を得た。
[Example 3]
A tablet was obtained in the same manner as in Example 1 except that crospovidone was changed to sodium starch glycolate.
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表２に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 2.
［実施例４］
クロスポビドンをクロスカルメロースナトリウムに変更した以外は、実施例１と同様の方法により、錠剤を得た。
[Example 4]
Tablets were obtained in the same manner as in Example 1 except that crospovidone was changed to croscarmellose sodium.
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表２に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 2.
［参考例１］
クロスカルメロースナトリウム３３．０ｍｇおよびタルク５．９ｍｇを加え、ステアリン酸マグネシウムの量を「１．１８ｍｇ」に変更した以外は、比較例１と同様の方法により、錠剤を得た。
[Reference Example 1]
A tablet was obtained in the same manner as in Comparative Example 1, except that 33.0 mg of croscarmellose sodium and 5.9 mg of talc were added and the amount of magnesium stearate was changed to “1.18 mg”.
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表２に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 2.
［結果］
内部滑沢法により微量のステアリン酸マグネシウムを添加した比較例１では、下杵への打錠用混合物の付着が見られた。また、錠剤表面には光沢が見られなかった。これらの結果より、比較例１では、打錠障害が生じていることが分かった。
[result]
In Comparative Example 1 in which a small amount of magnesium stearate was added by the internal lubrication method, adhesion of the tableting mixture to the lower punch was observed. Further, no gloss was seen on the tablet surface. From these results, it was found that a tableting failure occurred in Comparative Example 1.
また、内部滑沢法により１質量％のステアリン酸マグネシウムを添加した比較例２では、打錠障害は見られなかったものの、得られた錠剤の崩壊性に問題が生じた。 Further, in Comparative Example 2 in which 1% by mass of magnesium stearate was added by the internal lubrication method, a tableting failure was not observed, but a problem occurred in the disintegration property of the obtained tablet.
一方、外部滑沢法によりステアリン酸マグネシウムを添加した実施例１〜４では、打錠障害を生じることなく、かつ、速やかな崩壊性を示した。さらに、錠剤の硬度も、従来品（比較例）と比較して、同程度もしくは優れた硬度を示した。 On the other hand, in Examples 1 to 4 to which magnesium stearate was added by the external lubrication method, a tableting failure was not caused and rapid disintegration was shown. Furthermore, the hardness of the tablet was comparable or superior to that of the conventional product (comparative example).
また、特許文献２に記載の錠剤について評価を行ったところ、打錠障害が生じており、かつ、安定性試験後の崩壊性においても崩壊遅延が生じるか、またはそもそも崩壊しないことが分かった（参考例１）。さらに、比較例２および参考例２の結果より、内部滑沢法によりステアリン酸マグネシウムを添加した場合には、崩壊剤の種類に関係なく、安定性試験後の崩壊遅延が生じることが分かった。 Moreover, when the tablet of patent document 2 was evaluated, it turned out that the tableting trouble has arisen, and disintegration delay also occurs in disintegration after a stability test, or it does not disintegrate in the first place ( Reference example 1). Furthermore, from the results of Comparative Example 2 and Reference Example 2, it was found that when magnesium stearate was added by the internal lubrication method, disintegration delay after the stability test occurred regardless of the type of disintegrant.
［比較例４］
炭酸ランタン４水和物、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およびアスパルテームを、表３に記載の量で袋内に投入し、混合した。続いて、前記袋内にステアリン酸マグネシウムを、表３に記載の量で投入し、混合した。その後、直径１２ｍｍの杵に前記混合物（打錠用混合物）を投入し、ロータリー式打錠機（ＶＥＬＡ、菊水製作所社製）を用いて、２０ｋＮの打錠圧で打錠を行い、錠剤を得た。なお、表３中、比較例４の「微量」は、０．１質量％以下の量を、内部滑沢法で添加したことを示す。すなわち、前記打錠用混合物中に、０．１質量％以下の量のステアリン酸マグネシウムが含まれていることを示す。
[Comparative Example 4]
Lanthanum carbonate tetrahydrate, crospovidone, low-substituted hydroxypropylcellulose and aspartame were charged into the bag in the amounts shown in Table 3 and mixed. Subsequently, magnesium stearate was added in the amount shown in Table 3 and mixed in the bag. Thereafter, the mixture (mixing for tableting) is put into a 12 mm diameter punch, and tableting is performed using a rotary tableting machine (VELA, manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 20 kN. It was. In Table 3, “trace amount” in Comparative Example 4 indicates that an amount of 0.1% by mass or less was added by the internal lubrication method. That is, it shows that 0.1 mass% or less of magnesium stearate is contained in the tableting mixture.
