JP2017066134A - Solid preparation - Google Patents
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- JP2017066134A JP2017066134A JP2016183564A JP2016183564A JP2017066134A JP 2017066134 A JP2017066134 A JP 2017066134A JP 2016183564 A JP2016183564 A JP 2016183564A JP 2016183564 A JP2016183564 A JP 2016183564A JP 2017066134 A JP2017066134 A JP 2017066134A
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- ibuprofen
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- etenzamide
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- 239000007787 solid Substances 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims abstract description 51
- 229960001680 ibuprofen Drugs 0.000 claims abstract description 51
- SBNKFTQSBPKMBZ-UHFFFAOYSA-N ethenzamide Chemical compound CCOC1=CC=CC=C1C(N)=O SBNKFTQSBPKMBZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000004519 manufacturing process Methods 0.000 claims abstract description 23
- 229920002472 Starch Polymers 0.000 claims abstract description 15
- 235000019698 starch Nutrition 0.000 claims abstract description 15
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims abstract description 14
- 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 claims abstract description 14
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims abstract description 14
- 229950008138 carmellose Drugs 0.000 claims abstract description 14
- 239000011734 sodium Substances 0.000 claims abstract description 14
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 14
- 239000008107 starch Substances 0.000 claims abstract description 14
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000011575 calcium Substances 0.000 claims abstract description 13
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 238000009472 formulation Methods 0.000 claims description 8
- 239000002356 single layer Substances 0.000 claims description 5
- 238000005550 wet granulation Methods 0.000 claims description 4
- 238000013329 compounding Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 abstract description 12
- 230000003993 interaction Effects 0.000 abstract description 7
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- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 6
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- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 6
- 229960003943 hypromellose Drugs 0.000 description 6
- 238000002844 melting Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229940035676 analgesics Drugs 0.000 description 4
- 239000000730 antalgic agent Substances 0.000 description 4
- 230000001754 anti-pyretic effect Effects 0.000 description 4
- 239000002221 antipyretic Substances 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 3
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- 239000004698 Polyethylene Substances 0.000 description 2
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- 229940125715 antihistaminic agent Drugs 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
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- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000007721 medicinal effect Effects 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 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
- 208000008930 Low Back Pain Diseases 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
- 206010029240 Neuritis Diseases 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
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- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010072005 Spinal pain Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 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
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 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
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940124579 cold medicine Drugs 0.000 description 1
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- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940124568 digestive agent Drugs 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
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- 238000005516 engineering process Methods 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
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- 235000019634 flavors Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000002496 gastric effect Effects 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
- 231100000869 headache Toxicity 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 229960004708 noscapine Drugs 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
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
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- 150000005846 sugar alcohols Chemical class 0.000 description 1
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、イブプロフェンとエテンザミドを配合した固形製剤に関する。 The present invention relates to a solid preparation containing ibuprofen and etenzamide.
解熱鎮痛薬は風邪等の疾患に起因する発熱、頭痛、各種炎症を抑制するために汎用され、この解熱鎮痛薬の主成分として、イブプロフェンを用いたものが数多く存在する（非特許文献１）。イブプロフェンは、慢性関節リウマチ、関節痛及び関節炎、神経痛及び神経炎、脊腰痛等の疾患並びに症状の消炎・鎮痛に有効であるほか、急性上気道炎（風邪）の解熱・鎮痛等にも有効である（非特許文献２）。
イブプロフェンは融点７５〜７７℃の低融点薬物であり、さらに酸性基を有するためアルカリ性薬物と配合すると高湿度条件下において吸湿し塩を形成することが知られている。特に抗ヒスタミン薬、解熱鎮痛薬、消化薬と配合すると色調変化や湿潤化といった変化を認めるものが多い（非特許文献３）。イブプロフェンの他の成分との相互作用は、粉体のハンドリングを著しく困難にし、付着や凝集を引き起こす他、製品化後に変色等の問題を招来することがあった
解熱鎮痛薬や総合感冒薬の有効成分として知られるエテンザミドは、イブプロフェンと適切な配合比で投与すると、解熱鎮痛効果が相乗的に増加する事が開示されている（特許文献１）。一方で、イブプロフェンとエテンザミドとが混在すると、イブプロフェンの融点降下を引き起こすことが知られている。そのため、これらが互いに接触する簡便な方法で製造すると、製造機器へ付着が生じる。特に、錠剤製造の際に打錠機に付着すると、打錠機が動かなくなり、製造作業が停止する場合がある。このため、打錠機を頻繁に清掃する等の対応が必須となり、製造工程の短縮どころか生産効率の低下を招く。
Antipyretic analgesics are widely used to suppress fever, headache, and various inflammations caused by diseases such as colds, and many antipyretic analgesics use ibuprofen as the main component (Non-patent Document 1). Ibuprofen is effective for anti-inflammatory and analgesia of rheumatoid arthritis, joint pain and arthritis, neuralgia and neuritis, spinal and lower back pain, etc. Yes (Non-Patent Document 2).
