JP2019006682A - Orally disintegrating tablet - Google Patents
Orally disintegrating tablet Download PDFInfo
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- JP2019006682A JP2019006682A JP2017120544A JP2017120544A JP2019006682A JP 2019006682 A JP2019006682 A JP 2019006682A JP 2017120544 A JP2017120544 A JP 2017120544A JP 2017120544 A JP2017120544 A JP 2017120544A JP 2019006682 A JP2019006682 A JP 2019006682A
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- orally disintegrating
- disintegrating tablet
- torasemide
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- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 44
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 29
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229960005461 torasemide Drugs 0.000 claims abstract description 25
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229960000913 crospovidone Drugs 0.000 claims abstract description 16
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims abstract description 16
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims abstract description 16
- 235000010355 mannitol Nutrition 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000002245 particle Substances 0.000 claims description 24
- 239000000314 lubricant Substances 0.000 claims description 14
- 239000001913 cellulose Substances 0.000 claims description 10
- 229920002678 cellulose Polymers 0.000 claims description 10
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical group CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 5
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 5
- 239000003826 tablet Substances 0.000 description 28
- 238000003860 storage Methods 0.000 description 14
- 238000000034 method Methods 0.000 description 9
- 239000000796 flavoring agent Substances 0.000 description 7
- 235000013355 food flavoring agent Nutrition 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 210000000214 mouth Anatomy 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000002171 loop diuretic Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 206010030113 Oedema Diseases 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
- 230000006835 compression Effects 0.000 description 3
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- 239000000203 mixture Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 108010011485 Aspartame Proteins 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 208000001647 Renal Insufficiency Diseases 0.000 description 2
- 239000004376 Sucralose Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
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- 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 2
- 229960003438 aspartame Drugs 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
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- 239000008123 high-intensity sweetener Substances 0.000 description 2
- 201000006370 kidney failure Diseases 0.000 description 2
- 238000005461 lubrication Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000013615 non-nutritive sweetener Nutrition 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 235000019408 sucralose Nutrition 0.000 description 2
- 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 2
- -1 sucrose fatty acid ester Chemical class 0.000 description 2
- 239000000892 thaumatin Substances 0.000 description 2
- 235000010436 thaumatin Nutrition 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- 208000009447 Cardiac Edema Diseases 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 240000000560 Citrus x paradisi Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 244000024873 Mentha crispa Species 0.000 description 1
- 235000014749 Mentha crispa Nutrition 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 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
- 238000012550 audit Methods 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
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
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- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000004321 preservation Methods 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
- 235000019204 saccharin Nutrition 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
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000003746 surface roughness Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、ループ系利尿薬含有口腔内崩壊錠に関する。 The present invention relates to a loop diuretic-containing orally disintegrating tablet.
トラセミド（Ｎ−（１−メチルエチルアミノカルボニル）−４−（３−メチルフェニルアミノ）−３−ピリジンスルホンアミド）はループ系利尿薬の一つであり、心不全、腎不全、肝機能低下等に伴う浮腫等の改善に効果を有する。トラセミドを含有する医薬としては、トラセミドを４ｍｇ又は８ｍｇ含有する錠剤が販売されている（非特許文献１）。そして、トラセミドの製剤技術としては、トラセミド、ヒドロキシプロピルセルロース及びクロスカルメロースナトリウムを含有する組成物（特許文献１）、トラセミドとシクロデキストリン又はシクロデキストリン誘導体とからなる物理的混合物（特許文献２）、トラセミドとマトリックス形成ポリマーを含む持続放出型組成物（特許文献３）が報告されている。 Torasemide (N- (1-methylethylaminocarbonyl) -4- (3-methylphenylamino) -3-pyridinesulfonamide) is one of the loop diuretics for heart failure, renal failure, liver function decline, etc. Effective in improving accompanying edema. As a medicine containing torasemide, tablets containing 4 mg or 8 mg of torasemide are on the market (Non-patent Document 1). And as a preparation technique of torasemide, a composition containing torasemide, hydroxypropylcellulose and croscarmellose sodium (Patent Document 1), a physical mixture comprising torasemide and cyclodextrin or a cyclodextrin derivative (Patent Document 2), A sustained release composition containing torasemide and a matrix-forming polymer has been reported (Patent Document 3).
