JP5134802B2 - Method for preventing reduction of bromhexine hydrochloride content - Google Patents
Method for preventing reduction of bromhexine hydrochloride content Download PDFInfo
- Publication number
- JP5134802B2 JP5134802B2 JP2006263673A JP2006263673A JP5134802B2 JP 5134802 B2 JP5134802 B2 JP 5134802B2 JP 2006263673 A JP2006263673 A JP 2006263673A JP 2006263673 A JP2006263673 A JP 2006263673A JP 5134802 B2 JP5134802 B2 JP 5134802B2
- Authority
- JP
- Japan
- Prior art keywords
- bromhexine hydrochloride
- weight
- solid preparation
- parts
- hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229960002335 bromhexine hydrochloride Drugs 0.000 title claims description 93
- YRSGDLIATOURQO-UHFFFAOYSA-N ethyl 4-acetyl-5-oxohexanoate Chemical compound CCOC(=O)CCC(C(C)=O)C(C)=O YRSGDLIATOURQO-UHFFFAOYSA-N 0.000 title claims description 93
- 238000000034 method Methods 0.000 title description 30
- 239000007787 solid Substances 0.000 claims description 69
- 238000002360 preparation method Methods 0.000 claims description 67
- 239000004386 Erythritol Chemical group 0.000 claims description 28
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Chemical group OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 28
- 239000004373 Pullulan Chemical group 0.000 claims description 28
- 229920001218 Pullulan Chemical group 0.000 claims description 28
- 235000019414 erythritol Nutrition 0.000 claims description 28
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical group OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 28
- 229940009714 erythritol Drugs 0.000 claims description 28
- 235000019423 pullulan Nutrition 0.000 claims description 28
- 239000008187 granular material Substances 0.000 description 50
- 150000005846 sugar alcohols Chemical class 0.000 description 37
- 230000007423 decrease Effects 0.000 description 29
- 239000001913 cellulose Substances 0.000 description 27
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- 239000003795 chemical substances by application Substances 0.000 description 16
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- 230000000052 comparative effect Effects 0.000 description 10
- -1 dextromethorphan phenolphthalein Salt Chemical class 0.000 description 10
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- 239000000203 mixture Substances 0.000 description 9
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- 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 8
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 7
- NTCYWJCEOILKNG-ROLPUNSJSA-N [(1r,2s)-1-hydroxy-1-phenylpropan-2-yl]-dimethylazanium;chloride Chemical compound Cl.CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 NTCYWJCEOILKNG-ROLPUNSJSA-N 0.000 description 7
- 229960000920 dihydrocodeine Drugs 0.000 description 7
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 7
- 229960001680 ibuprofen Drugs 0.000 description 7
- 229940051020 methylephedrine hydrochloride Drugs 0.000 description 7
- 229960002477 riboflavin Drugs 0.000 description 7
- 108010011485 Aspartame Proteins 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000000605 aspartame Substances 0.000 description 5
- 235000010357 aspartame Nutrition 0.000 description 5
- 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 5
- 229960003438 aspartame Drugs 0.000 description 5
- UCDKONUHZNTQPY-UHFFFAOYSA-N bromhexine hydrochloride Chemical compound Cl.C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N UCDKONUHZNTQPY-UHFFFAOYSA-N 0.000 description 5
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 5
- 230000003419 expectorant effect Effects 0.000 description 5
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- 239000002151 riboflavin Substances 0.000 description 5
- 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 4
- 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 4
- 229920003157 Eudragit® RL 30 D Polymers 0.000 description 4
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 4
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 4
- 230000000954 anitussive effect Effects 0.000 description 4
- 229940124584 antitussives Drugs 0.000 description 4
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 4
- 239000000832 lactitol Substances 0.000 description 4
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- 235000010447 xylitol Nutrition 0.000 description 4
- 229960002675 xylitol Drugs 0.000 description 4
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 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
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 229960003870 bromhexine Drugs 0.000 description 3
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical compound C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
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- 239000003112 inhibitor Substances 0.000 description 3
- 238000004898 kneading Methods 0.000 description 3
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- 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 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- PMGQWSIVQFOFOQ-BDUVBVHRSA-N (e)-but-2-enedioic acid;(2r)-2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound OC(=O)\C=C\C(O)=O.CN1CCC[C@@H]1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PMGQWSIVQFOFOQ-BDUVBVHRSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
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Description
本発明は、塩酸ブロムヘキシン含有固形製剤において、塩酸ブロムヘキシン含有量低下を防止する方法に関する。 The present invention relates to a method for preventing a decrease in bromhexine hydrochloride content in a solid preparation containing bromhexine hydrochloride.
塩酸ブロムヘキシンは、気道粘膜の分泌促進作用、粘液の稀釈をはかる粘稠調整作用、肺表面活性物質の分泌促進作用および繊毛運動亢進作用等により、去痰作用をもたらすとされている。この去痰作用を期待して、塩酸ブロムヘキシン単独または他の有効成分と共に配合された総合感冒薬や鎮咳去痰剤などが、すでに市販されている。
しかしながら、塩酸ブロムヘキシンは固形製剤中から昇華して散逸しやすいという欠点がある。そのために、固形製剤中における塩酸ブロムヘキシンの含有量が、経時的に低下してしまうという問題点が知られている。この問題を解決するために、従来から様々な工夫が為されてきた。例えば、塩酸ブロムヘキシンを含有する散剤や顆粒剤を製造する際に、賦形剤として単糖類や二糖類を配合する方法（特許文献１参照）、ｐＨ調節剤を配合する方法（特許文献２参照）、界面活性剤を配合する方法（特許文献３参照）、塩酸ブロムヘキシンをフィルムコートする方法（特許文献４参照）などが知られている。しかしながら、これらの方法ではいずれも、塩酸ブロムヘキシンを含有する固形製剤（以下、塩酸ブロムヘキシン含有固形製剤と称す）における塩酸ブロムヘキシン含有量低下の防止が不十分であることや、塩酸ブロムヘキシン含有固形製剤を製造するにあたり、複雑な製造工程を必要としている等の問題点がある。
また、ブロムヘキシンを含有する液剤としては、以下の報告がある。例えば、シロップ基剤の糖質としてマルチトールを用いれば、ブロムヘキシンが経時的に安定なシロップ剤が得られることが開示されている（特許文献５参照）。また、ブロムヘキシン及びマルチトールを配合した液剤（特許文献６参照）、ブロムヘキシン、ソーマチン及び糖アルコールを配合した液剤（特許文献６参照）が開示されている。さらには、水溶性薬物、植物性の高分子ゲル化剤、糖アルコール及び水からなるゲル状組成物において、水溶性組成物として塩酸ブロムヘキシンが開示されている（特許文献７参照）。しかしながら、これらは基本的に液剤における技術であって、本発明の固形製剤（顆粒剤、錠剤等）に適用できるものではないことは明らかである。
Bromohexine hydrochloride is said to bring about expectorant action by promoting the secretion of airway mucosa, adjusting the viscosity of mucus, increasing the secretion of pulmonary surfactants, and promoting ciliary movement. In anticipation of this expectorant effect, general cold medicines and antitussive expectorants formulated with bromhexine hydrochloride alone or with other active ingredients are already on the market.