It is known that ibuprofen is a low-melting drug having a melting point of 75 to 77 ° C., and further has an acidic group, so that when it is combined with an alkaline drug, it absorbs moisture under high humidity conditions to form a salt. In particular, when combined with antihistamines, antipyretic analgesics, and digestives, there are many that recognize changes such as color change and wetting (Non-patent Document 3). Interaction with other components of ibuprofen makes powder handling extremely difficult, causing adhesion and aggregation, and may cause problems such as discoloration after commercialization Effectiveness of antipyretic analgesics and general cold medicine It has been disclosed that ethenamide, known as a component, synergistically increases antipyretic analgesic effect when administered with ibuprofen at an appropriate blending ratio (Patent Document 1). On the other hand, it is known that when ibuprofen and etenzamid are mixed, the melting point of ibuprofen is lowered. Therefore, if they are manufactured by a simple method in which they are in contact with each other, adhesion occurs to the manufacturing equipment. In particular, if it adheres to a tableting machine during tablet manufacture, the tableting machine may not move and the manufacturing operation may stop. For this reason, it is indispensable to frequently clean the tableting machine, which leads to a decrease in production efficiency as well as a shortening of the manufacturing process.
今まで、イブプロフェン及びエテンザミドを配合した錠剤を製造する場合、これらを異なる層に配合し、二重錠や多層錠として提供すれば、これら成分が同一の製剤中に配合されていても、直接の接触を回避してイブプロフェンの融点降下を防止することが可能であった（非特許文献３参照）。
また、イブプロフェンとエテンザミドを含有する顆粒を製造する場合は、単にこれらを異なる造粒物に配合しただけでは相互作用を充分に抑制することができなかった。これに対し、常套手段としてはイブプロフェンとエテンザミドを異なる造粒物に配合した後、少なくともその何れかをフィルムコーティングすることが考えられる（特許文献２〜３）。また、同一造粒物に配合する方法として、イブプロフェン含有層とエテンザミド含有層の間にヒプロメロースを含む中間層を配し、融点降下を抑制したレイヤリング粒子が報告されている（特許文献４）。しかしながら、これら二重錠や多層錠は層間剥離などの打錠障害の問題や、製造面においても専用の設備が必要であり、造粒物の被覆やレイヤリング粒子の製造はコストの増大、製造の複雑化があり、未だ改善の余地がある。
Until now, when manufacturing tablets containing ibuprofen and etenzamide, if they are combined in different layers and provided as double tablets or multilayer tablets, even if these ingredients are combined in the same preparation, It was possible to avoid contact and prevent a drop in melting point of ibuprofen (see Non-Patent Document 3).
Further, when producing granules containing ibuprofen and etenzamide, the interaction could not be sufficiently suppressed simply by blending these into different granulated products. On the other hand, as a conventional means, it is conceivable that ibuprofen and etenzamide are blended in different granulated products and then at least one of them is film-coated (Patent Documents 2 to 3). In addition, as a method of blending into the same granulated product, layering particles in which an intermediate layer containing hypromellose is disposed between the ibuprofen-containing layer and the etenzamide-containing layer to suppress a melting point drop has been reported (Patent Document 4). However, these double tablets and multilayer tablets require tableting problems such as delamination and production facilities, and the production of granulated coatings and layering particles increases the production cost. There is still room for improvement.
本発明の目的は、イブプロフェンとエテンザミドが相互作用を引き起こす状態で配合しても、製造機器への付着の生じない、安定な固形製剤を提供することにある。 An object of the present invention is to provide a stable solid preparation that does not adhere to production equipment even if it is formulated in a state where ibuprofen and etenzamide cause an interaction.