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表４に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 4.
［比較例５］
低置換度ヒドロキシプロピルセルロースの量を「１４．０ｍｇ」に変更し、ステアリン酸マグネシウムの量を「１０．０ｍｇ」に変更した以外は、比較例４と同様の方法により、錠剤を得た。
[Comparative Example 5]
Tablets were obtained in the same manner as in Comparative Example 4, except that the amount of low-substituted hydroxypropylcellulose was changed to “14.0 mg” and the amount of magnesium stearate was changed to “10.0 mg”.
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表３に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 3.
［実施例５］
炭酸ランタン４水和物、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およびアスパルテームを、表３に記載の量で袋内に投入し、混合した。その後、直径１２ｍｍの杵に前記混合物（打錠用混合物）を投入し、ロータリー式打錠機を用いて、微量のステアリン酸マグネシウムを噴霧しながら、２０ｋＮの打錠圧で打錠を行い、錠剤を得た。なお、表３中、実施例５の「微量」は、０．１質量％以下の量を、外部滑沢法で添加したこと（杵に噴霧したこと）を示す。
[Example 5]
Lanthanum carbonate tetrahydrate, crospovidone, low-substituted hydroxypropylcellulose and aspartame were charged into the bag in the amounts shown in Table 3 and mixed. Thereafter, the mixture (mixing for tableting) is put into a 12 mm diameter punch, and tableting is performed at a tableting pressure of 20 kN while spraying a small amount of magnesium stearate using a rotary tableting machine. Got. In Table 3, “trace amount” of Example 5 indicates that an amount of 0.1% by mass or less was added by the external lubrication method (sprayed on the soot).
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表４に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 4.
［結果］
比較例４および５と、実施例５との比較により、炭酸ランタンの４水和物を用いた場合も、炭酸ランタンの８水和物を用いた場合（実施例１〜４）と同様に、外部滑沢法により、打錠障害を生じることなく、かつ、速やかな崩壊性を示した。さらに、錠剤の硬度も、従来品（比較例）と比較して、同程度もしくは優れた硬度を示した。
[result]
Comparison between Comparative Examples 4 and 5 and Example 5 shows that when lanthanum carbonate tetrahydrate is used, as well as when lanthanum carbonate octahydrate is used (Examples 1 to 4), The external lubrication method showed rapid disintegration without causing tableting problems. Furthermore, the hardness of the tablet was comparable or superior to that of the conventional product (comparative example).
［比較例６］
クエン酸第二鉄、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およびアスパルテームを、表５に記載の量で袋内に投入し、混合した。続いて、前記袋内にステアリン酸マグネシウムを、表５に記載の量で投入し、混合した。その後、直径８．５ｍｍの杵に前記混合物（打錠用混合物）を投入し、ロータリー式打錠機（ＶＥＬＡ、菊水製作所社製）を用いて、１２ｋＮの打錠圧で打錠を行い、錠剤を得た。なお、表５中、比較例６の「微量」は、０．１質量％以下の量を、内部滑沢法で添加したことを示す。すなわち、前記打錠用混合物中に、０．１質量％以下の量のステアリン酸マグネシウムが含まれていることを示す。
[Comparative Example 6]
Ferric citrate, crospovidone, low-substituted hydroxypropylcellulose and aspartame were charged into the bag in the amounts shown in Table 5 and mixed. Subsequently, magnesium stearate was added in the amount shown in Table 5 and mixed in the bag. Thereafter, the mixture (mixture for tableting) is put into a punch having a diameter of 8.5 mm, and tableting is performed with a tableting pressure of 12 kN using a rotary tableting machine (VELA, manufactured by Kikusui Seisakusho). Got. In Table 5, “trace amount” in Comparative Example 6 indicates that an amount of 0.1% by mass or less was added by the internal lubrication method. That is, it shows that 0.1 mass% or less of magnesium stearate is contained in the tableting mixture.
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表６に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 6.
［比較例７］
低置換度ヒドロキシプロピルセルロースの量を「２．３５ｍｇ」に変更し、ステアリン酸マグネシウムの量を「５．０２ｍｇ」に変更した以外は、比較例６と同様の方法により、錠剤を得た。
[Comparative Example 7]
A tablet was obtained in the same manner as in Comparative Example 6, except that the amount of low-substituted hydroxypropylcellulose was changed to “2.35 mg” and the amount of magnesium stearate was changed to “5.02 mg”.
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表６に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 6.
