JP4911274B2 - Stabilized solid formulation - Google Patents
Stabilized solid formulation Download PDFInfo
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- JP4911274B2 JP4911274B2 JP2005136806A JP2005136806A JP4911274B2 JP 4911274 B2 JP4911274 B2 JP 4911274B2 JP 2005136806 A JP2005136806 A JP 2005136806A JP 2005136806 A JP2005136806 A JP 2005136806A JP 4911274 B2 JP4911274 B2 JP 4911274B2
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- bromhexine hydrochloride
- solid preparation
- polyethylene glycol
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- glycine
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- 239000007787 solid Substances 0.000 title claims description 27
- 239000000203 mixture Substances 0.000 title claims description 22
- 238000009472 formulation Methods 0.000 title claims description 19
- YRSGDLIATOURQO-UHFFFAOYSA-N ethyl 4-acetyl-5-oxohexanoate Chemical compound CCOC(=O)CCC(C(C)=O)C(C)=O YRSGDLIATOURQO-UHFFFAOYSA-N 0.000 claims description 41
- 229960002335 bromhexine hydrochloride Drugs 0.000 claims description 39
- 238000002360 preparation method Methods 0.000 claims description 25
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 20
- 235000001014 amino acid Nutrition 0.000 claims description 16
- 150000001413 amino acids Chemical class 0.000 claims description 16
- 239000002202 Polyethylene glycol Substances 0.000 claims description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims description 15
- 239000004471 Glycine Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 9
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 9
- 229960001680 ibuprofen Drugs 0.000 claims description 9
- 108010011485 Aspartame Proteins 0.000 claims description 8
- 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 claims description 8
- 235000010357 aspartame Nutrition 0.000 claims description 8
- 239000000605 aspartame Substances 0.000 claims description 8
- 229960003438 aspartame Drugs 0.000 claims description 8
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 7
- 235000003704 aspartic acid Nutrition 0.000 claims description 6
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 6
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 6
- 230000000087 stabilizing effect Effects 0.000 claims description 4
- 108060006613 prolamin Proteins 0.000 claims 2
- 235000004554 glutamine Nutrition 0.000 claims 1
- 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 18
- 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 18
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 18
- 229960004708 noscapine Drugs 0.000 description 18
- 229940024606 amino acid Drugs 0.000 description 12
- 108090000765 processed proteins & peptides Proteins 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- 238000013329 compounding Methods 0.000 description 6
- 229960005261 aspartic acid Drugs 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 3
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 3
- UCDKONUHZNTQPY-UHFFFAOYSA-N bromhexine hydrochloride Chemical compound Cl.C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N UCDKONUHZNTQPY-UHFFFAOYSA-N 0.000 description 3
- 229960002743 glutamine Drugs 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000000368 destabilizing effect Effects 0.000 description 2
- 239000003172 expectorant agent Substances 0.000 description 2
- 230000003419 expectorant effect Effects 0.000 description 2
- 229960002449 glycine Drugs 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- 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 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
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000805 Polyaspartic acid Polymers 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 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 1
- -1 and the like Chemical compound 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 1
- 229960000456 carbinoxamine maleate Drugs 0.000 description 1
- GVNWHCVWDRNXAZ-BTJKTKAUSA-N carbinoxamine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 GVNWHCVWDRNXAZ-BTJKTKAUSA-N 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229960000920 dihydrocodeine Drugs 0.000 description 1
- 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 1
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 1
- 229940073563 dl- methylephedrine hydrochloride Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- UIERGBJEBXXIGO-UHFFFAOYSA-N thiamine mononitrate Chemical compound [O-][N+]([O-])=O.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UIERGBJEBXXIGO-UHFFFAOYSA-N 0.000 description 1
Description
本発明は固形製剤に関し、さらに詳しくは塩酸ブロムヘキシンの安定性が向上した固形製剤に関する。 The present invention relates to a solid preparation, and more particularly to a solid preparation with improved stability of bromhexine hydrochloride.
塩酸ブロムヘキシンは去痰薬として広く使われている成分である。しかし、塩酸ブロムヘキシンはある種の化合物（ポリエチレングリコール、ノスカピンまたはその塩など）と共存させると保存中に分解するため、効力の低下、商品価値の低下などにつながっていた。 Bromhexine hydrochloride is a widely used ingredient as an expectorant. However, bromhexine hydrochloride decomposes during storage when it coexists with certain compounds (polyethylene glycol, noscapine or its salt, etc.), leading to a decrease in efficacy and a decrease in commercial value.