本発明者らは、上記目的を達成するために種々の検討を行ったところ、カルボキシメチルスターチナトリウム及び／又はカルメロースカルシウムを配合することにより、製造機器への付着を生じない、安定な固形製剤が得られることを見出し、本発明を完成した。 The inventors of the present invention have made various studies in order to achieve the above object, and as a result, a stable solid preparation that does not cause adhesion to production equipment by blending sodium carboxymethyl starch and / or carmellose calcium. Was found and the present invention was completed.
すなわち、本発明は
（１）（ａ）イブプロフェン、（ｂ）エテンザミド、及び（ｃ）カルボキシメチルスターチナトリウム及び／又はカルメロースカルシウムを含有することを特徴とする固形製剤、
（２）（ａ）イブプロフェン、及び（ｂ）エテンザミドを同時配合かつ共存させたことを特徴とする、（１）に記載の固形製剤、
（３）（ａ）イブプロフェンと（ｂ）エテンザミドを別々の造粒物中に配合し、これら造粒物を同時配合かつ共存させたことを特徴とする、（１）に記載の固形製剤、
（４）（ａ）イブプロフェン１質量部に対し、（ｂ）エテンザミドの配合量が０．１〜１０質量部である、（１）〜（３）のいずれかに記載の固形製剤、
（５）（ｃ）カルボキシメチルスターチナトリウム及び／又はカルメロースカルシウムの含有量が、固形製剤全体に対して１〜５０質量％である、（１）に記載の固形製剤、
（６）固形製剤が錠剤である、（１）〜（５）のいずれかに記載の固形製剤、
（７）錠剤が単層錠である、（６）に記載の固形製剤、
（８）湿式造粒法により製造される、（１）〜（７）のいずれかに記載の固形製剤の製造方法、
である。
That is, the present invention comprises (1) (a) ibuprofen, (b) etezamide, and (c) carboxymethyl starch sodium and / or carmellose calcium,
(2) The solid preparation according to (1), wherein (a) ibuprofen and (b) ethenzamide are simultaneously blended and coexisted,
(3) (a) ibuprofen and (b) etenzaamide are blended in separate granulated products, and these granulated products are blended simultaneously and coexisted, The solid preparation according to (1),
(4) The solid preparation according to any one of (1) to (3), wherein the amount of (b) etezamide is 0.1 to 10 parts by mass relative to 1 part by mass of (a) ibuprofen,
(5) The solid preparation according to (1), wherein the content of (c) sodium carboxymethyl starch and / or carmellose calcium is 1 to 50% by mass relative to the whole solid preparation,
(6) The solid preparation according to any one of (1) to (5), wherein the solid preparation is a tablet,
(7) The solid preparation according to (6), wherein the tablet is a monolayer tablet,
(8) The manufacturing method of the solid formulation in any one of (1)-(7) manufactured by the wet granulation method,
It is.
本発明により、イブプロフェン及びエテンザミドを配合し、製造性及び生産性に優れた固形製剤の提供が可能となった。 According to the present invention, it was possible to provide a solid preparation excellent in manufacturability and productivity by blending ibuprofen and etenzamide.
本発明の固形製剤は、今までイブプロフェンとエテンザミドを安定に配合するために必要であったフィルムコーティング操作、多層錠化、レイヤリング粒子化を必要としないため、これら操作に必要な賦形剤を使用する必要がない。そのため、本願発明の固形製剤は、製剤を小型化することができる上、製造法も簡便であり、利点が大きい。 The solid preparation of the present invention does not require the film coating operation, multi-layered tableting, and layering particle formation, which have been necessary for stable blending of ibuprofen and etezamide until now. There is no need to use it. For this reason, the solid preparation of the present invention can be miniaturized and the production method is simple and has great advantages.
本発明の固形製剤に用いられるイブプロフェンは、日本薬局方に準拠したイブプロフェンであり、公知の方法により製造できるほか、市販のものを用いることができる。本発明の固形製剤中におけるイブプロフェンの含有量は、その薬効を示す量であれば特に限定されるものではないが、通常１〜８０質量％、好ましくは５〜７０質量％である。本発明のイブプロフェンは原末のまま配合してもよいが、本発明の効果の点から、造粒粒子として配合するのが好ましい。イブプロフェン含有造粒粒子には、造粒粒子を製造する際に通常使用される賦形剤、崩壊剤、結合剤、滑沢剤などを配合することができる。 The ibuprofen used for the solid preparation of the present invention is ibuprofen based on the Japanese Pharmacopoeia, and can be produced by a known method or commercially available. The content of ibuprofen in the solid preparation of the present invention is not particularly limited as long as it shows the medicinal effect, but is usually 1 to 80% by mass, preferably 5 to 70% by mass. The ibuprofen of the present invention may be blended as the raw powder, but is preferably blended as granulated particles from the viewpoint of the effect of the present invention. The ibuprofen-containing granulated particles can be blended with excipients, disintegrants, binders, lubricants and the like that are usually used in producing granulated particles.