心不全や腎不全の患者においては水分制限が課されている場合があり、少量の水又は水なしで服用が可能なループ系利尿薬を含有する口腔内崩壊錠が望まれている。
さらに近年、調剤を行う際に患者が複数の薬を服用する場合には、一包化による服薬アドヒアランス改善の取り組みがしばしば行われている。このため、薬剤がパッケージやＰＴＰシートから取り出されてから、患者が服用するまでの期間が長くなり、高温条件下などの薬剤の保存にとっては好ましくない条件下にさらされる可能性が高まっている。そのような条件下において、口腔内崩壊錠は、崩壊時間に変化が生じることで口腔内崩壊錠の特性が失われるおそれがあり、また錠剤表面に外観変化が生じることで錠剤表面に施した印字の識別性が低下するおそれがある。
また、近年、製品名をカタカナで錠剤に表示する製品が増加しており、医師、薬剤師など医療関係者の８割以上が鑑別・監査のしやすさ、製品名がひと目でわかる等の理由から錠剤への製品名や含量表示を希望しているとの報告もある。
従って、本発明の課題は、高温条件下又は加湿度条件下で保存しても、崩壊性が変化しないトラセミドを含有する口腔内崩壊錠、さらには、崩壊性が変化せず、かつ経時的な外観の変化がほとんど認められないトラセミドを含有する口腔内崩壊錠を提供することである。
In patients with heart failure or renal failure, water restriction may be imposed, and an orally disintegrating tablet containing a loop diuretic that can be taken with a small amount of water or without water is desired.
Furthermore, in recent years, when a patient takes a plurality of medicines at the time of dispensing, efforts have been often made to improve medication adherence by packaging. For this reason, the period from when the drug is taken out from the package or PTP sheet until the patient takes it becomes longer, and there is an increased possibility of being exposed to conditions unfavorable for storage of the drug such as high temperature conditions. Under such conditions, orally disintegrating tablets may lose the properties of orally disintegrating tablets due to changes in disintegration time, and printing applied to the tablet surface due to appearance changes on the tablet surface. There is a risk that the discriminability of the will deteriorate.
In recent years, the number of products that display product names on tablets in katakana has increased, and more than 80% of medical personnel such as doctors and pharmacists can easily identify and audit, and the product names can be seen at a glance. There are reports that they wish to display the product name and content on tablets.
Therefore, an object of the present invention is to provide an orally disintegrating tablet containing torasemide that does not change disintegration even when stored under high temperature conditions or humidification conditions. It is to provide an orally disintegrating tablet containing torasemide that hardly changes in appearance.
そこで、本発明者らは、高温条件下又は加湿度条件下での保存後においても、崩壊性が変化しないトラセミドを含有する口腔内崩壊錠を開発すべく、鋭意検討を行った結果、添加物としてクロスポビドン、Ｄ−マンニトール、活性成分としてトラセミドを組み合わせることにより、高温条件下又は加湿度条件下での保存後においても、崩壊性が変化しない安定な口腔内崩壊錠が得られることを見出し、さらに特定のクロスポビドンを使用することにより、経時的な外観の変化がほとんど認められない口腔内崩壊錠が得られることを見出し、本発明を完成するに至った。 Therefore, the present inventors have conducted extensive studies to develop an orally disintegrating tablet containing torasemide that does not change disintegration even after storage under high temperature conditions or humidified conditions. As a combination of crospovidone, D-mannitol and torasemide as an active ingredient, it was found that a stable orally disintegrating tablet that does not change disintegration even after storage under high temperature conditions or humidified conditions can be obtained, Furthermore, by using a specific crospovidone, it was found that an orally disintegrating tablet with little change in appearance over time was obtained, and the present invention was completed.
すなわち、本発明は、次の〔１〕〜〔６〕を提供するものである。 That is, the present invention provides the following [1] to [6].
〔１〕（ａ）トラセミド又はその塩、（ｂ）クロスポビドン及び（ｃ）Ｄ−マンニトールを含有する口腔内崩壊錠。
〔２〕成分（ａ）を１〜１０質量％、成分（ｂ）を１〜２０質量％、成分（ｃ）を５０〜９５質量％含有する〔１〕記載の口腔内崩壊錠。
〔３〕（ｂ）クロスポビドンの平均粒子径が５〜１００μｍである〔１〕又は〔２〕記載の口腔内崩壊錠。
〔４〕さらに（ｄ）結晶セルロースを含有する〔１〕〜〔３〕のいずれかに記載の口腔内崩壊錠。
〔５〕さらに（ｅ）滑沢剤を含有する〔１〕〜〔４〕のいずれかに記載の口腔内崩壊錠。
〔６〕（ｅ）滑沢剤がフマル酸ステアリルナトリウムである〔５〕記載の口腔内崩壊錠。
[1] An orally disintegrating tablet containing (a) torasemide or a salt thereof, (b) crospovidone and (c) D-mannitol.
[2] The orally disintegrating tablet according to [1], comprising 1 to 10% by mass of component (a), 1 to 20% by mass of component (b), and 50 to 95% by mass of component (c).