［実施例６］
クエン酸第二鉄、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およびアスパルテームを、表５に記載の量で袋内に投入し、混合した。その後、直径８．５ｍｍの杵に前記混合物（打錠用混合物）を投入し、ロータリー式打錠機を用いて、微量のステアリン酸マグネシウムを噴霧しながら、６．５ｋＮの打錠圧で打錠を行い、錠剤を得た。なお、表５中、実施例６の「微量」は、０．１質量％以下の量を、外部滑沢法で添加したこと（杵に噴霧したこと）を示す。
[Example 6]
Ferric citrate, crospovidone, low-substituted hydroxypropylcellulose and aspartame were charged into the bag in the amounts shown in Table 5 and mixed. Then, the mixture (mixing for tableting) is put into a 8.5 mm diameter punch and tableted with a tableting pressure of 6.5 kN while spraying a small amount of magnesium stearate using a rotary tableting machine. To obtain tablets. In Table 5, “trace amount” in Example 6 indicates that an amount of 0.1% by mass or less was added by the external lubrication method (sprayed on the soot).
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表６に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 6.
［実施例７］
クエン酸第二鉄の量を「１３９．５４ｍｇ」に変更し、トウモロコシデンプン２０．１６ｍｇを加えた以外は、実施例６と同様の方法により、錠剤を得た。
[Example 7]
A tablet was obtained in the same manner as in Example 6 except that the amount of ferric citrate was changed to “139.54 mg” and 20.16 mg of corn starch was added.
得られた錠剤について、前記の評価方法に基づき、杵の状態、錠剤の状態、錠剤硬度および崩壊性を評価した。結果を表６に示す。 About the obtained tablet, based on the said evaluation method, the state of a wrinkle, the state of a tablet, tablet hardness, and disintegration were evaluated. The results are shown in Table 6.
［結果］
比較例６および７と、実施例６との比較により、クエン酸第二鉄を用いた場合も、炭酸ランタンを用いた場合（実施例１〜５）と同様に、外部滑沢法により、打錠障害を生じることなく、かつ、速やかな崩壊性を示した。さらに、錠剤の硬度も、従来品（比較例）と比較して、同程度もしくは優れた硬度を示した。
[result]
Comparison between Comparative Examples 6 and 7 and Example 6 shows that when ferric citrate is used, as in the case of using lanthanum carbonate (Examples 1 to 5), the external lubrication method is used. It showed rapid disintegration without causing a lock disorder. Furthermore, the hardness of the tablet was comparable or superior to that of the conventional product (comparative example).
また、実施例１〜７の結果より、錠剤に含まれる金属系の医薬有効成分の量に関係なく、上記の効果を奏することが分かった。 Moreover, it turned out that said effect is show | played from the result of Examples 1-7 irrespective of the quantity of the metal type pharmaceutical active ingredient contained in a tablet.
［処方例１］
炭酸ランタン４水和物、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、アスパルテームおよびステアリン酸マグネシウムを、表７に記載の量で袋内に投入し、混合する。その後、直径１２ｍｍの杵に前記混合物（打錠用混合物）を投入し、ロータリー式打錠機を用いて、微量のステアリン酸マグネシウムを噴霧しながら、２０ｋＮの打錠圧で打錠を行い、錠剤を得る。すなわち、表７で示す処方量により、錠剤を得る。
[Prescription Example 1]
Lanthanum carbonate tetrahydrate, crospovidone, low-substituted hydroxypropylcellulose, aspartame and magnesium stearate are charged into the bag in the amounts shown in Table 7 and mixed. Thereafter, the mixture (mixing for tableting) is put into a 12 mm diameter punch, and tableting is performed at a tableting pressure of 20 kN while spraying a small amount of magnesium stearate using a rotary tableting machine. Get. That is, tablets are obtained with the prescribed amounts shown in Table 7.
［処方例２］
炭酸ランタン４水和物、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、アスパルテームおよびステアリン酸マグネシウムの各量を、処方例１の各成分の２倍量とした以外は、処方例１と同様の方法により、錠剤を得る。すなわち、表７で示す処方量により、錠剤を得る。
[Prescription Example 2]
By the same method as in Formulation Example 1 except that each amount of lanthanum carbonate tetrahydrate, crospovidone, low-substituted hydroxypropylcellulose, aspartame and magnesium stearate was doubled from each component of Formulation Example 1. Get tablets. That is, tablets are obtained with the prescribed amounts shown in Table 7.