本発明の固形製剤に用いられるエテンザミドは、日本薬局方に準拠したエテンザミドであり、公知の方法により製造できるほか、市販のものを用いることができる。本発明の固形製剤中におけるエテンザミドの含有量は、その薬効を示す量であれば特に限定されるものではないが、通常１〜９０質量％、好ましくは１５〜８５質量％、より好ましくは２０〜８５質量％である。本発明のエテンザミドは原末のまま配合してもよいが、本発明の効果の点から、造粒粒子として配合するのが好ましい。エテンザミド含有造粒粒子には、造粒粒子を製造する際に通常使用される賦形剤、崩壊剤、結合剤、滑沢剤などを配合することができる。 Etenzamide used in the solid preparation of the present invention is etenzamide based on the Japanese Pharmacopoeia, and can be produced by a known method or commercially available. The content of etenzamide in the solid preparation of the present invention is not particularly limited as long as it shows the medicinal effect, but is usually 1 to 90% by mass, preferably 15 to 85% by mass, more preferably 20 to 20%. It is 85 mass%. The etenzamide of the present invention may be blended as a raw powder, but is preferably blended as granulated particles from the viewpoint of the effect of the present invention. The ethenamide-containing granulated particles can be blended with excipients, disintegrants, binders, lubricants and the like that are usually used in producing granulated particles.
また、イブプロフェンとエテンザミドの配合比は、イブプロフェン１質量部に対し、エテンザミドを０．１〜１０質量部が好ましく、特に好ましくは０．４２〜５質量部である。また、本発明の固形製剤中におけるイブプロフェン及びエテンザミドの合計量は、３０質量％以上、好ましくは６０〜８５質量％である。 In addition, the blending ratio of ibuprofen and etenzamide is preferably 0.1 to 10 parts by mass, particularly preferably 0.42 to 5 parts by mass of etenzamide with respect to 1 part by mass of ibuprofen. The total amount of ibuprofen and etenzamide in the solid preparation of the present invention is 30% by mass or more, preferably 60 to 85% by mass.
本発明の「同時配合かつ共存させた」とは、イブプロフェンとエテンザミド、又はイブプロフェンを含む造粒物とエテンザミドを含む造粒物とが物理的／又は化学的に隔離されることなく混在している状態のことである。ただし、イブプロフェンとエテンザミド以外の成分の配合を排除するものではなく、他の成分の共存は許容される。 In the present invention, “simultaneous blending and coexistence” means that ibuprofen and etenzamide, or a granulated product containing ibuprofen and a granulated product containing ethenamide are mixed without being physically or chemically isolated. It is a state. However, the addition of components other than ibuprofen and etenzamide is not excluded, and the coexistence of other components is allowed.
本発明の固形製剤に用いられるカルボキシメチルスターチナトリウムとカルメロースカルシウムは、一般に崩壊剤として用いられる。本発明の固形製剤は、この２種の崩壊剤のどちらか又は両方を固形製剤中に配合することにより、イブプロフェンとエテンザミドの相互作用を抑制できる。これらはイブプロフェンとエテンザミドと共に混合してもよく、イブプロフェン含有造粒物、エテンザミド含有造粒物、又はイブプロフェンとエテンザミド含有する造粒物中に配合してもよく、造粒物の外に配合してもよい。本発明の固形製剤中におけるカルボキシメチルスターチナトリウム及び／又はカルメロースカルシウムの含有量は、特に限定されるものではないが、通常１〜５０質量％、好ましくは２〜２０質量％、さらに好ましくは３〜１５質量％である。 Sodium carboxymethyl starch and carmellose calcium used in the solid preparation of the present invention are generally used as disintegrants. The solid preparation of the present invention can suppress the interaction between ibuprofen and etenzamide by blending either or both of these two disintegrants into the solid preparation. These may be mixed with ibuprofen and etenzamide, and may be blended in an ibuprofen-containing granulated product, an ethenamide-containing granulated product, or a granulated product containing ibuprofen and etenzamide, and blended outside the granulated product. Also good. The content of sodium carboxymethyl starch and / or carmellose calcium in the solid preparation of the present invention is not particularly limited, but is usually 1 to 50% by mass, preferably 2 to 20% by mass, and more preferably 3 ˜15 mass%.