[3] (b) The orally disintegrating tablet according to [1] or [2], wherein the average particle size of crospovidone is 5 to 100 μm.
[4] The orally disintegrating tablet according to any one of [1] to [3], further comprising (d) crystalline cellulose.
[5] The orally disintegrating tablet according to any one of [1] to [4], further comprising (e) a lubricant.
[6] The orally disintegrating tablet according to [5], wherein (e) the lubricant is sodium stearyl fumarate.
本発明により、高温条件下又は加湿度条件下での保存後においても、崩壊性に変化を生じないトラセミドを含有する口腔内崩壊錠を提供することができる。また、崩壊性が変化せず、かつ経時的な外観の変化がほとんど認められないトラセミドを含有する口腔内崩壊錠を提供することができる。 According to the present invention, an orally disintegrating tablet containing torasemide that does not change in disintegration even after storage under high temperature conditions or humidified conditions can be provided. In addition, an orally disintegrating tablet containing torasemide that does not change disintegration and hardly changes in appearance over time can be provided.
本発明の口腔内崩壊錠は、（ａ）トラセミド又はその塩、（ｂ）クロスポビドン及び（ｃ）Ｄ−マンニトールを含有する。 The orally disintegrating tablet of the present invention contains (a) torasemide or a salt thereof, (b) crospovidone, and (c) D-mannitol.
本発明に用いる（ａ）トラセミド又はその塩は、式（１） (A) Torasemide or a salt thereof used in the present invention has the formula (1)
で表されるＮ−（１−メチルエチルアミノカルボニル）−４−（３−メチルフェニルアミノ）−３−ピリジンスルホンアミド又はその薬学的に許容される塩である。ここで、トラセミドの塩としては、塩酸塩、硫酸塩等の酸付加塩が挙げられる。成分（ａ）としては、トラセミドが好ましい。トラセミド又はその塩は、ループ系利尿薬であり、心性浮腫、腎性浮腫及び肝性浮腫の治療薬としての有効成分である。 N- (1-methylethylaminocarbonyl) -4- (3-methylphenylamino) -3-pyridinesulfonamide or a pharmaceutically acceptable salt thereof. Here, examples of the salt of torasemide include acid addition salts such as hydrochloride and sulfate. As component (a), torasemide is preferred. Torasemide or a salt thereof is a loop diuretic and is an active ingredient as a therapeutic agent for cardiac edema, renal edema and hepatic edema.
本発明の口腔内崩壊錠においてトラセミドの含有量は特に限定されないが、良好な崩壊性の確保及び経時的な外観変化防止の観点から、口腔内崩壊錠に対して好ましくは１〜１０質量％が好ましく、より好ましくは２〜８質量％であり、さらに好ましくは３〜６質量％である。 The content of torasemide in the orally disintegrating tablet of the present invention is not particularly limited, but preferably 1 to 10% by mass with respect to the orally disintegrating tablet from the viewpoint of ensuring good disintegration and preventing change in appearance over time. More preferably, it is 2-8 mass%, More preferably, it is 3-6 mass%.
（ｂ）クロスポビドンは、１−ビニル−２−ピロリドンの架橋重合物である。本発明において、崩壊剤として作用する他、高温条件下又は加湿度条件下における崩壊性の維持に寄与する。
本発明で用いるクロスポビドンの平均粒子径の範囲は、加湿度条件下で保存した後の表面の荒れへの影響の観点から、好ましくは５〜２００μｍであり、より好ましくは５〜１００μｍであり、さらに好ましくは１０〜５０μｍである。また、クロスポビドンの粒子径が小さすぎると流動性の悪化により混合均一性が低下するおそれがある。なお、本明細書中の平均粒子径は、レーザー回折式粒度分布測定装置を用いて乾式法によって測定されたメディアン径（累積５０％粒子径）を表し，例えば、レーザー回折式粒度分布測定装置ＭＴ３２００（日機装社製）を使用して測定することができる。
(B) Crospovidone is a crosslinked polymer of 1-vinyl-2-pyrrolidone. In the present invention, in addition to acting as a disintegrant, it contributes to maintaining disintegration under high temperature conditions or humidification conditions.
The range of the average particle diameter of crospovidone used in the present invention is preferably 5 to 200 μm, more preferably 5 to 100 μm, from the viewpoint of the effect on surface roughness after storage under humidified conditions, More preferably, it is 10-50 micrometers. On the other hand, if the particle size of crospovidone is too small, the mixing uniformity may be lowered due to deterioration of fluidity. In addition, the average particle diameter in this specification represents the median diameter (cumulative 50% particle diameter) measured by a dry method using a laser diffraction particle size distribution analyzer, for example, a laser diffraction particle size distribution analyzer MT3200. It can be measured using (Nikkiso Co., Ltd.).