However, bromhexine hydrochloride has a drawback that it is easily sublimated from the solid preparation. Therefore, a problem is known that the content of bromhexine hydrochloride in the solid preparation decreases with time. In order to solve this problem, various ideas have been made conventionally. For example, when producing a powder or granule containing bromhexine hydrochloride, a method of blending a monosaccharide or disaccharide as an excipient (see Patent Document 1), a method of blending a pH regulator (see Patent Document 2) A method of blending a surfactant (see Patent Document 3), a method of film-coating bromhexine hydrochloride (see Patent Document 4), and the like are known. However, in any of these methods, the prevention of a decrease in bromhexine hydrochloride content in a solid preparation containing bromhexine hydrochloride (hereinafter referred to as bromhexine hydrochloride-containing solid preparation) is insufficient, or a solid preparation containing bromhexine hydrochloride is produced. In doing so, there are problems such as requiring a complicated manufacturing process.
Moreover, there are the following reports as a liquid agent containing bromohexine. For example, it is disclosed that when maltitol is used as the saccharide of the syrup base, a syrup agent in which bromohexine is stable over time can be obtained (see Patent Document 5). Moreover, the liquid agent (refer patent document 6) which mix | blended bromohexine and maltitol (refer patent document 6) and the liquid agent (refer patent document 6) which mix | blended bromhexine, thaumatin, and sugar alcohol are disclosed. Furthermore, bromhexine hydrochloride is disclosed as a water-soluble composition in a gel composition comprising a water-soluble drug, a vegetable polymer gelling agent, a sugar alcohol, and water (see Patent Document 7). However, these are basically techniques for liquid preparations, and are obviously not applicable to the solid preparation (granule, tablet, etc.) of the present invention.
本発明は、塩酸ブロムヘキシン含有固形製剤における固形製剤中の塩酸ブロムヘキシン含有量低下の防止方法、固形製剤中の塩酸ブロムヘキシンの含有量低下を防止する塩酸ブロムヘキシン含有量低下防止剤、および塩酸ブロムヘキシン含有量低下が防止された塩酸ブロムヘキシン含有固形製剤（以下、本発明の固形製剤と称す）を提供するものである。 The present invention relates to a method for preventing a decrease in bromhexine hydrochloride content in a solid preparation in a solid preparation containing bromhexine hydrochloride, a bromhexine hydrochloride content decrease preventing agent for preventing a decrease in the content of bromhexine hydrochloride in a solid preparation, and a decrease in the content of bromhexine hydrochloride It is intended to provide a bromhexine hydrochloride-containing solid preparation (hereinafter referred to as the solid preparation of the present invention) in which the above is prevented.
本発明者らは鋭意研究の結果、塩酸ブロムヘキシン含有固形製剤に糖アルコール類を配合することにより、固形製剤中の塩酸ブロムヘキシンの含有量低下が防止されることを見出した。また、塩酸ブロムヘキシン含有固形製剤において、糖アルコール類に加えて、プルランおよび／またはセルロース誘導体を配合することにより、固形製剤中の塩酸ブロムヘキシンの含有量低下がより防止されることを見出し、本発明を完成させた。 As a result of diligent research, the present inventors have found that a decrease in the content of bromhexine hydrochloride in the solid preparation can be prevented by adding sugar alcohols to the solid preparation containing bromhexine hydrochloride. In addition, in the solid preparation containing bromohexine hydrochloride, it was found that by adding pullulan and / or a cellulose derivative in addition to sugar alcohols, a decrease in the content of bromhexine hydrochloride in the solid preparation is further prevented. Completed.
すなわち本発明は、
１．塩酸ブロムヘキシン含有固形製剤において、糖アルコール類を配合することを特徴とする固形製剤中の塩酸ブロムヘキシン含有量低下を防止する方法、
２．塩酸ブロムヘキシン含有固形製剤において、糖アルコール類、ならびにプルランおよび／またはセルロース誘導体を配合することを特徴とする固形製剤中の塩酸ブロムヘキシン含有量低下を防止する方法、
３．セルロース誘導体が、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースおよびメチルセルロースからなる群より選ばれる１種または２種以上である２に記載の固形製剤中の塩酸ブロムヘキシン含有量低下を防止する方法、
４．セルロース誘導体が、ヒドロキシプロピルセルロースである２に記載の固形製剤中の塩酸ブロムヘキシン含有量低下を防止する方法、
５．塩酸ブロムヘキシン含有固形製剤において、糖アルコール類およびプルランを配合することを特徴とする固形製剤中の塩酸ブロムヘキシン含有量低下を防止する方法、
６．糖アルコール類が、エリスリトール、マンニトール、ソルビトール、キシリトールおよびラクチトールからなる群より選ばれる１種または２種以上である１〜５のいずれか１に記載の固形製剤中の塩酸ブロムヘキシン含有量低下を防止する方法、
７．糖アルコール類が、エリスリトールである１〜５のいずれか１に記載の固形製剤中の塩酸ブロムヘキシン含有量低下を防止する方法、
８．糖アルコール類が、マンニトールである１〜５のいずれか１に記載の固形製剤中の塩酸ブロムヘキシン含有量低下を防止する方法、
９．塩酸ブロムヘキシン含有固形製剤において、エリスリトールおよびプルランを配合することを特徴とする固形製剤中の塩酸ブロムヘキシン含有量低下を防止する方法、
１０．糖アルコール類を含有することを特徴とする塩酸ブロムヘキシン含有量低下防止剤、
１１．糖アルコール類、ならびにプルランおよび／またはセルロース誘導体を含有することを特徴とする塩酸ブロムヘキシン含有量低下防止剤、
１２．セルロース誘導体が、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースおよびメチルセルロースからなる群より選ばれる１種または２種以上である１１に記載の塩酸ブロムヘキシン含有量低下防止剤、
１３．セルロース誘導体が、ヒドロキシプロピルセルロースである１１に記載の塩酸ブロムヘキシン含有量低下防止剤、
１４．糖アルコール類およびプルランを含有することを特徴とする塩酸ブロムヘキシン含有量低下防止剤、
１５．糖アルコール類が、エリスリトール、マンニトール、ソルビトール、キシリトールおよびラクチトールからなる群より選ばれる１種または２種以上である１０〜１４のいずれか１に記載の塩酸ブロムヘキシン含有量低下防止剤、
１６．糖アルコール類が、エリスリトールである１０〜１４のいずれか１に記載の塩酸ブロムヘキシン含有量低下防止剤、
１７．糖アルコール類が、マンニトールである１０〜１４のいずれか１に記載の塩酸ブロムヘキシン含有量低下防止剤、
１８．エリスリトールおよびプルランを含有することを特徴とする塩酸ブロムヘキシン含有量低下防止剤、
１９．塩酸ブロムヘキシンおよび糖アルコール類を含有する固形製剤、
２０．塩酸ブロムヘキシン、糖アルコール類、ならびにプルランおよび／またはセルロース誘導体を含有する固形製剤、
２１．セルロース誘導体が、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースおよびメチルセルロースからなる群より選ばれる１種または２種以上である２０に記載の固形製剤、
２２．セルロース誘導体が、ヒドロキシプロピルセルロースである２０に記載の固形製剤、
２３．塩酸ブロムヘキシン、糖アルコール類およびプルランを含有する固形製剤、
２４．糖アルコール類が、エリスリトール、マンニトール、ソルビトール、キシリトールおよびラクチトールからなる群より選ばれる１種または２種以上である１９〜２３のいずれか１に記載の固形製剤、
２５．糖アルコール類が、エリスリトールである１９〜２３のいずれか１に記載の固形製剤、
２６．糖アルコール類が、マンニトールである１９〜２３のいずれか１に記載の固形製剤、
２７．塩酸ブロムヘキシン、エリスリトールおよびプルランを含有する固形製剤、
２８．剤形が顆粒剤または錠剤である１９〜２７のいずれか１に記載の固形製剤である。
That is, the present invention
1. A method for preventing a decrease in the content of bromhexine hydrochloride in a solid preparation, characterized by containing sugar alcohols in the bromhexine hydrochloride-containing solid preparation,
2. A method for preventing a decrease in the content of bromhexine hydrochloride in a solid preparation, characterized by containing sugar alcohols and pullulan and / or a cellulose derivative in the solid preparation containing bromhexine hydrochloride,