また、カルボキシメチルスターチナトリウム又は/カルメロースカルシウムと、イブプロフェン及びエテンザミドの配合比は、カルボキシメチルスターチナトリウム又は/カルメロースカルシウム１質量部に対し、イブプロフェン及びエテンザミドを０．１〜３０質量部が好ましく、１〜３０質量部がより好ましく、特に好ましくは３〜２０質量部である。 The compounding ratio of carboxymethyl starch sodium or carmellose calcium and ibuprofen and etenzamide is preferably 0.1 to 30 parts by mass of ibuprofen and etenzamide with respect to 1 part by mass of sodium carboxymethyl starch or / carmellose calcium, 1-30 mass parts is more preferable, Especially preferably, it is 3-20 mass parts.
本発明の固形製剤の剤形は特に限定されず、錠剤、散剤、細粒剤、顆粒剤、丸剤、カプセル剤等の剤形を包含するが、特に錠剤が好ましい。なお、固形製剤はフィルムコーティングや糖衣による剤皮を施しても良い。錠剤としては、単一の層である単層錠、複数の層が積層され積層錠であってもよい。本発明においては、特に、イブプロフェンとエテンザミドとカルボキシメチルスターチナトリウム又は/カルメロースカルシウムは同一層に含まれるのが好ましく、製造の容易さや小型化できる観点などから単層錠が好ましい。これらを同一層に含んでも、相互作用は抑制されており、製造機器への付着は生じない。 The dosage form of the solid preparation of the present invention is not particularly limited, and includes dosage forms such as tablets, powders, fine granules, granules, pills, capsules, etc. Tablets are particularly preferable. The solid preparation may be coated with film coating or sugar coating. The tablet may be a single layer tablet which is a single layer, or a multilayer tablet in which a plurality of layers are laminated. In the present invention, ibuprofen, etenzamide, sodium carboxymethyl starch or carmellose calcium are preferably contained in the same layer, and a monolayer tablet is preferred from the viewpoint of ease of production and miniaturization. Even if these are contained in the same layer, the interaction is suppressed and adhesion to the manufacturing equipment does not occur.
本発明の固形製剤中には本発明の効果を損なわない質的、量的範囲で、通常用いられる他の有効成分、賦形剤、崩壊剤、結合剤、滑沢剤、着色剤、矯味矯臭剤、香料などを配合することができる。 In the solid preparation of the present invention, other active ingredients, excipients, disintegrants, binders, lubricants, colorants, flavoring, etc. that are usually used within the qualitative and quantitative ranges that do not impair the effects of the present invention. An agent, a fragrance | flavor, etc. can be mix | blended.
本発明の固形製剤に配合できる他の有効成分としては、例えば、抗ヒスタミン剤、鎮咳剤、ノスカピン類、気管支拡張剤、去痰剤、催眠鎮静剤、ビタミン類、抗炎症剤、胃粘膜保護剤、生薬類、漢方処方、カフェイン類等があげられ、これらからなる群より選ばれる１種又は２種以上を含有しても良い。 Other active ingredients that can be incorporated into the solid preparation of the present invention include, for example, antihistamines, antitussives, noscapine, bronchodilators, expectorants, hypnotic sedatives, vitamins, anti-inflammatory agents, gastric mucosal protective agents, herbal medicines, Chinese herbal prescriptions, caffeine and the like may be mentioned, and one or more selected from the group consisting of these may be contained.
本発明の固形製剤に配合できる賦形剤としては、例えば、乳糖、デンプン類、結晶セルロース、ショ糖、糖アルコール等が挙げられ、結合剤としては、ヒドロキシプロピルセルロース、ヒプロメロース、ゼラチン、アルファー化デンプン、ポリビニルピロリドン、プルラン等が挙げられ、滑沢剤としては、ショ糖脂肪酸エステル、硬化油、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム等が挙げられる。 Excipients that can be blended in the solid preparation of the present invention include, for example, lactose, starches, crystalline cellulose, sucrose, sugar alcohol and the like, and binders include hydroxypropylcellulose, hypromellose, gelatin, pregelatinized starch , Polyvinyl pyrrolidone, pullulan and the like, and examples of the lubricant include sucrose fatty acid ester, hydrogenated oil, stearic acid, magnesium stearate, calcium stearate and the like.