本発明の口腔内崩壊錠中においてクロスポビドンの含有量は特に限定されないが、崩壊性、高温や加湿度条件下での崩壊性の安定性、硬度、摩擦度とのバランスの観点から、口腔内崩壊錠に対して好ましくは１〜２０質量％であり、より好ましくは１〜１０質量％であり、さらに好ましくは１〜５質量％である。 In the orally disintegrating tablet of the present invention, the content of crospovidone is not particularly limited, but from the viewpoint of disintegration, stability of disintegration under high temperature and humidified conditions, hardness, and balance of friction, Preferably it is 1-20 mass% with respect to a disintegrating tablet, More preferably, it is 1-10 mass%, More preferably, it is 1-5 mass%.
（ｃ）Ｄ−マンニトールは、本発明口腔内崩壊錠において、成形性、崩壊性に寄与し、また高温や加湿度条件下での崩壊性の安定性にも寄与する。
本発明で用いるＤ−マンニトールは平均粒子径が好ましくは１０〜５００μｍ以下であり、より好ましくは１０〜２００μｍ以下であり、さらに好ましくは４０〜１５０μｍ以下である。Ｄ−マンニトールの粒子径が小さすぎると圧縮成形性は向上するものの崩壊性が著しく低下するおそれがあり、逆に粒子径が大きすぎると圧縮成形性が悪く、錠剤の強度が低くなるおそれがあり、かつ口腔内でざらつきを感じ、服用感が悪化するおそれがある。また、Ｄ−マンニトールはα、β、δ型の結晶多形が存在することが知られており、本発明においてはその結晶形は特に限定されないが、α及びδ型は、温度や湿度によって比較的容易に結晶形が変化することがあることから、最も安定形であるβ型を用いることが好ましい。
本発明の口腔内崩壊錠中においてＤ−マンニトールの含有量は特に限定されないが、成形性、崩壊性及び崩壊性の安定性の観点から、好ましくは５０〜９５質量％であり、より好ましくは６０〜９０質量％であり、更に好ましくは７０〜９０質量％である。
(C) D-mannitol contributes to moldability and disintegration in the orally disintegrating tablet of the present invention, and also contributes to disintegration stability under high temperature and humidification conditions.
D-mannitol used in the present invention has an average particle size of preferably 10 to 500 μm or less, more preferably 10 to 200 μm or less, and further preferably 40 to 150 μm or less. If the particle size of D-mannitol is too small, the compression moldability is improved, but the disintegration property may be remarkably lowered. Conversely, if the particle size is too large, the compression moldability is poor and the tablet strength may be lowered. In addition, there is a risk of feeling rough in the oral cavity and worsening the feeling of administration. In addition, D-mannitol is known to have α, β, and δ crystal polymorphs, and the crystal form is not particularly limited in the present invention, but α and δ types are compared according to temperature and humidity. Since the crystal form may change easily, it is preferable to use the most stable β form.
The content of D-mannitol in the orally disintegrating tablet of the present invention is not particularly limited, but is preferably 50 to 95% by mass, more preferably 60 from the viewpoint of moldability, disintegration and disintegration stability. It is -90 mass%, More preferably, it is 70-90 mass%.
本発明の口腔内崩壊錠は前記成分に加え、さらに結晶セルロース又は滑沢剤を含むことが好ましく、結晶セルロース及び滑沢剤を含むことがより好ましい。
本発明で用いる結晶セルロースは、繊維性植物から得られたα−セルロースを酸で部分的に解重合して精製したものであり、経口投与が可能なものであれば特に限定されない。結晶セルロースの平均粒子径が大きいと口腔内で崩壊した後に、ざらつきを感じることがあるため、服用感の観点から、本発明に用いる結晶セルロースの平均粒子径は好ましくは２００μｍ以下であり、より好ましくは１５０μｍ以下であり、さらに好ましくは１００μｍ以下である。
本発明の口腔内崩壊錠中において結晶セルロースの含有量は特に限定されないが、硬度、崩壊時間及び打錠圧の許容幅の観点から、好ましくは５〜４０質量％であり、より好ましくは５〜３０質量％であり、さらに好ましくは５〜２０質量％である。
In addition to the above components, the orally disintegrating tablet of the present invention preferably further contains crystalline cellulose or a lubricant, and more preferably contains crystalline cellulose and a lubricant.