3. The method for preventing a decrease in bromhexine hydrochloride content in the solid preparation according to 2, wherein the cellulose derivative is one or more selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose,
4). 2. A method for preventing a decrease in bromhexine hydrochloride content in the solid preparation according to 2, wherein the cellulose derivative is hydroxypropyl cellulose,
5. A method for preventing a decrease in the content of bromhexine hydrochloride in a solid preparation, characterized in that in the solid preparation containing bromhexine hydrochloride, a sugar alcohol and pullulan are blended,
6). The sugar alcohol is one or two or more selected from the group consisting of erythritol, mannitol, sorbitol, xylitol and lactitol, and prevents a decrease in bromhexine hydrochloride content in the solid preparation according to any one of 1 to 5 Method,
7). A method for preventing a decrease in bromhexine hydrochloride content in the solid preparation according to any one of 1 to 5, wherein the sugar alcohol is erythritol,
8). A method for preventing a decrease in bromhexine hydrochloride content in the solid preparation according to any one of 1 to 5, wherein the sugar alcohol is mannitol,
9. A method for preventing a decrease in the content of bromhexine hydrochloride in a solid preparation, characterized in that erythritol and pullulan are blended in the solid preparation containing bromhexine hydrochloride,
10. Bromhexine hydrochloride content lowering preventive agent characterized by containing sugar alcohols,
11. Bromhexine hydrochloride content lowering preventive agent characterized by containing sugar alcohols and pullulan and / or cellulose derivatives,
12 The bromhexine hydrochloride content-reducing inhibitor according to 11, wherein the cellulose derivative is one or more selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose,
13. The bromhexine hydrochloride content-reducing inhibitor according to 11, wherein the cellulose derivative is hydroxypropylcellulose,
14 Bromhexine hydrochloride content lowering preventive agent characterized by containing sugar alcohols and pullulan,
15. The bromhexine hydrochloride content lowering preventive agent according to any one of 10 to 14, wherein the sugar alcohol is one or more selected from the group consisting of erythritol, mannitol, sorbitol, xylitol and lactitol,
16. The bromhexine hydrochloride content lowering preventive agent according to any one of 10 to 14, wherein the sugar alcohol is erythritol,
17. The bromhexine hydrochloride content lowering preventive agent according to any one of 10 to 14, wherein the sugar alcohol is mannitol,
18. A bromhexine hydrochloride content lowering inhibitor characterized by containing erythritol and pullulan,
19. A solid preparation containing bromhexine hydrochloride and sugar alcohols,
20. A solid preparation containing bromhexine hydrochloride, sugar alcohols, and pullulan and / or cellulose derivatives,
21. 20. The solid preparation according to 20, wherein the cellulose derivative is one or more selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose.
22. The solid preparation according to 20, wherein the cellulose derivative is hydroxypropylcellulose,
23. A solid preparation containing bromhexine hydrochloride, sugar alcohols and pullulan,
24. The solid preparation according to any one of 19 to 23, wherein the sugar alcohol is one or more selected from the group consisting of erythritol, mannitol, sorbitol, xylitol and lactitol,
25. The solid preparation according to any one of 19 to 23, wherein the sugar alcohol is erythritol,
26. The solid preparation according to any one of 19 to 23, wherein the sugar alcohol is mannitol,
27. A solid formulation containing bromhexine hydrochloride, erythritol and pullulan,
28. 28. The solid preparation according to any one of 19 to 27, wherein the dosage form is a granule or a tablet.
後記実施例から明らかなように、塩酸ブロムヘキシン含有固形製剤において、糖アルコール類を配合することにより、固形製剤中の塩酸ブロムヘキシン含有量低下を防止することができる。さらに、糖アルコール類に加えて、プルランおよび／またはセルロース誘導体を配合することにより、固形製剤中の塩酸ブロムヘキシン含有量低下をより防止することができる。
本発明により、塩酸ブロムヘキシン含有固形製剤における新しい塩酸ブロムヘキシン含有量低下の防止方法、塩酸ブロムヘキシンの含有量低下を防止する塩酸ブロムヘキシン含有量低下防止剤、および塩酸ブロムヘキシン含有量が低下しない安定した塩酸ブロムヘキシン含有固形製剤を提供することができる。
As will be apparent from Examples described later, in the solid preparation containing bromhexine hydrochloride, by adding sugar alcohols, it is possible to prevent a decrease in the content of bromhexine hydrochloride in the solid preparation. Furthermore, by adding pullulan and / or a cellulose derivative in addition to sugar alcohols, it is possible to further prevent a decrease in the content of bromhexine hydrochloride in the solid preparation.
According to the present invention, a novel method for preventing a decrease in bromhexine hydrochloride content in a solid preparation containing bromhexine hydrochloride, a bromhexine hydrochloride content decrease preventing agent for preventing a decrease in bromhexine hydrochloride content, and a stable bromhexine hydrochloride content that does not decrease the bromhexine hydrochloride content A solid formulation can be provided.
本発明にかかる塩酸ブロムヘキシンは、公知の化合物であり、その入手方法としては、市販のものを用いてもよく、また公知の方法を用いて製造することも可能である。 Bromohexine hydrochloride according to the present invention is a known compound, and as a method for obtaining it, a commercially available product may be used, and it can also be produced using a known method.
本発明にかかる糖アルコール類としては、例えば、エリスリトール、マンニトール、ソルビトール、キシリトール、ラクチトール等が挙げられる。これらの糖アルコール類は、１種または２種以上を組み合わせてもよい。本発明にかかる糖アルコール類としては、エリスリトールまたはマンニトールが好ましく、エリスリトールが最も好ましい。
上記に挙げた糖アルコール類は、いずれも公知の化合物であり、市販のものを用いても良く、公知の方法を用いて製造することも可能である。
Examples of the sugar alcohol according to the present invention include erythritol, mannitol, sorbitol, xylitol, lactitol and the like. These sugar alcohols may be used alone or in combination of two or more. As the sugar alcohol according to the present invention, erythritol or mannitol is preferable, and erythritol is most preferable.
