JP2020132613A - Ramelteon-containing solid formulation - Google Patents
Ramelteon-containing solid formulation Download PDFInfo
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- JP2020132613A JP2020132613A JP2019034921A JP2019034921A JP2020132613A JP 2020132613 A JP2020132613 A JP 2020132613A JP 2019034921 A JP2019034921 A JP 2019034921A JP 2019034921 A JP2019034921 A JP 2019034921A JP 2020132613 A JP2020132613 A JP 2020132613A
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- JP
- Japan
- Prior art keywords
- ramelteon
- tablet
- present
- lubricant
- hydroxypropyl cellulose
- Prior art date
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- YLXDSYKOBKBWJQ-LBPRGKRZSA-N N-[2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e]benzofuran-8-yl]ethyl]propanamide Chemical compound C1=C2OCCC2=C2[C@H](CCNC(=O)CC)CCC2=C1 YLXDSYKOBKBWJQ-LBPRGKRZSA-N 0.000 title claims abstract description 23
- 229960001150 ramelteon Drugs 0.000 title claims abstract description 23
- 239000000203 mixture Substances 0.000 title description 7
- 238000009472 formulation Methods 0.000 title description 6
- 239000007787 solid Substances 0.000 title 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 14
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 14
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 14
- 239000000314 lubricant Substances 0.000 claims abstract description 11
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims abstract description 9
- 239000008116 calcium stearate Substances 0.000 claims abstract description 9
- 235000013539 calcium stearate Nutrition 0.000 claims abstract description 9
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims abstract description 6
- 239000011230 binding agent Substances 0.000 claims abstract description 5
- 238000010828 elution Methods 0.000 abstract description 8
- 239000003826 tablet Substances 0.000 description 39
- 238000004090 dissolution Methods 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 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 6
- 239000008101 lactose Substances 0.000 description 6
- 239000011248 coating agent Substances 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 239000008120 corn starch 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
- 229920002451 polyvinyl alcohol Polymers 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-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 3
- MCRNHLQVPJEMSQ-UHFFFAOYSA-N C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] Chemical compound C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] MCRNHLQVPJEMSQ-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 229960003943 hypromellose Drugs 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 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
- 239000004480 active ingredient Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 229920000578 graft copolymer Polymers 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 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
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 229940121723 Melatonin receptor agonist Drugs 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction 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
- 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 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 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 1
- 229960003438 aspartame Drugs 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- -1 etc.) Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 230000001939 inductive effect Effects 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
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- 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 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 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 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 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 1
- 238000004513 sizing Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 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
- 239000005720 sucrose Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、ラメルテオンを含有し、ばらつきがなく速やかな溶出性を示す錠剤に関する。 The present invention relates to tablets containing ramelteon and exhibiting rapid dissolution without variation.
ラメルテオンは難溶性の睡眠誘発作用を示すメラトニン受容体作動薬である。難溶性の有効成分は錠剤からの溶出挙動にばらつきを生じやすく、このばらつきは消化管からの有効成分の吸収に影響する。したがって、ばらつきがなく速やかな溶出性を示すラメルテオン含有錠剤の提供は、医薬品の有効性および安全性を保証する上でも極めて重要である。 Ramelteon is a melatonin receptor agonist that exhibits a poorly soluble sleep-inducing effect. The poorly soluble active ingredient tends to cause variations in the dissolution behavior from tablets, and this variation affects the absorption of the active ingredient from the digestive tract. Therefore, the provision of ramelteon-containing tablets that show uniform and rapid dissolution is extremely important for guaranteeing the efficacy and safety of pharmaceutical products.
この点を考慮したラメルテオンの錠剤が既に上市されている。特許文献１はこの上市錠剤関連の特許であり、ラメルテオン含有錠剤にステアリン酸マグネシウムおよび粘度２〜３．４ｍＰａ・ｓのヒドロキシプロピルセルロ−スを使用することの有用性が示されている。 Ramelteon tablets have already been put on the market in consideration of this point. Patent Document 1 is a patent related to this marketable tablet, and shows the usefulness of using magnesium stearate and hydroxypropyl cellulose having a viscosity of 2 to 3.4 mPa · s for a ramelteon-containing tablet.