本発明の固形製剤は、常法により製造することができ、その方法は特に限定されるものではない。造粒する場合の方法も特に限定されず、湿式造粒法、乾式造粒法もしくは溶融造粒法などにより製造できるが、製造性の観点から特に湿式造粒法が好ましい。また得られた造粒物に適宜上記有効成分や賦形剤などの慣用の製剤添加剤を配合してもよく、また、このようにして得た混合物を打錠して錠剤とすることもできる。錠剤を製造する場合は、直接打錠法により製造してもよい。 The solid preparation of the present invention can be produced by a conventional method, and the method is not particularly limited. The method for granulation is not particularly limited, and it can be produced by a wet granulation method, a dry granulation method, a melt granulation method, or the like, but the wet granulation method is particularly preferable from the viewpoint of productivity. In addition, conventional granule additives such as the above active ingredients and excipients may be appropriately blended with the obtained granulated product, and the mixture thus obtained can be tableted into tablets. . When a tablet is produced, it may be produced by a direct tableting method.
以下に実施例及び比較例を挙げ、本発明をより詳しく説明するが、本発明はこれら実施例等に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 Comparative Examples, but the present invention is not limited to these Examples and the like.
（比較例１）
イブプロフェン３６ｇ、エテンザミド３６ｇ、ヒプロメロース８．４ｇをポリエチレン製の袋を用いて混合した。混合物と適量の水を加え乳鉢で練合した後、十分に乾燥させた。その後全量を篩（目開き７１０μｍ）に通過させ造粒物を得た。造粒物にステアリン酸マグネシウム１．２ｇを秤量し、混合した後、表１の組成となるように卓上簡易錠剤成型機（商品名：ＨＡＮＤＴＡＢ；市橋精機）を用いて１０ｋＮで打錠し、錠剤径８．５ｍｍの錠剤を得た。表１に６錠中に配合される処方を示す。
(Comparative Example 1)
36 g of ibuprofen, 36 g of etenzamide, and 8.4 g of hypromellose were mixed using a polyethylene bag. The mixture and an appropriate amount of water were added and kneaded in a mortar, and then sufficiently dried. Thereafter, the entire amount was passed through a sieve (aperture 710 μm) to obtain a granulated product. After weighing and mixing 1.2 g of magnesium stearate into the granulated product, it is tableted at 10 kN using a tabletop simple tablet molding machine (trade name: HANDTAB; Ichihashi Seiki) so that the composition shown in Table 1 is obtained. A tablet with a diameter of 8.5 mm was obtained. Table 1 shows the formulation formulated in 6 tablets.
（比較例２〜３、実施例１〜２）
イブプロフェン３６ｇ、エテンザミド３６ｇ、ヒプロメロース８．４ｇ、各種崩壊剤７．２ｇをポリエチレン製の袋を用いて混合し、比較例１と同様の方法により錠剤を得た。表１に６錠中に配合される処方を示す。
(Comparative Examples 2-3, Examples 1-2)
36 g of ibuprofen, 36 g of etenzamide, 8.4 g of hypromellose, and 7.2 g of various disintegrants were mixed using a polyethylene bag, and tablets were obtained in the same manner as in Comparative Example 1. Table 1 shows the formulation formulated in 6 tablets.
（付着評価）
各実施例及び比較例の錠剤について、打錠機（臼杵）への付着状況を目視で観察し、下記の評価基準に従って付着を評価した。
＜評価基準＞
◎：付着なし
○：わずかに付着あり
×：著しい付着あり
(Adhesion evaluation)
About the tablet of each Example and a comparative example, the adhesion condition to the tableting machine (usuki) was observed visually, and adhesion was evaluated according to the following evaluation criteria.