All of the sugar alcohols listed above are known compounds, and commercially available products may be used, or they can be produced using known methods.
本発明にかかるプルランは、公知の化合物であり、市販のものを用いてもよく、公知の方法を用いて製造することも可能である。 The pullulan according to the present invention is a known compound, and a commercially available product may be used, or the pullulan may be produced using a known method.
本発明にかかるセルロース誘導体としては、例えば、ヒドロキシプロピルセルロース（以下、ＨＰＣと称す）、ヒドロキシプロピルメチルセルロース、メチルセルロース等が挙げられる。これらのセルロース誘導体は、１種または２種以上を組み合わせてもよい。本発明にかかるセルロース誘導体としては、ＨＰＣが好ましい。上記に挙げたセルロース誘導体は、いずれも公知の化合物であり、市販のものを用いてもよく、公知の方法を用いて製造することも可能である。 Examples of the cellulose derivative according to the present invention include hydroxypropylcellulose (hereinafter referred to as HPC), hydroxypropylmethylcellulose, methylcellulose and the like. These cellulose derivatives may be used alone or in combination of two or more. As the cellulose derivative according to the present invention, HPC is preferable. Any of the cellulose derivatives listed above is a known compound, and a commercially available one may be used, or it can be produced using a known method.
本発明の塩酸ブロムヘキシン含有量低下を防止する方法は、塩酸ブロムヘキシン含有固形製剤において、固形製剤中に糖アルコール類を配合することを特徴とする。さらに糖アルコール類に加えて、プルランおよび／またはセルロース誘導体を配合することが好ましい。特に、塩酸ブロムヘキシン含有固形製剤において、固形製剤中に糖アルコール類およびプルランを配合することがより好ましく、固形製剤中にエリスリトールおよびプルランを配合することが、最も好ましい。 The method for preventing a decrease in the content of bromohexine hydrochloride according to the present invention is characterized in that a sugar alcohol is added to the solid preparation in the solid preparation containing bromohexine hydrochloride. In addition to sugar alcohols, pullulan and / or cellulose derivatives are preferably blended. In particular, in a bromhexine hydrochloride-containing solid preparation, it is more preferable to mix sugar alcohols and pullulan in the solid preparation, and it is most preferable to mix erythritol and pullulan in the solid preparation.
本発明の塩酸ブロムヘキシン含有量低下防止剤は、糖アルコール類を含有することを特徴とする。さらに糖アルコール類に加えて、プルランおよび／またはセルロース誘導体を含有することが好ましい。特に塩酸ブロムヘキシン含有量低下防止剤としては、糖アルコール類およびプルランを含有することがより好ましく、エリスリトールおよびプルランを含有することが最も好ましい。 The bromhexine hydrochloride content lowering preventive agent of the present invention is characterized by containing sugar alcohols. Furthermore, it is preferable to contain pullulan and / or a cellulose derivative in addition to sugar alcohols. In particular, the bromhexine hydrochloride content lowering preventive agent preferably contains sugar alcohols and pullulan, and most preferably contains erythritol and pullulan.
本発明の固形製剤は、塩酸ブロムヘキシンに糖アルコール類が配合されていることを特徴とする。さらに糖アルコール類に加えて、プルランおよび／またはセルロース誘導体が配合されていることが好ましい。本発明の固形製剤としては、塩酸ブロムヘキシンに糖アルコール類およびプルランが配合されることがより好ましく、塩酸ブロムヘキシンにエリスリトールおよびプルランが配合されていることが最も好ましい。 The solid preparation of the present invention is characterized in that sugar alcohols are blended in bromhexine hydrochloride. Furthermore, it is preferable that a pullulan and / or cellulose derivative is blended in addition to the sugar alcohols. In the solid preparation of the present invention, sugar alcohols and pullulan are more preferably blended with bromhexine hydrochloride, and most preferably erythritol and pullulan are blended with bromhexine hydrochloride.
本発明の固形製剤の患者への投与量は、患者の病状、性別、年齢、体重等に応じて適宜調節が可能であるが、例えば塩酸ブロムヘキシンを含有する経口固形製剤の場合、塩酸ブロムヘキシンの１日当たりの投与量として通常２〜２４ｍｇであり、４〜１２ｍｇが好ましく、１２ｍｇが最も好ましい。また、本発明の固形製剤における塩酸ブロムヘキシンの含有量は、特に制限されないが、上記塩酸ブロムヘキシンの１日当たりの投与量に合わせて適宜に決定すればよい。 The dose of the solid preparation of the present invention to a patient can be appropriately adjusted according to the patient's medical condition, sex, age, weight, etc. For example, in the case of an oral solid preparation containing bromhexine hydrochloride, 1 of bromhexine hydrochloride The daily dose is usually 2 to 24 mg, preferably 4 to 12 mg, and most preferably 12 mg. Further, the content of bromhexine hydrochloride in the solid preparation of the present invention is not particularly limited, but may be appropriately determined according to the daily dose of bromhexine hydrochloride.
塩酸ブロムヘキシンの含有量低下を防止するためのエリスリトールの配合量は、塩酸ブロムヘキシン１重量部に対して、糖アルコール類を１〜１０００重量部、好ましくは１〜５００重量部配合する。
プルランの配合量は、塩酸ブロムヘキシン１重量部に対して、プルランを１〜２００重量部、好ましくは１〜５０重量部配合する。
また、セルロース誘導体の配合量は、塩酸ブロムヘキシン１重量部に対して、セルロース誘導体を１〜１０００重量部、好ましくは１〜５００重量部配合する。
The blending amount of erythritol for preventing a decrease in the content of bromhexine hydrochloride is 1 to 1000 parts by weight, preferably 1 to 500 parts by weight, based on 1 part by weight of bromhexine hydrochloride.
The compounding amount of pullulan is 1 to 200 parts by weight, preferably 1 to 50 parts by weight of pullulan per 1 part by weight of bromhexine hydrochloride.
Moreover, the compounding quantity of a cellulose derivative is 1-1000 weight part of cellulose derivatives with respect to 1 weight part of bromhexine hydrochloride, Preferably 1-500 weight part is mix | blended.