しかしながら、ステアリン酸マグネシウムおよび粘度２〜３．４ｍＰａ・ｓのヒドロキシプロピルセルロ−スの組合わせ以外については、いかなる添加剤の組合わせがラメルテオン含有錠剤のばらつきを抑え、速やかな溶出性を発揮するか知られておらず、ラメルテオン含有錠剤の製造において、課題となっていた。 However, except for the combination of magnesium stearate and hydroxypropyl cellulose having a viscosity of 2 to 3.4 mPa · s, what kind of additive combination suppresses variation in ramelteon-containing tablets and exhibits rapid dissolution. It is unknown and has been a problem in the production of ramelteon-containing tablets.
本発明は、ラメルテオンを含有し、ばらつきがなく速やかな溶出性を示す錠剤に関する。 The present invention relates to tablets containing ramelteon and exhibiting rapid dissolution without variation.
本発明者らは、上記課題を解決するため鋭意検討したところ、驚くべきことに、ヒドロキシプロピルセルロースとフマル酸ステアリルナトリウムまたはステアリン酸カルシウムを組合わせることで、ばらつきがなく速やかな溶出性を示すことを見出し、本発明を完成した。 As a result of diligent studies to solve the above problems, the present inventors have surprisingly found that the combination of hydroxypropyl cellulose with stearyl sodium fumarate or calcium stearate exhibits consistent and rapid elution. The heading, the present invention was completed.
すなわち、本発明は＜１＞錠剤全体に対して３〜３０重量％のラメルテオン、結合剤としてヒドロキシプロピルセルロース、および滑沢剤としてフマル酸ステアリルナトリウムもしくはステアリン酸カルシウムを含有する錠剤を提供する。
＜２＞錠剤全体に対して０．５〜３重量％の滑沢剤を含有する前記＜１＞記載の錠剤を提供する。
＜３＞滑沢剤がフマル酸ステアリルナトリウムである前記＜１＞〜＜２＞記載の錠剤を提供する。
＜４＞滑沢剤がステアリン酸カルシウムである前記＜１＞〜＜２＞記載の錠剤を提供する。That is, the present invention provides a tablet containing 3 to 30% by weight of ramelteon, hydroxypropyl cellulose as a binder, and sodium stearyl fumarate or calcium stearate as a lubricant with respect to the entire <1> tablet.
<2> The tablet according to <1> above, which contains 0.5 to 3% by weight of a lubricant with respect to the entire tablet, is provided.
<3> The tablets according to <1> to <2> above, wherein the lubricant is sodium stearyl fumarate.
<4> The tablets according to <1> to <2> above, wherein the lubricant is calcium stearate.
本発明によれば、ラメルテオンのばらつきが抑制された、ラメルテロン含有錠剤が提供される。 According to the present invention, there is provided a ramelteon-containing tablet in which the variation of ramelteon is suppressed.
本発明において、ラメルテオン（Ｎ−｛２−［（８Ｓ）−１，６，７，８−Ｔｅｔｒａｈｙｄｒｏ−２Ｈ−ｉｎｄｅｎｏ［５，４−ｂ］ｆｕｒａｎ−８−ｙｌ］ｅｔｈｙｌ｝ｐｒｏｐａｎａｍｉｄｅ）は、以下の化学式により表される化合物である。ラメルテオンは、例えば、特許第２８８４１５３号公報に記載の方法によって製造されうる。また、ラメルテオンの含有量は、１錠剤あたり１〜２０重量％が好ましく、５〜１０重量％がより好ましい。
本発明において、ヒドロキシプロピルセルロ−スは、当技術分野で用いられているものであれば何でもよい。 In the present invention, the hydroxypropyl cellulose may be anything as used in the art.
本発明において、滑沢剤とは、フマル酸ステアリルナトリウム、ステアリン酸カルシウムを言う。また、フマル酸ステアリルナトリウム、ステアリン酸カルシウムは、当技術分野で用いられているものであれば何でもよい。含有量は、１錠剤当たり０．５〜３重量％が好ましい。 In the present invention, the lubricant refers to stearyl sodium fumarate and calcium stearate. Further, the stearyl sodium fumarate and calcium stearate may be anything as long as they are used in the art. The content is preferably 0.5 to 3% by weight per tablet.
本発において、錠剤とは、素錠、コーティング錠、口腔内崩壊錠の形態をとりうる。また、コーティング錠は、素錠をコーティング剤で被覆したものをいう。 In the present invention, the tablet may take the form of an uncoated tablet, a coated tablet, or an orally disintegrating tablet. Further, the coated tablet refers to an uncoated tablet coated with a coating agent.