The crystalline cellulose used in the present invention is not particularly limited as long as it is obtained by partially depolymerizing α-cellulose obtained from a fibrous plant with an acid and can be administered orally. If the average particle size of the crystalline cellulose is large, it may feel rough after disintegrating in the oral cavity. From the viewpoint of taking feeling, the average particle size of the crystalline cellulose used in the present invention is preferably 200 μm or less, and more preferably Is 150 μm or less, more preferably 100 μm or less.
The content of crystalline cellulose in the orally disintegrating tablet of the present invention is not particularly limited, but is preferably 5 to 40% by mass, more preferably 5 to 5% from the viewpoints of hardness, disintegration time, and allowable range of tableting pressure. It is 30 mass%, More preferably, it is 5-20 mass%.
本発明で用いる滑沢剤としては、ステアリン酸カルシウム、ステアリン酸マグネシウム、タルク、ショ糖脂肪酸エステル、及びフマル酸ステアリルナトリウムなどが挙げられ、滑沢剤の過混合による崩壊時間の遅延の抑制の観点から、フマル酸ステアリルナトリウムが好ましい。本発明の口腔内崩壊錠において滑沢剤の含有量は特に限定されないが、好ましくは０．１〜５質量％であり、より好ましくは０．５〜２質量％である。 Examples of the lubricant used in the present invention include calcium stearate, magnesium stearate, talc, sucrose fatty acid ester, and sodium stearyl fumarate. From the viewpoint of suppressing a delay in disintegration time due to overmixing of the lubricant. Sodium stearyl fumarate is preferred. Although content of a lubricant is not specifically limited in the orally disintegrating tablet of this invention, Preferably it is 0.1-5 mass%, More preferably, it is 0.5-2 mass%.
また、本発明の製剤においては、本発明の効果に影響を与えない範囲であれば、上記成分以外の製剤分野において通常使用される無毒性かつ不活性な添加剤を添加することもできる。
使用する添加剤としては、医薬的に許容されるものであればよく、例えば、賦形剤、流動化剤、甘味剤、矯味剤、着香剤・香料、着色剤、安定化剤が挙げられる。流動化剤では、例えば、軽質無水ケイ酸、メタケイ酸アルミン酸マグネシウムが挙げられる。甘味剤、矯味剤では、例えば、アスパルテーム、サッカリン、サッカリンナトリウム、グリチルリチン酸二カリウム、ステビア、タウマチン、スクラロース、アセスルファムＫ等の高甘味度甘味料が挙げられる。なかでも、好ましい高甘味度甘味料としては、アスパルテーム、タウマチン、及びスクラロースが挙げられる。着香剤、香料としては、例えば、ペパーミント、スペアミント、メントール、レモン、オレンジ、グレープフルーツ、パイン、フルーツ、ヨーグルトが挙げられる。前述の甘味剤、矯味剤、着香剤、香料の配合によって、より好ましい服用感が得られる場合がある。これらの添加剤は、一種又は二種以上を組み合わせて適宜、適量添加することができる。
In the preparation of the present invention, non-toxic and inert additives usually used in the pharmaceutical field other than the above components can be added as long as the effects of the present invention are not affected.
The additive to be used may be any pharmaceutically acceptable, and examples thereof include excipients, fluidizers, sweeteners, flavoring agents, flavoring agents / fragrances, coloring agents, and stabilizers. . Examples of the fluidizing agent include light anhydrous silicic acid and magnesium aluminate metasilicate. Examples of sweeteners and flavoring agents include high-intensity sweeteners such as aspartame, saccharin, sodium saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose, and acesulfame K. Among these, preferred high-intensity sweeteners include aspartame, thaumatin, and sucralose. Examples of the flavoring agent and flavoring agent include peppermint, spearmint, menthol, lemon, orange, grapefruit, pine, fruit, and yogurt. There may be a case where a more preferable feeling is obtained by blending the aforementioned sweetener, flavoring agent, flavoring agent, and fragrance. These additives can be appropriately added in an appropriate amount, alone or in combination of two or more.
本発明において口腔内崩壊錠とは、錠剤を服用するために水を摂取することなく、又は少量の水で口腔内において速やかに崩壊する錠剤を意味し、口腔内の崩壊時間は６０秒以内、好ましくは３０秒以内である。 In the present invention, the orally disintegrating tablet means a tablet that rapidly disintegrates in the oral cavity without ingesting water to take the tablet or with a small amount of water, and the disintegration time in the oral cavity is within 60 seconds, Preferably, it is within 30 seconds.