本発明の固形製剤は、塩酸ブロムヘキシン以外の薬効成分を配合することができる。例えば、アスピリン、アスピリンアルミニウム、サザピリン、エテンザミド、サリチルアミド、イブプロフェン、アセトアミノフェン、イソプロピルアンチピリン等の解熱鎮痛薬、カフェイン、無水カフェイン、安息香酸ナトリウムカフェイン等の中枢神経興奮薬、ブロムワレリル尿素、アリルイソプロピルアセチル尿素等の鎮静剤、マレイン酸クロルフェニラミン、ジフェンヒドラミン、サリチル酸ジフェンヒドラミン、マレイン酸カルビノキサミン、メキタジン、酒石酸アリメマジン、塩酸ジフェニルピラリン、塩酸トリプロリジン、フマル酸クレマスチン等の抗ヒスタミン薬、塩化リゾチーム、ブロメライン、セラペプターゼ、セミアルカリプロティナーゼ、グリチルリチン酸、グリチルリチン酸ジカリウム、グリチルリチン酸アンモニウム、グリチルレチン酸、アズレンスルホン酸ナトリウム等の抗炎症薬、トラネキサム酸等の抗プラスミン剤、リン酸ジヒドロコデイン、リン酸コデイン、塩酸ノスカピン、ノスカピン、臭化水素酸デキストロメトルファン、デキストロメトルファンフェノールフタリン塩、リン酸ジメモルファン、ヒベンズ酸チペピジン、クエン酸チペピジン、塩酸エプラジノン、メチルエフェドリン、塩酸メチルエフェドリン、塩酸メトキシフェナミン、塩酸トリメトキノール、塩酸フェニルプロパノールアミン等の鎮咳薬、塩酸Ｌ−エチルシステイン、グアヤコールスルホン酸カリウム、クレゾール酸カリウム、グアイフェネシン、カルボシステイン、塩酸アンブロキソール等の去痰薬、テオフィリン、アミノフィリン、ジプロフィリン等の気管拡張薬、ベラドンナ（総）アルカロイド、べラドンナエキス、ヨウ化イソプロパミド、臭化水素酸スコポラミン、ロートエキス、臭化ブチルスコポラミン、臭化メチルベナクチジウム、ピレンゼピン等の抗アセチルコリン薬、セチルピリジニウム、塩化セチルピリジニウム、ポビドンヨード、グルコン酸クロルヘキシジン、塩化ベンザルコニウム、塩化デカリニウム、チモール、ヨウ素・ヨウ化カリウム、フェノール、塩酸クロルヘキシジン、クレオソート、塩化ベンゼトニウム等の酸化消毒剤、塩酸ジブカイン、アミノ安息香酸エチル、リドカイン、塩酸リドカイン、オキセサゼイン等の局所麻酔剤、炭酸水素ナトリウム、沈降炭酸カルシウム、炭酸マグネシウム、水酸化マグネシウム、酸化マグネシウム、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、メタケイ酸アルミン酸マグネシウム、合成ヒドロタルサイト、乾燥水酸化アルミニウムゲル、合成ケイ酸アルミニウム、水酸化アルミナマグネシウム、水酸化アルミニウムゲル等の制酸剤、塩酸セトラキサート、スクラルファート、アズレン等の胃粘膜保護剤、ビタミンＡ、ビタミンＢ１、ビタミンＢ２、ビタミンＢ６、ビタミンＢ１２、ビタミンＣ、アスコルビン酸カルシウム、ビタミンＤ、ビタミンＥ、コハク酸トコフェノールカルシウム等のビタミン剤、パントテン酸、パンテノール、パントテン酸カルシウム、パントテン酸ナトリウム、パンテチン、ニコチン酸、ニコチン酸アミド、グルクロン酸、グルクロノラクトン、アミノエチルスルホン酸、ビオチン、γ−オリザノール等の代謝性成分、地竜、ケイヒ、ゴオウ、ショウキョウ、キキョウ、マオウ、カンゾウ、キョウニン、ハンゲ、シャゼンソウ、セネガ、サイコ、ブクリョウ、シンイ等の生薬およびこれら生薬の抽出物（エキス、チンキ等）等を挙げることができるが、上記のもののみに限定されるべきではない。これらの薬効成分は、単一成分を配合してもよく、２種以上のものを組み合わせて配合してもよい。中でも、抗プラスミン剤、解熱鎮痛薬、抗ヒスタミン薬、鎮咳薬、ビタミン剤が配合成分として好ましく、抗プラスミン剤としては、トラネキサム酸が特に好ましく、解熱鎮痛薬としては、イブプロフェンが特に好ましく、抗ヒスタミン薬としては、フマル酸クレマスチンが特に好ましく、鎮咳剤としては、リン酸ジヒドロコデイン、塩酸メチルエフェドリンが特に好ましく、ビタミン剤としては、ビタミンＢ１、ビタミンＢ２が特に好ましい。 The solid preparation of the present invention can contain a medicinal component other than bromhexine hydrochloride. For example, antipyretic analgesics such as aspirin, aspirin aluminum, sazapyrine, ethenamide, salicylamide, ibuprofen, acetaminophen, isopropylantipyrine, central nervous stimulants such as caffeine, anhydrous caffeine, sodium benzoate caffeine, bromvalerylurea, Sedatives such as allylisopropylacetylurea, chlorpheniramine maleate, diphenhydramine, diphenhydramine salicylate, carbinoxamine maleate, mequitazine, alimemazine tartrate, diphenylpyraline hydrochloride, triprolidine hydrochloride, clemastine fumarate, etc., lysozyme chloride, bromelain , Serrapeptase, semi-alkaline proteinase, glycyrrhizic acid, dipotassium glycyrrhizinate, glycyrrhizinate ammo Anti-inflammatory drugs such as sodium, glycyrrhetinic acid and sodium azulene sulfonate, antiplasmin drugs such as tranexamic acid, dihydrocodeine phosphate, codeine phosphate, noscapine hydrochloride, noscapine, dextromethorphan hydrobromide, dextromethorphan phenolphthalein Salt, Dimemorphan phosphate, Tipepidine hibenzate, Tipepidine citrate, Eprazinone hydrochloride, Methylephedrine, Methylephedrine hydrochloride, Methoxyphenamine hydrochloride, Trimethquinol hydrochloride, Phenylpropanolamine, and other antitussives, L-ethylcysteine hydrochloride, guaiacol Tracheal dilation such as expectorants such as potassium sulfonate, potassium cresolate, guaifenesin, carbocysteine, ambroxol hydrochloride, theophylline, aminophylline, diprofylline , Belladonna (total) alkaloids, belladonna extract, isopropamide iodide, scopolamine hydrobromide, funnel extract, butyl scopolamine bromide, methyl benzactidium bromide, pirenzepine and other antiacetylcholine drugs, cetylpyridinium, cetylpyridinium chloride, Povidone iodine, chlorhexidine gluconate, benzalkonium chloride, decalinium chloride, thymol, iodine / potassium iodide, phenol, chlorhexidine hydrochloride, creosote, benzethonium chloride and other oxidative disinfectants, dibucaine hydrochloride, ethyl aminobenzoate, lidocaine, lidocaine hydrochloride , Local anesthetics such as oxesasein, sodium bicarbonate, precipitated calcium carbonate, magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium silicate, aluminum silicate Antacids such as magnesium silicate, magnesium aluminate metasilicate, synthetic hydrotalcite, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium alumina hydroxide, aluminum hydroxide gel, gastric mucosa such as cetraxate hydrochloride, sucralfate, azulene, etc. Protective agents, vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, calcium ascorbate, vitamin D, vitamin E, tocophenol calcium succinate, etc., pantothenic acid, panthenol, calcium pantothenate Metabolic components such as sodium pantothenate, pantethine, nicotinic acid, nicotinamide, glucuronic acid, glucuronolactone, aminoethylsulfonic acid, biotin, γ-oryzanol, earth dragon, keihi, goo , Herb, chrysanthemum, licorice, kyonin, hangage, shazensou, senega, psycho, bukkyou, shinny, etc. Should not be limited to. These medicinal components may be blended with a single component or in combination of two or more. Among them, an antiplasmin agent, an antipyretic analgesic, an antihistamine, an antitussive, and a vitamin are preferable as a combination component, and as an antiplasmin agent, tranexamic acid is particularly preferable, and as an antipyretic analgesic, ibuprofen is particularly preferable, and an antihistamine. The drug is particularly preferably clemastine fumarate, the antitussive is particularly preferably dihydrocodeine phosphate or methylephedrine hydrochloride, and the vitamin is particularly preferably vitamin B1 or vitamin B2.