本発明において、コーティング剤とは、例えば、ヒプロメロース、ヒドロキシプロピルセルロース、プロピレングリコール、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、ポリビニルピロリドン、ポリビニルアルコール、ポリビニルアルコールアクリル酸メタクリル酸メチル共重合体およびポリエチレングリコールなどが挙げられるが、ラメルテオンの安定性の観点から、ヒプロメロース、ヒドロキシプロピルセルロース、プロピレングリコール、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が好ましく、ヒプロメロース、プロピレングリコールがより好ましい。 In the present invention, examples of the coating agent include hypromellose, hydroxypropyl cellulose, propylene glycol, polyvinyl alcohol polyethylene glycol graft copolymer, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol methyl methacrylate copolymer and polyethylene glycol. However, from the viewpoint of the stability of lamerteon, hypromerose, hydroxypropyl cellulose, propylene glycol, polyvinyl alcohol polyethylene glycol graft copolymer is preferable, and hypromerose and propylene glycol are more preferable.
本発明において、遮光剤とは、例えば、酸化チタン、黄色三二酸化鉄、三二酸化鉄、黒酸化鉄、食用黄色５号、食用赤色１０２号が挙げられ、酸化チタン、黄色三二酸化鉄が好ましい。 In the present invention, examples of the light-shielding agent include titanium oxide, yellow iron sesquioxide, iron sesquioxide, black iron oxide, edible yellow No. 5 and edible red No. 102, and titanium oxide and yellow iron sesquioxide are preferable.
本発明において、添加剤とは、賦形剤、結合剤、崩壊剤を言うが、特にこれらに制限されない。当該添加剤以外に、当技術分野で用いられる着色剤、抗酸化剤、増粘剤、緩衝化剤、甘味付与剤、フレーバー付与剤、又はパフューム剤などを本発明のフィルムコーティング錠剤に配合してもよい。甘味付与剤としては、アスパルテーム、アセスルファムカリウム、スクラロース、ステビア、マルチトール、グリセリン、ラクチトール、ガラクチトールなどが挙げられる。 In the present invention, the additive refers to an excipient, a binder, and a disintegrant, but is not particularly limited thereto. In addition to the additives, colorants, antioxidants, thickeners, buffers, sweetening agents, flavoring agents, perfumes and the like used in the art are blended into the film-coated tablets of the present invention. May be good. Examples of the sweetening agent include aspartame, acesulfame potassium, sucralose, stevia, maltitol, glycerin, lactitol, galactitol and the like.
本発明において、賦形剤とは、例えばＤ−マンニトール、乳糖（乳糖水和物、噴霧乾燥乳糖、流動層造粒乳糖、異性化乳糖、還元乳糖等）、トウモロコシデンプン、ショ糖、エリスリトール、ソルビトール、キシリトールなどが挙げられる。本発明においては、乳糖、トウモロコシデンプンが好ましい。 In the present invention, the excipient includes, for example, D-mannitol, lactose (lactose hydrate, spray-dried lactose, fluidized bed granulated lactose, isomerized lactose, reduced lactose, etc.), corn starch, sucrose, erythritol, sorbitol, etc. , Xylitol and the like. In the present invention, lactose and corn starch are preferable.
本発明において、崩壊剤とは、例えば、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、クロスポビドン、アルギン酸、部分アルファー化デンプン、ベントナイト等が挙げられる。 In the present invention, examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, low-degree-of-substitution hydroxypropyl cellulose, crospovidone, alginic acid, partially pregelatinized starch, bentonite and the like.
本発明の錠剤は、通常の錠剤製造方法により製造することが可能である。 The tablet of the present invention can be produced by a conventional tablet production method.
具体的には、本発明のラメルテオン含有錠剤は、例えば、ラメルテオンと賦形剤を混合し、結合剤を溶解した液を噴霧しながら、流動層造粒機で造粒後、ステンレス篩で整粒し、その整粒品に滑沢剤を混合後、打錠し、素錠を得えた後、その素錠に、被覆剤を噴霧することで、得られる。 Specifically, the ramelteon-containing tablet of the present invention is, for example, granulated with a fluidized bed granulator while spraying a solution prepared by mixing ramelteon and an excipient and dissolving a binder, and then sizing with a stainless sieve. Then, the granulated product is mixed with a lubricant, then tableted to obtain an uncoated tablet, and then the uncoated tablet is sprayed with a coating agent to obtain the uncoated tablet.
以下に、実施例等により本発明をさらに具体的に説明するが、本発明は下記の実施例等に何ら限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples and the like, but the present invention is not limited to the following Examples and the like.