本発明の口腔内崩壊錠は、後記実施例に示すように、優れた口腔内崩壊性を有するとともに、良好な硬度を有する。また、その崩壊性と硬度は、高温条件及び加湿度条件下に保存しても低下せず良好に維持される。さらには、長期保存しても、経時的な外観の変化がほとんど認められず、安定性も良好である。本発明において「経時的な外観の変化がほとんど認められない」とは、口腔内崩壊錠が加湿度条件下に晒された場合においても、吸湿により、錠剤表面の印字の識別性が低下することを特徴とする、わずかな外観の変化も生じないことを意味する。外観の変化は、例えば、口腔内崩壊錠を３０℃相対湿度７５％の雰囲気下に１箇月間保存し、外観を肉眼観察することで評価できる。 The orally disintegrating tablet of the present invention has excellent disintegration property in the oral cavity and good hardness, as shown in Examples below. Moreover, the disintegration property and hardness are maintained well without being lowered even when stored under high temperature conditions and humidification conditions. Furthermore, even after long-term storage, almost no change in appearance over time is observed, and the stability is also good. In the present invention, “almost no change in appearance over time” is meant that even when an orally disintegrating tablet is exposed to humidified conditions, the discrimination of printing on the tablet surface is reduced due to moisture absorption. This means that even a slight change in appearance does not occur. The change in appearance can be evaluated by, for example, storing the orally disintegrating tablet in an atmosphere of 30 ° C. and 75% relative humidity for one month and observing the appearance with the naked eye.
本発明の錠剤の製造方法は特に限定されないが、たとえば以下の方法により製造することが出来る。Ｄ−マンニトール、活性成分トラセミド、滑沢剤を混合して倍散とした後、さらにＤ−マンニトール、結晶セルロース、クロスポビドンを加えて混合した顆粒を、圧縮成型することで錠剤を得ることが出来る。使用する各成分が凝集性であったり、結晶や造粒物が大きなものであったりする等、活性成分の含量均一性を阻害する可能性がある場合は、各成分を混合前又は混合後に粉砕等の手法を利用して、含量均一性を保証できる粒子径に整えることが望ましい。錠剤の成型方法については、特に限定されないが、商業的に製造する場合はロータリー式打錠機又を用いた圧縮成型法が用いられる。 Although the manufacturing method of the tablet of this invention is not specifically limited, For example, it can manufacture by the following method. Tablets can be obtained by mixing D-mannitol, active ingredient torasemide, and lubricant to make a trituration, and then compression-molding the granules that are further mixed with D-mannitol, crystalline cellulose, and crospovidone. . If there is a possibility of inhibiting the uniformity of the active ingredient content, such as when each component used is agglomerated or crystals or granules are large, each component is ground before or after mixing. It is desirable to adjust the particle diameter so that the content uniformity can be ensured by using such a method. The method for molding the tablet is not particularly limited, but in the case of commercial production, a compression molding method using a rotary tableting machine or the like is used.
なお、本発明の錠剤は、外部滑沢法を用いなくとも圧縮成型が可能であるが、勿論、外部滑沢法を用いても成型可能である。この場合には、滑沢剤を除く成分を混合した後、滑沢剤を杵臼に噴霧しながら打錠を行うか、あるいは、滑沢剤の一部をあらかじめ混合した後、残りの滑沢剤を杵臼に噴霧しながら打錠を行う。 The tablet of the present invention can be compression-molded without using an external lubrication method, but of course can also be molded using an external lubrication method. In this case, after mixing the ingredients excluding the lubricant, the tableting is performed while spraying the lubricant on the tooling, or a part of the lubricant is mixed in advance, and then the remaining lubricant is mixed. Tablet while spraying on the tool.
圧縮成型力は、錠剤に十分な強度を与える程度であれば特に限定されないが、６ｋＮ（約６００ｋｇｆ）以上の圧縮力が好ましい。本発明で得られる錠剤の形状は、特に限定されず、円形錠、円形Ｒ錠、円形隅角錠や各種異形錠等いずれの形状でもよく、また分割錠としても良い。 The compression molding force is not particularly limited as long as it gives sufficient strength to the tablet, but a compression force of 6 kN (about 600 kgf) or more is preferable. The shape of the tablet obtained in the present invention is not particularly limited, and may be any shape such as a round tablet, a round R tablet, a round corner tablet, various irregular tablets, or a split tablet.