本発明の固形製剤は、本発明に係る各種成分を公知の製造方法にて製剤化することにより得ることができる。例えば、粉砕、混合、練合、造粒、圧縮、乾燥、整粒、篩過等を必要に応じて行なうことができる。造粒の方法としては、例えば湿式造粒法、乾式造粒法、溶融造粒法等を挙げることができる。得られた造粒物は、必要に応じて圧縮処理を行ない、成型することができる。圧縮処理は一般的な成型機を用いて、所望の圧縮成型圧にて行なうことができる。 The solid preparation of the present invention can be obtained by formulating various components according to the present invention by a known production method. For example, pulverization, mixing, kneading, granulation, compression, drying, sizing, and sieving can be performed as necessary. Examples of the granulation method include a wet granulation method, a dry granulation method, and a melt granulation method. The obtained granulated product can be molded by performing a compression treatment as necessary. The compression process can be performed using a general molding machine at a desired compression molding pressure.
さらに、本発明の固形製剤を製造するにあたり、本発明の効果に影響を及ぼさない範囲内で、該固形製剤中に適当な添加物を加えることができる。具体的には、賦形剤、結合剤、崩壊剤、滑沢剤等を挙げることができる。
賦形剤としては、例えば、結晶セルロース、粉末セルロース、バレイショデンプン、軽質無水ケイ酸、含水二酸化ケイ素、二酸化ケイ素、沈降炭酸カルシウム、無水リン酸水素カルシウム、酸化マグネシウム、乳酸カルシウム、ケイ酸カルシウム、メタケイ酸アルミン酸マグネシウム、合成ヒドロタルサイト、合成ケイ酸アルミニウム、乳糖、トレハロース、白糖、ブドウ糖、果糖等を挙げることができる。
崩壊剤としては、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、ベントナイト等を挙げることができる。
結合剤としては、例えば、ポリビニルアルコール、ポビドン、アラビアゴム、アルギン酸ナトリウム、カルボキシビニルポリマー、ゼラチン、デキストリン、ペクチン、アミノアルキルメタクリレートコポリマー、ポリアクリル酸ナトリウム等を挙げることができる。
滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、ショ糖脂肪酸エステル、グリセリン脂肪酸エステル、ラウリル硫酸ナトリウム、硬化油等を挙げることができる。
これらの添加物は、１種または２種以上を組み合わせてもよい。
Furthermore, in producing the solid preparation of the present invention, an appropriate additive can be added to the solid preparation within a range that does not affect the effects of the present invention. Specific examples include excipients, binders, disintegrants, and lubricants.
Examples of excipients include crystalline cellulose, powdered cellulose, potato starch, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, calcium lactate, calcium silicate, and metasilica. Examples include magnesium aluminate, synthetic hydrotalcite, synthetic aluminum silicate, lactose, trehalose, sucrose, glucose, fructose and the like.
Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, alginic acid, partially pregelatinized starch, and bentonite.
Examples of the binder include polyvinyl alcohol, povidone, gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, aminoalkyl methacrylate copolymer, sodium polyacrylate and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, sodium lauryl sulfate, and hardened oil.
These additives may be used alone or in combination of two or more.
本発明の固形製剤の剤形は、錠剤、顆粒剤、細粒剤、散剤またはカプセル剤が好ましく、特に顆粒剤または錠剤がより好ましい。 The dosage form of the solid preparation of the present invention is preferably a tablet, granule, fine granule, powder or capsule, and more preferably a granule or tablet.
以下に実施例、比較例、試験例を示して本発明をさらに詳しく説明するが、本発明はこれらのみに限定されるべきものではない。
（実施例１）
イブプロフェンを４５０重量部およびアミノアルキルメタクリレートコポリマーＲＳ（商品名：オイドラギットＲＬ−３０Ｄ レームファーマ社）を１３．５重量部混合し、エタノールを適量加えて練合、乾燥、整粒した。得られた造粒物に、塩酸メチルエフェドリンを６０重量部、リン酸ジヒドロコデインを２４重量部、リボフラビンを６．５重量部、塩酸ブロムヘキシンを１２重量部、エリスリトールを１１７１重量部、結晶セルロースを２００重量部、ＨＰＣを４５重量部、アスパルテームを１８重量部加え、混合し、精製水を適量加えて練合、造粒、乾燥、整粒、篩過し、Ａ顆粒を得た。さらに表１に記載されている実施例１のＢ顆粒の原料を混合し、精製水を適量加えて造粒、乾燥、整粒、篩過し、Ｂ顆粒を得た。次いでＡ顆粒とＢ顆粒を混合し、実施例１の顆粒剤を得た。
Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples, but the present invention should not be limited to these.
Example 1
450 parts by weight of ibuprofen and 13.5 parts by weight of aminoalkyl methacrylate copolymer RS (trade name: Eudragit RL-30D Ream Pharma Co., Ltd.) were mixed, and an appropriate amount of ethanol was added and kneaded, dried and sized. The obtained granulated product was mixed with 60 parts by weight of methylephedrine hydrochloride, 24 parts by weight of dihydrocodeine phosphate, 6.5 parts by weight of riboflavin, 12 parts by weight of bromhexine hydrochloride, 1171 parts by weight of erythritol, and 200 parts by weight of crystalline cellulose. Part, 45 parts by weight of HPC and 18 parts by weight of aspartame were mixed and mixed, and an appropriate amount of purified water was added to knead, granulate, dry, granulate and sieve to obtain A granules. Furthermore, the raw material of the B granule of Example 1 described in Table 1 was mixed, and an appropriate amount of purified water was added, and granulated, dried, sized and sieved to obtain B granule. Subsequently, A granule and B granule were mixed and the granule of Example 1 was obtained.
（比較例１）
実施例１のエリスリトールをコーンスターチに換え、実施例１と同様の操作により比較例1の顆粒剤を得た。
(Comparative Example 1)
The erythritol of Example 1 was replaced with corn starch, and a granule of Comparative Example 1 was obtained in the same manner as in Example 1.
（試験例１）
実施例１および比較例１の顆粒剤を、各々アルミ包装に入れ、５０℃にて１０日間保存し、１０日後における顆粒剤中の塩酸ブロムヘキシンの残存率を、高速液体クロマトグラフィーを用いて測定した。結果を表２に示す。
(Test Example 1)
The granules of Example 1 and Comparative Example 1 were each placed in an aluminum package and stored at 50 ° C. for 10 days. The residual rate of bromhexine hydrochloride in the granules after 10 days was measured using high performance liquid chromatography. . The results are shown in Table 2.