ラメルテオン３２ｇ、乳糖水和物３８８ｇ、トウモロコシデンプン８０ｇを混合し、ヒドロキシプロピルセルロース（粘度２〜２．９ｍＰａ・ｓ）１６ｇを精製水２５０．７ｇに溶解した液を噴霧しながら流動層造粒機で造粒後、目開き８５０μｍのステンレス篩で整粒する。この整粒品１９３．５ｇにステアリン酸カルシウム１．５ｇを混合後、打錠する。さらに、ヒプロメロース１０４．７ｇ、ヒドロキシプロピルセルロース（粘度２〜２．９ｍＰａ・ｓ）２１ｇを精製水１３５０ｇに溶解した、酸化チタン１５ｇ、クラウンタルク９ｇ、黄色三二酸化鉄０．３ｇが分散された液を噴霧しながらフィルムコーティング機で一錠当たり５ｍｇのコーティングを行い本発明の錠剤を得た（１錠当たりの重量：１３５ｍｇ）。これを各３回行い、各３ロット（Ｌｏｔ Ｎｏ．ＪＧ１８０９−２−１、Ｌｏｔ Ｎｏ．ＪＧ１８０９−３−３、Ｌｏｔ Ｎｏ．ＪＧ１８０９−３−４）の錠剤を得た。 A fluidized bed granulator is used to mix 32 g of ramelteon, 388 g of lactose hydrate, and 80 g of corn starch, and spray a solution of 16 g of hydroxypropyl cellulose (viscosity 2 to 2.9 mPa · s) in 250.7 g of purified water. After granulation, the granules are sized with a stainless steel sieve having an opening of 850 μm. After mixing 1.5 g of calcium stearate with 193.5 g of this sized product, tableting is performed. Further, a solution prepared by dissolving 104.7 g of hypromellose and 21 g of hydroxypropyl cellulose (viscosity 2 to 2.9 mPa · s) in 1350 g of purified water and dispersing 15 g of titanium oxide, 9 g of crown talc, and 0.3 g of yellow iron sesquioxide. The tablet of the present invention was obtained by coating 5 mg per tablet with a film coating machine while spraying (weight per tablet: 135 mg). This was carried out 3 times each to obtain tablets of 3 lots each (Lot No. JG1809-2-1, Lot No. JG1809-3-3, Lot No. JG1809-3-4).
ラメルテオン３２ｇ、乳糖水和物３７６ｇ、トウモロコシデンプン８０ｇを混合し、ヒドロキシプロピルセルロース（粘度２〜２．９ｍＰａ・ｓ）１６ｇを精製水２５０．７ｇに溶解した液を噴霧しながら流動層造粒機で造粒後、目開き８５０μｍのステンレス篩で整粒する。この整粒品２５２ｇにフマル酸ステアリルナトリウム８ｇを混合後、打錠する。さらに、ヒプロメロース１０４．７ｇ、ヒドロキシプロピルセルロース（粘度２〜２．９ｍＰａ・ｓ）２１ｇを精製水１３５０ｇに溶解した、酸化チタン１５ｇ、クラウンタルク９ｇ、黄色三二酸化鉄０．３ｇが分散された液を噴霧しながらフィルムコーティング機で一錠当たり５ｍｇのコーティングを行い本発明の錠剤を得た（１錠当たりの重量：１３５ｍｇ）。これを各３回行い、各３ロット（Ｌｏｔ Ｎｏ．ＪＧ１８０９−１−１−１、Ｌｏｔ Ｎｏ．ＪＧ１８０９−３−１、Ｌｏｔ Ｎｏ．ＪＧ１８０９−３−２）の錠剤を得た。 A fluidized bed granulator is used to mix 32 g of ramelteon, 376 g of lactose hydrate, and 80 g of corn starch, and spray a solution of 16 g of hydroxypropyl cellulose (viscosity 2 to 2.9 mPa · s) in 250.7 g of purified water. After granulation, the granules are sized with a stainless steel sieve having an opening of 850 μm. After mixing 8 g of sodium stearyl fumarate with 252 g of this sized product, tableting is performed. Further, a solution prepared by dissolving 104.7 g of hypromellose and 21 g of hydroxypropyl cellulose (viscosity 2 to 2.9 mPa · s) in 1350 g of purified water and dispersing 15 g of titanium oxide, 9 g of crown talc, and 0.3 g of yellow iron sesquioxide. The tablet of the present invention was obtained by coating 5 mg per tablet with a film coating machine while spraying (weight per tablet: 135 mg). This was carried out 3 times each to obtain tablets of 3 lots each (Lot No. JG1809-1-1, Lot No. JG1809-3-1, Lot No. JG1809-3-2).