以下、実施例をあげて本発明を更に詳しく説明するが、本発明を限定するものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
実施例１
トラセミド１５．３ｇ、Ｄ−マンニトール（商品名：グラニュトールＳ、フロイント産業、平均粒子径：７６μｍ）１３５ｇ、フマル酸ステアリルナトリウム４．５ｇを混合し、原薬倍散混合品１５４．８ｇを得た。原薬倍散混合品にＤ−マンニトール（商品名：グラニュトールＳ、フロイント産業、平均粒子径：７６μｍ）２３６．７ｇ、結晶セルロース（商品名：セオラスＰＨ−１０１、旭化成、平均粒子径：６５μｍ）４５ｇ、クロスポビドン（商品名：Ｐｏｌｙｐｌａｓｄｏｎｅ ＸＬ−１０、ＩＳＰ、平均粒子径：２８μｍ）１３．５ｇを加えて混合し、打錠用顆粒とした。得られた打錠用顆粒を、単発打錠機（ＲＩＶＡ社製）を用いて、約６ｋＮの圧縮力で打錠し、直径７ｍｍ、重量１２０ｍｇの口腔内崩壊錠を得た。なお、各添加剤の平均粒子径は、レーザー回折式粒度分布測定装置ＭＴ３２００（日機装社製）を使用して乾式法により測定した。
Example 1
15.3 g of toracemide, 135 g of D-mannitol (trade name: Granitol S, Freund's industry, average particle size: 76 μm) and 4.5 g of sodium stearyl fumarate were mixed to obtain 154.8 g of a drug substance trituration mixed product. . D-Mannitol (trade name: Granitol S, Freund Sangyo, average particle size: 76 μm) 236.7 g, crystalline cellulose (trade name: Theolas PH-101, Asahi Kasei, average particle size: 65 μm) 45 g and 13.5 g of crospovidone (trade name: Polyplastdone XL-10, ISP, average particle size: 28 μm) were added and mixed to obtain granules for tableting. The obtained granules for tableting were tableted with a compressive force of about 6 kN using a single tableting machine (manufactured by RIVA) to obtain an orally disintegrating tablet having a diameter of 7 mm and a weight of 120 mg. The average particle size of each additive was measured by a dry method using a laser diffraction particle size distribution analyzer MT3200 (manufactured by Nikkiso Co., Ltd.).
実施例２〜４、及び比較例１〜２
実施例１に準じて表１の組成からなる５種の製剤を調製した。
なお、実施例２〜４、及び比較例１〜２においてクロスポビドンはＰｏｌｙｐｌａｓｄｏｎｅ ＸＬ−１０（ＩＳＰ、平均粒子径：２８μｍ）、Ｐｏｌｙｐｌａｓｄｏｎｅ ＸＬ（ＩＳＰ、平均粒子径：１１７μｍ）及びＫｏｌｌｉｄｏｎ ＣＬ−Ｆ（ＢＡＳＦ、平均粒子径：２７μｍ）から選択される１種を、デンプングリコール酸ナトリウムはＶＩＶＡＳＴＡＲ（ＪＲＳ ＰＨＡＲＭＡ）を、クロスカルメロースナトリウムはＡｃ−Ｄｉ−Ｓｏｌ（ＦＭＣ）を用い、それ以外の成分は実施例１と同じものを用いた。
Examples 2-4 and Comparative Examples 1-2
According to Example 1, five types of preparations having the composition shown in Table 1 were prepared.
In Examples 2 to 4 and Comparative Examples 1 and 2, crospovidone was Polyplasmone XL-10 (ISP, average particle size: 28 μm), Polyplasmone XL (ISP, average particle size: 117 μm), and Kollidon CL-F (BASF). , Mean particle size: 27 μm), sodium starch glycolate uses VIVASTAR (JRS PHARMA), croscarmellose sodium uses Ac-Di-Sol (FMC), and other components are examples. The same as 1 was used.
試験例１
実施例１〜３及び比較例１〜２により製造された錠剤について、保存前、６０℃及び３０℃相対湿度７５％の雰囲気下で１箇月間保存後に、口腔内崩壊錠試験器（岡田精工、トリコープテスタ）を用いて、試験液：水、上メッシュ質量：２０ｇの条件にて崩壊時間を測定した。また、それぞれ錠剤物性測定装置（ＴＭ３−３、菊水製作所）で硬度を測定した結果を表２及び表３に示す。
Test example 1
About the tablet manufactured by Examples 1-3 and Comparative Examples 1-2, after storage for 1 month in the atmosphere of 60 degreeC and 30 degreeC relative humidity 75% before storage, an orally disintegrating tablet tester (Okada Seiko, Using a tricope tester, the disintegration time was measured under the conditions of test solution: water, upper mesh mass: 20 g. In addition, Tables 2 and 3 show the results of measuring the hardness with a tablet physical property measuring apparatus (TM3-3, Kikusui Seisakusho).