表１
表２
表２の結果から、塩酸ブロムヘキシンを含有する固形製剤において、コーンスターチを配合した場合（比較例１）と比較して、エリスリトールを配合した場合（実施例１）の方が、固形製剤中の塩酸ブロムヘキシンの残存率が高いことが認められた。 From the results in Table 2, in the solid preparation containing bromhexine hydrochloride, bromhexine hydrochloride in the solid preparation is more effective when erythritol is added (Example 1) than when corn starch is added (Comparative Example 1). It was confirmed that the residual rate of was high.
（実施例２）
イブプロフェンを４５０重量部およびアミノアルキルメタクリレートコポリマーＲＳ（商品名：オイドラギットＲＬ−３０Ｄ レームファーマ社）を１３．５重量部混合し、エタノールを適量加えて練合、乾燥、整粒した。得られた造粒物に、塩酸メチルエフェドリンを６０重量部、リン酸ジヒドロコデインを２４重量部、リボフラビンを６．５重量部、塩酸ブロムヘキシンを１２重量部、エリスリトールを１１７１重量部、結晶セルロースを２００重量部、ＨＰＣを４５重量部、アスパルテームを１８重量部加え、混合し、精製水を適量加えて練合、造粒、乾燥、整粒、篩過し、Ａ顆粒を得た。さらに表３に記載されている実施例２のＢ顆粒の原料を混合し、精製水を適量加えて練合、造粒、乾燥、整粒、篩過し、Ｂ顆粒を得た。次いでＡ顆粒とＢ顆粒を混合し、実施例２の顆粒剤を得た。
(Example 2)
450 parts by weight of ibuprofen and 13.5 parts by weight of aminoalkyl methacrylate copolymer RS (trade name: Eudragit RL-30D Ream Pharma Co., Ltd.) were mixed, and an appropriate amount of ethanol was added and kneaded, dried and sized. The obtained granulated product was mixed with 60 parts by weight of methylephedrine hydrochloride, 24 parts by weight of dihydrocodeine phosphate, 6.5 parts by weight of riboflavin, 12 parts by weight of bromhexine hydrochloride, 1171 parts by weight of erythritol, and 200 parts by weight of crystalline cellulose. Part, 45 parts by weight of HPC and 18 parts by weight of aspartame were mixed and mixed, and an appropriate amount of purified water was added to knead, granulate, dry, granulate and sieve to obtain A granules. Furthermore, the raw material of the B granule of Example 2 described in Table 3 was mixed, an appropriate amount of purified water was added, and kneading, granulation, drying, sizing and sieving were performed to obtain B granule. Subsequently, A granule and B granule were mixed and the granule of Example 2 was obtained.
（比較例２）
イブプロフェンを４５０重量部およびアミノアルキルメタクリレートコポリマーＲＳ（商品名：オイドラギットＲＬ−３０Ｄ レームファーマ社）を１３．５重量部混合し、エタノールを適量加えて練合、乾燥、整粒した。得られた造粒物に、塩酸メチルエフェドリンを６０重量部、リン酸ジヒドロコデインを２４重量部、リボフラビンを６．５重量部、塩酸ブロムヘキシンを１２重量部、エリスリトールを１０１６重量部、結晶セルロースを２００重量部、ポリエチレングリコール６０００（ＰＥＧ６０００）を２００重量部、アスパルテームを１８重量部加え、混合し、精製水を適量加えて練合、造粒、乾燥、整粒、篩過し、Ａ顆粒を得た。さらに表３に記載されている比較例２のＢ顆粒の原料を混合し、精製水を適量加えて造粒、乾燥、整粒、篩過し、Ｂ顆粒を得た。次いでＡ顆粒とＢ顆粒を混合し、比較例２の顆粒剤を得た。
(Comparative Example 2)
450 parts by weight of ibuprofen and 13.5 parts by weight of aminoalkyl methacrylate copolymer RS (trade name: Eudragit RL-30D Ream Pharma Co., Ltd.) were mixed, and an appropriate amount of ethanol was added and kneaded, dried and sized. The obtained granulated product was mixed with 60 parts by weight of methylephedrine hydrochloride, 24 parts by weight of dihydrocodeine phosphate, 6.5 parts by weight of riboflavin, 12 parts by weight of bromhexine hydrochloride, 1016 parts by weight of erythritol, and 200 parts by weight of crystalline cellulose. Part, 200 parts by weight of polyethylene glycol 6000 (PEG 6000) and 18 parts by weight of aspartame were added and mixed, and an appropriate amount of purified water was added to knead, granulate, dry, granulate and sieve to obtain A granules. Furthermore, the raw material of the B granule of Comparative Example 2 described in Table 3 was mixed, and an appropriate amount of purified water was added, followed by granulation, drying, granulation, and sieving to obtain B granule. Subsequently, A granule and B granule were mixed and the granule of the comparative example 2 was obtained.
（試験例２）
実施例２および比較例２の顆粒剤を、各々アルミ包装に入れ、５０℃にて１０日間、２０日間、３０日間保存し、１０日後、２０日後、３０日後における顆粒剤中の塩酸ブロムヘキシンの残存率を、高速液体クロマトグラフィーを用いて測定した。結果を表４に示す。
(Test Example 2)
The granules of Example 2 and Comparative Example 2 were each placed in an aluminum package and stored at 50 ° C. for 10 days, 20 days, and 30 days. Remaining bromhexine hydrochloride in the granules after 10 days, 20 days, and 30 days The rate was measured using high performance liquid chromatography. The results are shown in Table 4.
表３
表４
表４の結果から、塩酸ブロムヘキシンを含有する固形製剤において、エリスリトールおよびＰＥＧ６０００を配合した場合（比較例２）と比較して、エリスリトールおよびＨＰＣを配合した場合（実施例２）の方が、固形製剤中の塩酸ブロムヘキシンの残存率が高いことが認められた。 From the results shown in Table 4, in the solid preparation containing bromhexine hydrochloride, the case where erythritol and HPC were blended (Example 2) was more solid than the case where erythritol and PEG6000 were blended (Comparative Example 2). A high residual ratio of bromhexine hydrochloride was observed.