実施例１〜２の組成は表１の通り。 The compositions of Examples 1 and 2 are as shown in Table 1.
（試験例１）
実施例１（ＪＧ１８０９−２−１、ＪＧ１８０９−３−３、ＪＧ１８０９−３−４の３ロット）および実施例２（ＪＧ１８０９−１−１−１、ＪＧ１８０９−３−１、ＪＧ１８０９−３−２の３ロット）の錠剤からのラメルテオンの溶出性を溶出試験（水９００ｍＬ、３７℃、パドル法、回転数５０ｒｐｍ、ｎ＝６）により評価した。その結果を下記グラフに示す。また、表２および表３に、それぞれの類似因子の計算結果を示す。(Test Example 1)
Of Example 1 (3 lots of JG1809-2-1, JG1809-3-3, JG1809-3-4) and Example 2 (JG1809-1-1-1, JG1809-3-1, JG1809-3-2) The elution of ramelteon from tablets of 3 lots) was evaluated by an dissolution test (water 900 mL, 37 ° C., paddle method, rotation speed 50 rpm, n = 6). The results are shown in the graph below. In addition, Tables 2 and 3 show the calculation results of the respective similar factors.
溶出試験の結果、上記グラフに示す通り、実施例１〜２は、速やかな溶出性を示した。 As a result of the dissolution test, as shown in the graph above, Examples 1 and 2 showed rapid dissolution.
＜類似因子の計算方法＞
本明細書で溶出挙動の同等性の評価は、同一処方製剤の任意に選択した異なる２ロットにおける類似因子（ｆ２関数）において行う。この類似因子（ｆ２関数）の値が、１００に近づくほど２製剤の溶出挙動にばらつきが少ないとされ、５０以上のとき同等とされる。なお、類似因子（ｆ２関数）は，次式で表わされる．次式：
Equivalence of elution behavior is assessed herein with similar factors (f2 function) in two arbitrarily selected different lots of the same formulation. It is said that the closer the value of this similar factor (f2 function) is to 100, the less the variation in the dissolution behavior of the two preparations is, and when it is 50 or more, it is equivalent. The similar factor (f2 function) is expressed by the following equation. The following formula:
式中のＴｉおよびＲｉは各製剤の平均溶出率、ｎは平均溶出率を比較する時点の数である。溶出率比較時点とは、基準となる製剤が１５分〜３０分に平均８５％以上溶出する場合は、１５分、３０分、４５分とする。基準となる製剤が３０分以降、規定された試験時間以内に平均８５％以上溶出する場合は、基準となる製剤の平均溶出率が約８５％となる適当な時点をＴａとするとき、Ｔａ／４、２Ｔａ／４、３Ｔａ／４、Ｔａとする。規定された試験時間において基準となる製剤の平均溶出率が約８５％に達しない場合は、規定された試験時間における基準となる製剤の平均溶出率の約８５％となる適当な時点をＴａとするとき、Ｔａ／４、２Ｔａ／４、３Ｔａ／４、Ｔａとする。 Ti and Ri in the formula are the average elution rates of each preparation, and n is the number of time points for comparing the average elution rates. The elution rate comparison time point is 15 minutes, 30 minutes, and 45 minutes when the standard preparation elutes at an average of 85% or more in 15 to 30 minutes. If the standard formulation elutes at an average of 85% or more within the specified test time after 30 minutes, Ta / is the appropriate time point at which the average dissolution rate of the reference formulation becomes about 85%. Let it be 4, 2Ta / 4, 3Ta / 4, and Ta. If the average elution rate of the reference formulation does not reach about 85% in the specified test time, Ta is an appropriate time point when the average dissolution rate of the reference formulation in the specified test time is about 85%. When doing so, it is set to Ta / 4, 2Ta / 4, 3Ta / 4, Ta.
また、類似因子より、表２および表３に示す通り、実施例１〜２は、ロット間で溶出にばらつきの少ない錠剤であることが示された。 Further, from similar factors, as shown in Tables 2 and 3, it was shown that Examples 1 and 2 were tablets having little variation in dissolution between lots.
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| WO2009084023A2 (en) * | 2007-10-19 | 2009-07-09 | Glenmark Generics Limited | Amorphous ramelteon and process for the preparation thereof |
| JP2014528395A (en) * | 2011-10-14 | 2014-10-27 | 武田薬品工業株式会社 | Oral dispersible formulation |
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