<Evaluation criteria>
◎: No adhesion ○: Slight adhesion x: Significant adhesion
表２に示すように、崩壊剤を配合しない比較例１では打錠機への付着が確認された。また崩壊剤であるクロスポビドン又はカルメロースを配合しても打錠機への付着は改善されなかったが(比較例２〜３)、カルボキシメチルスターチナトリウム及びカルメロースカルシウムを配合した実施例１及び実施例２は、打錠機への付着が認められなかった。 As shown in Table 2, adhesion to the tableting machine was confirmed in Comparative Example 1 in which no disintegrant was blended. Further, even when crospovidone or carmellose as a disintegrant was added, adhesion to the tableting machine was not improved (Comparative Examples 2 to 3), but Example 1 and Example where carboxymethyl starch sodium and carmellose calcium were added In Example 2, adhesion to the tableting machine was not observed.
（製造例１ イブプロフェン顆粒Ａ）
表３の製造例１に示す各成分を秤量後、混合した粉末を流動層造粒乾燥機（パウレック社製）を用いて水・アルコール混液にヒプロメロースを溶解させた造粒液を添加し、常法により造粒、乾燥した後２２メッシュの篩で整粒を行い、イブプロフェン顆粒Ａを得た。
(Production Example 1 ibuprofen granule A)
After weighing each component shown in Production Example 1 in Table 3, a granulated solution obtained by dissolving hypromellose in a water / alcohol mixture was added to the mixed powder using a fluidized bed granulator / dryer (manufactured by POWREC). After granulating and drying by the method, the particles were sized with a 22 mesh sieve to obtain ibuprofen granules A.
（製造例２ イブプロフェン顆粒Ｂ）
表３の製造例２に示す各成分を秤量後、混合した粉末を流動層造粒乾燥機（パウレック社製）を用いて水・アルコール混液にヒプロメロースを溶解させた造粒液を添加し、常法により造粒、乾燥した後２２メッシュの篩で整粒を行い、イブプロフェン顆粒Ｂを得た。
(Production Example 2 ibuprofen granule B)
After weighing each component shown in Production Example 2 in Table 3, a granulated liquid obtained by dissolving hypromellose in a water / alcohol mixture was added to the mixed powder using a fluidized bed granulator / dryer (manufactured by POWREC). Granulation and drying were carried out by the method, followed by sizing with a 22 mesh sieve to obtain ibuprofen granules B.
（製造例３ エテンザミド顆粒）
表３の製造例３に示す各成分を秤量後、混合した粉末を攪拌混合造粒装置（ＶＧ-２５：パウレック社製）を用いて水・アルコールの混合液を添加し、常法により造粒、乾燥した後、２２メッシュの篩で整粒を行い、エテンザミド顆粒を得た。
(Production Example 3 Ethenzamid granules)
After weighing each component shown in Production Example 3 in Table 3, the mixed powder was mixed with water / alcohol using a stirring and mixing granulator (VG-25: manufactured by Paulek), and granulated by a conventional method. After drying, the particles were sized with a 22-mesh sieve to obtain ethenamide granules.
（比較例４、実施例３〜５）
表４の組成となるように、各成分を秤量し、混合して打錠用顆粒を得た。ロータリー式打錠機（コレクト１２UH：菊水製作所製）を用い、回転数４０ｒｐｍにて得られた混合物を連続的に打錠した。打錠後の回転盤、杵、臼を確認し、上記の評価方法にて付着を評価した。
(Comparative Example 4, Examples 3-5)
Each component was weighed so as to have the composition shown in Table 4 and mixed to obtain granules for tableting. Using a rotary tableting machine (Collect 12UH: manufactured by Kikusui Seisakusho), the mixture obtained at a rotation speed of 40 rpm was continuously tableted. The tablet, tablet, and die after tableting were confirmed, and adhesion was evaluated by the above evaluation method.
表５に示すように、カルボキシメチルスターチナトリウムを配合した実施例３〜５では付着は発生しなかったが、崩壊剤に低置換度ヒドロキシプロピルセルロースを配合した比較例４では打錠機への付着が確認された。 As shown in Table 5, adhesion did not occur in Examples 3 to 5 in which sodium carboxymethyl starch was blended, but in Comparative Example 4 in which low-displacement hydroxypropylcellulose was blended into the disintegrant, adhesion to the tablet press. Was confirmed.
本発明によれば、イブプロフェンとエテンザミドを含有し、製造性及び生産性が向上した固形製剤の提供が可能となる。 According to the present invention, it is possible to provide a solid preparation containing ibuprofen and etenzamid and having improved manufacturability and productivity.
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