（実施例３）
イブプロフェンを４５０重量部、アミノアルキルメタクリルコポリマーＲＳ（商品名：オイドラギットＲＬ−３０Ｄ レームファーマ社）を２７重量部、硬化油を９０重量部、ＨＰＣを２７重量部混合し、さらにエタノールを適量加えて練合、乾燥、整粒した。得られた造粒物に、塩酸メチルエフェドリンを６０重量部、リン酸ジヒドロコデインを２４重量部、リボフラビンを６．５重量部、塩酸ブロムヘキシンを１２重量部、エリスリトールを９４５．５重量部、結晶セルロースを２００重量部、プルランを１００重量部、クロスカルメロースナトリウムを４０重量部、アスパルテームを１８重量部加え、混合し、精製水を適量加えて練合、造粒、乾燥、整粒、篩過し、Ａ顆粒を得た。さらに表５に記載された実施例３のＢ顆粒の原料を混合し、精製水を適量加えて造粒、乾燥、整粒、篩過し、Ｂ顆粒を得た。Ａ顆粒とＢ顆粒を混合し、実施例３の顆粒剤を得た。
(Example 3)
Mix 450 parts by weight of ibuprofen, 27 parts by weight of aminoalkyl methacrylic copolymer RS (trade name: Eudragit RL-30D Ream Pharma), 90 parts by weight of hardened oil, 27 parts by weight of HPC, and knead by adding an appropriate amount of ethanol. Combined, dried and sized. The obtained granulated product was mixed with 60 parts by weight of methylephedrine hydrochloride, 24 parts by weight of dihydrocodeine phosphate, 6.5 parts by weight of riboflavin, 12 parts by weight of bromhexine hydrochloride, 945.5 parts by weight of erythritol, and crystalline cellulose. 200 parts by weight, 100 parts by weight of pullulan, 40 parts by weight of croscarmellose sodium, 18 parts by weight of aspartame, mix, add an appropriate amount of purified water, knead, granulate, dry, granulate, sieve, A granules were obtained. Furthermore, the raw material of the B granule of Example 3 described in Table 5 was mixed, and an appropriate amount of purified water was added, and granulated, dried, sized and sieved to obtain B granule. A granule and B granule were mixed, and the granule of Example 3 was obtained.
（実施例４）
イブプロフェン４５０重量部、およびアミノアルキルメタクリルコポリマーＲＳ（商品名：オイドラギットＲＬＰＯ レームファーマ社）を９０重量部混合し、さらにエタノールを適量加えて練合、乾燥、整粒した。得られた造粒物に、塩酸メチルエフェドリンを６０重量部、リン酸ジヒドロコデインを２４重量部、リボフラビンを６．５重量部、塩酸ブロムヘキシンを１２重量部、エリスリトールを９７３．５重量部、結晶セルロースを２００重量部、プルランを１２０重量部、クロスカルメロースナトリウムを４０重量部加え、さらにアスパルテームを１８重量部、アミノアルキルメタクリルコポリマーＲＳ（商品名：オイドラギットＲＬＰＯ レームファーマ社）を６重量部加え、混合し、精製水を適量加えて練合、造粒、乾燥、整粒、篩過し、Ａ顆粒を得た。さらに表５に記載された実施例４のＢ顆粒の原料を、実施例３と同様の操作により処理し、Ｂ顆粒を得た。Ａ顆粒とＢ顆粒を混合し、実施例４の顆粒剤を得た。
Example 4
450 parts by weight of ibuprofen and 90 parts by weight of an aminoalkyl methacrylic copolymer RS (trade name: Eudragit RLPO Ream Pharma) were mixed, and an appropriate amount of ethanol was added, followed by kneading, drying and sizing. To the resulting granulated product, 60 parts by weight of methylephedrine hydrochloride, 24 parts by weight of dihydrocodeine phosphate, 6.5 parts by weight of riboflavin, 12 parts by weight of bromhexine hydrochloride, 973.5 parts by weight of erythritol, crystalline cellulose 200 parts by weight, 120 parts by weight of pullulan, 40 parts by weight of croscarmellose sodium, 18 parts by weight of aspartame, and 6 parts by weight of aminoalkyl methacrylic copolymer RS (trade name: Eudragit RLPO Ream Pharma) are added and mixed. Then, an appropriate amount of purified water was added and kneaded, granulated, dried, sized and sieved to obtain A granules. Furthermore, the raw material of B granule of Example 4 described in Table 5 was processed by the same operation as Example 3, and B granule was obtained. A granule and B granule were mixed, and the granule of Example 4 was obtained.
（試験例３）
実施例３、実施例４にて得られた顆粒剤を各々アルミ包装に入れ、５０℃にて１０日間、２０日間、３０日間保存し、１０日後、２０日後、３０日後における顆粒剤中の塩酸ブロムヘキシンの残存率を、高速液体クロマトグラフィーを用いて測定した。結果を表６に示す。
(Test Example 3)
The granules obtained in Example 3 and Example 4 were each put in an aluminum package, stored at 50 ° C. for 10, 20, and 30 days, and hydrochloric acid in the granules after 10, 20, and 30 days. The residual rate of bromhexine was measured using high performance liquid chromatography. The results are shown in Table 6.
表５
表６
表６の結果から、塩酸ブロムヘキシンを含有する固形製剤において、エリスリトールに加えてプルランを配合した場合（実施例３および４）においても、エリスリトールおよびＨＰＣを配合した場合と同様に、固形製剤中の塩酸ブロムヘキシンの残存率が高いことが認められた。 From the results of Table 6, in the solid preparation containing bromhexine hydrochloride, in the case where pullulan was added in addition to erythritol (Examples 3 and 4), the hydrochloric acid in the solid preparation was similar to the case where erythritol and HPC were added. A high residual rate of bromhexine was observed.
本発明により、塩酸ブロムヘキシン含有固形製剤における新しい塩酸ブロムヘキシン含有量低下の防止方法、および塩酸ブロムヘキシン含有量が低下しない安定した塩酸ブロムヘキシン含有固形製剤を提供することができる。すなわち、塩酸ブロムヘキシンを主成分とした去痰薬や、塩酸ブロムヘキシンを有効成分として含む総合感冒薬において、塩酸ブロムヘキシン含有量が低下しないものを提供することができる。 INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a novel method for preventing a decrease in bromhexine hydrochloride content in a bromhexine hydrochloride-containing solid preparation and a stable bromhexine hydrochloride-containing solid preparation in which the bromhexine hydrochloride content does not decrease. That is, it is possible to provide an expectorant containing bromhexine hydrochloride as a main component or a general cold medicine containing bromhexine hydrochloride as an active ingredient, in which the bromhexine hydrochloride content does not decrease.
Claims (1)
塩酸ブロムヘキシン、エリスリトールおよびプルランを含有することを特徴とする、
固形製剤。 In a solid preparation containing bromhexine hydrochloride,
Containing bromhexine hydrochloride, erythritol and pullulan ,
Solid form preparations.
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| JP2009001548A (en) * | 2007-05-21 | 2009-01-08 | Daiichi Sankyo Healthcare Co Ltd | Airway goblet cell hyperplasia inhibitor composed of trehalose |
| US9220693B2 (en) | 2010-07-12 | 2015-12-29 | Boehringer Ingelheim International Gmbh | Aqueous composition comprising bromhexine |
| TW201247195A (en) * | 2011-04-28 | 2012-12-01 | Kowa Co | Stable pharmaceutical composition |
| JP2019081757A (en) * | 2017-10-31 | 2019-05-30 | 武田コンシューマーヘルスケア株式会社 | Method for producing solid preparation |
| CN111789817A (en) * | 2020-08-11 | 2020-10-20 | 河北科星药业有限公司 | Bromhexine hydrochloride soluble powder for livestock and poultry as well as preparation method and application thereof |
| CN114831942A (en) * | 2022-05-19 | 2022-08-02 | 齐鲁动物保健品有限公司 | Veterinary medicine bromhexine hydrochloride soluble powder and preparation method thereof |
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