［処方例３］
低置換度ヒドロキシプロピルセルロースのグレードをＮＢＤ−０２２に変更した以外は、実施例５と同様の方法により、錠剤を得る。すなわち、表７で示す処方量により、錠剤を得る。なお、表７中、処方例３の「微量」は、０．１質量％以下の量を、外部滑沢法で添加したこと（杵に噴霧したこと）を示す。
[Prescription Example 3]
A tablet is obtained in the same manner as in Example 5 except that the grade of low-substituted hydroxypropylcellulose is changed to NBD-022. That is, tablets are obtained with the prescribed amounts shown in Table 7. In Table 7, “Trace” in Formulation Example 3 indicates that an amount of 0.1% by mass or less was added by the external lubrication method (sprayed on the candy).
［処方例４］
低置換度ヒドロキシプロピルセルロースの量を「適量（４７１．４５ｍｇ）」に変更し、アスパルテームの量を「１４．４ｍｇ」に変更し、ステアリン酸マグネシウムの量を「０．１５ｍｇ」に変更し、クロスポビドンを加えないこと以外は、処方例３と同様の方法により、錠剤を得る。すなわち、表７で示す処方量により、錠剤を得る。得られる錠剤の錠剤径は、１４ｍｍである。なお、表７中、処方例４の「微量」は、０．１質量％以下の量（具体的には、０．０１質量％（０．１５ｍｇ））を、外部滑沢法で添加したこと（杵に噴霧したこと）を示す。
[Prescription Example 4]
Change the amount of low-substituted hydroxypropyl cellulose to “appropriate amount (471.45 mg)”, change the amount of aspartame to “14.4 mg”, change the amount of magnesium stearate to “0.15 mg”, and cross A tablet is obtained by the same method as in Formulation Example 3 except that povidone is not added. That is, tablets are obtained with the prescribed amounts shown in Table 7. The tablet diameter of the obtained tablet is 14 mm. In Table 7, the “trace amount” in Formulation Example 4 is an amount of 0.1% by mass or less (specifically, 0.01% by mass (0.15 mg)) added by the external lubrication method. (It was sprayed on the eyelids).
［処方例５］
低置換度ヒドロキシプロピルセルロースの量を「適量（２９３．２７ｍｇ）」に変更し、アスパルテームの量を「１２．６ｍｇ」に変更し、ステアリン酸マグネシウムの量を「０．１３ｍｇ」に変更し、クロスポビドンを加えないこと以外は、処方例３と同様の方法により、錠剤を得る。すなわち、表７で示す処方量により、錠剤を得る。得られる錠剤の錠剤径は、１３ｍｍである。なお、表７中、処方例５の「微量」は、０．１質量％以下の量（具体的には、０．０１質量％（０．１３ｍｇ））を、外部滑沢法で添加したこと（杵に噴霧したこと）を示す。
[Prescription Example 5]
Change the amount of low-substituted hydroxypropyl cellulose to “appropriate amount (293.27 mg)”, change the amount of aspartame to “12.6 mg”, change the amount of magnesium stearate to “0.13 mg”, A tablet is obtained by the same method as in Formulation Example 3 except that povidone is not added. That is, tablets are obtained with the prescribed amounts shown in Table 7. The tablet diameter of the obtained tablet is 13 mm. In Table 7, the “trace amount” of Formulation Example 5 is an amount of 0.1% by mass or less (specifically, 0.01% by mass (0.13 mg)) added by the external lubrication method. (It was sprayed on the eyelids).
本発明の一実施形態に係る口腔内崩壊錠は、製造性が改善され、かつ、速やかな崩壊性を有するため、金属系の医薬有効成分、例えば、炭酸ランタン等の新規製剤として好適に利用することができる。 The orally disintegrating tablet according to an embodiment of the present invention is preferably used as a novel pharmaceutical preparation of a metal-based pharmaceutical active ingredient, for example, lanthanum carbonate, because the productivity is improved and it has rapid disintegration. be able to.
Claims (8)
Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ ・・・（１）
（式中、ｘは、３〜９である。） The orally disintegrating tablet according to claim 3, wherein the lanthanum carbonate is a lanthanum carbonate hydrate represented by the following formula (1).
La 2 (CO 3 ) 3 · xH 2 O (1)
(In the formula, x is 3 to 9.)
前記口腔内崩壊錠に外部滑沢法により滑沢剤を含ませることを特徴とする、方法。 An orally disintegrating tablet containing a metal-based pharmaceutically active ingredient or a pharmaceutically acceptable salt thereof, improving disintegration property of the orally disintegrating tablet and / or tableting failure in the production process of the orally disintegrating tablet Is a way to improve
A method comprising incorporating a lubricant into the orally disintegrating tablet by an external lubricant method.
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| JP2023054786A (en) * | 2021-10-04 | 2023-04-14 | 備前化成株式会社 | Method for manufacturing food tablet |
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