表１、２に示すように各実施例の口腔内崩壊錠は、いずれも保存前において３０秒以内の崩壊時間を示し、崩壊性に優れることが示された。また、いずれの実施例も高温条件で保存した後と保存前の崩壊時間の差、及び加湿度条件下で保存した後と保存前の崩壊時間の差は崩壊剤としてデンプングリコール酸ナトリウム、又はクロスカルメロースナトリウムを使用した比較例より小さく、満足するものであった。また各実施例は高温条件又は加湿度条件下で保存した後も良好な硬度を有していた。 As shown in Tables 1 and 2, each of the orally disintegrating tablets of each Example showed a disintegration time of 30 seconds or less before storage, and was excellent in disintegration. In all of the examples, the difference between the disintegration time after storage under high temperature conditions and before storage, and the difference between the disintegration time after storage under humidified conditions and before storage is sodium starch glycolate or cloth as a disintegrant. It was smaller than the comparative example using carmellose sodium, and was satisfactory. In addition, each example had good hardness even after being stored under high temperature conditions or humidified conditions.
試験例２
実施例１〜３について、３０℃相対湿度７５％の雰囲気下に１箇月間保存し、外観を肉眼観察することで「外観の変化」の程度を４段階で評価した。結果を表４に、外観を図１に示す。
本発明の「外観の変化」の程度は４段階で評価し、製造直後と比較して変化がない場合を１（変化なし）、製造直後と３０℃相対湿度７５％の雰囲気下に１箇月保存後の錠剤を並べて同時観察した時に、認識できる外観の変化があった場合を２（ごくわずかに変化あり）、製造直後と３０℃相対湿度７５％の雰囲気下に１箇月保存後の錠剤を個々に観察した時に、認識できる外観の変化があった場合を３（わずかに変化あり）、３０℃相対湿度７５％の雰囲気下に１箇月保存後の錠剤を単独で観察した時に、外観の変化が表面の荒れに限らず、亀裂など、認識できる変化があった場合を４（変化あり）とした。
Test example 2
About Examples 1-3, it preserve | saved for one month in the atmosphere of 30 degreeC relative humidity 75%, and the grade of the "change of an external appearance" was evaluated in four steps by observing the external appearance visually. The results are shown in Table 4, and the appearance is shown in FIG.
The degree of “change in appearance” of the present invention is evaluated in four stages, and 1 (no change) when there is no change compared to immediately after manufacture, and stored for one month immediately after manufacture and in an atmosphere of 30 ° C. and 75% relative humidity. When the subsequent tablets are lined up and observed at the same time, there is a change in the appearance that can be recognized 2 (there is a slight change). Each tablet after storage for 1 month in an atmosphere of 30 ° C and 75% relative humidity 3 (when there was a slight change) when the tablet had been stored alone for 1 month in an atmosphere of 30% relative humidity and 75% relative humidity. The case where there was a change that can be recognized, such as a crack, as well as the roughness of the surface was set to 4 (changed).
表３、図１に示すように、本発明の製剤はいずれも評価４に相当する大きな外観の変化は認められなかったが、特に使用したクロスポビドンの平均粒子径が１００μｍ以下である実施例１、及び実施例３の口腔内崩壊錠は経時的な外観の変化がほとんどあるいは全く認められなかった。 As shown in Table 3 and FIG. 1, none of the preparations of the present invention showed a significant change in appearance corresponding to Evaluation 4. However, the average particle size of crospovidone used was 100 μm or less. The orally disintegrating tablet of Example 3 showed little or no change in appearance over time.
Claims (6)
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2007513975A (en) * | 2003-12-12 | 2007-05-31 | ペンウェスト ファーマシューティカルズ カンパニー | Sustained release torsemide dosage form |
| WO2011019045A1 (en) * | 2009-08-11 | 2011-02-17 | 富士化学工業株式会社 | Disintegrating particle composition and orally rapidly disintegrating tablet |
| JP2014196360A (en) * | 2008-11-25 | 2014-10-16 | 田辺三菱製薬株式会社 | Orally rapidly disintegrating tablet and process for producing the same |
| JP2017071561A (en) * | 2015-10-05 | 2017-04-13 | 大同化成工業株式会社 | Composite granule comprising sugar or sugar alcohol, swellable binder, disintegrator and superabsorbent excipient and method for producing the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2007513975A (en) * | 2003-12-12 | 2007-05-31 | ペンウェスト ファーマシューティカルズ カンパニー | Sustained release torsemide dosage form |
| JP2014196360A (en) * | 2008-11-25 | 2014-10-16 | 田辺三菱製薬株式会社 | Orally rapidly disintegrating tablet and process for producing the same |
| WO2011019045A1 (en) * | 2009-08-11 | 2011-02-17 | 富士化学工業株式会社 | Disintegrating particle composition and orally rapidly disintegrating tablet |
| JP2017071561A (en) * | 2015-10-05 | 2017-04-13 | 大同化成工業株式会社 | Composite granule comprising sugar or sugar alcohol, swellable binder, disintegrator and superabsorbent excipient and method for producing the same |
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