従来、塩酸ブロムヘキシンを安定化させる技術としては、還元剤、キレート剤などを配合する技術（特許文献１）、アセトアミノフェンを配合する技術（特許文献２）などが知られている。 Conventionally, as a technique for stabilizing bromhexine hydrochloride, a technique for blending a reducing agent, a chelating agent, etc. (Patent Document 1), a technique for blending acetaminophen (Patent Document 2), and the like are known.
しかし、従来知られた塩酸ブロムヘキシンを安定化する技術は、製品とする際の処方が限定されるなどの欠点があることから、より簡便な方法が求められていた。 However, the conventionally known technology for stabilizing bromhexine hydrochloride has disadvantages such as limited prescriptions for use as a product, and thus a simpler method has been demanded.
本発明は、塩酸ブロムヘキシンとポリエチレングリコールまたはノスカピンを同時配合しても塩酸ブロムヘキシンを安定に配合した固形製剤を得ることを目的とする。 An object of the present invention is to obtain a solid preparation in which bromhexine hydrochloride is stably blended even when bromhexine hydrochloride and polyethylene glycol or noscapine are blended simultaneously.
本発明者らは種々検討した結果、塩酸ブロムヘキシンを配合した製剤中に、塩酸ブロムヘキシンを不安定化させる成分であるポリエチレングリコールまたはノスカピンを共存させた系であっても、さらにアミノ酸またはペプチドを配合することにより塩酸ブロムヘキシンの安定性が向上することを見出した。 As a result of various investigations, the present inventors have further formulated an amino acid or peptide even in a system in which polyethylene glycol or noscapine, which is a component destabilizing bromhexine hydrochloride, is coexisted in a formulation containing bromhexine hydrochloride. It has been found that the stability of bromhexine hydrochloride is improved.
また、不安定化物質としてノスカピンが共存する場合には、アミノ酸またはペプチドを配合することによりノスカピン自身の安定性も向上することを見出した。 Moreover, when noscapine coexists as a destabilizing substance, it discovered that the stability of noscapine itself was improved by mix | blending an amino acid or a peptide.
さらに塩酸ブロムヘキシンおよび、ポリエチレングリコールまたはノスカピンを含む系にさらにイブプロフェンを配合すると、より塩酸ブロムヘキシンの安定性の低下を招くが、アミノ酸またはペプチドを配合することにより塩酸ブロムヘキシンの安定性が向上されることを見出し本発明を完成した。 Furthermore, when ibuprofen is further added to a system containing bromhexine hydrochloride and polyethylene glycol or noscapine, the stability of bromhexine hydrochloride is further reduced, but the addition of amino acids or peptides improves the stability of bromhexine hydrochloride. The present invention has been completed.
すなわち本発明は
１．（１）塩酸ブロムヘキシン、（２）ポリエチレングリコールおよびノスカピンから選ばれる１種または２種、ならびに（３）アミノ酸およびペプチドから選ばれる少なくとも１種、を含む固形製剤。
２．アミノ酸がグリシン、アスパラギン酸およびグルタミンからなる群から選ばれる１種または２種以上である１記載の固形製剤。
３．ペプチドがアスパルテームである１記載の固形製剤。
４．塩酸ブロムヘキシンに対し、アミノ酸およびペプチドから選ばれる少なくとも１種の量が、アミノ基の数で１〜５００モル当量になる量である１〜３のいずれかに記載の固形製剤。
５．さらにイブプロフェンを配合したことを特徴とする１〜４のいずれかに記載の固形製剤。
６．ポリエチレングリコールおよびノスカピンから選ばれる１種または２種ならびに塩酸ブロムヘキシンを含む固形製剤に、アミノ酸およびペプチドから選ばれる少なくとも１種を配合することを特徴とする塩酸ブロムヘキシンの安定化方法。
である。
That is, the present invention is 1. (1) A solid preparation comprising bromhexine hydrochloride, (2) one or two selected from polyethylene glycol and noscapine, and (3) at least one selected from amino acids and peptides.
2. 2. The solid preparation according to 1, wherein the amino acid is one or more selected from the group consisting of glycine, aspartic acid and glutamine.
3. 2. The solid preparation according to 1, wherein the peptide is aspartame.
4). The solid preparation according to any one of 1 to 3, wherein the amount of at least one selected from an amino acid and a peptide is 1 to 500 molar equivalents based on the number of amino groups with respect to bromhexine hydrochloride.
5. Furthermore, the solid formulation in any one of 1-4 characterized by mix | blending ibuprofen.
6). A method for stabilizing bromhexine hydrochloride, comprising blending at least one selected from amino acids and peptides into a solid preparation containing one or two selected from polyethylene glycol and noscapine and bromhexine hydrochloride.
It is.
本発明では安定性向上効果の点から、塩酸ブロムヘキシンの配合量は製剤全体の0.2〜5.0質量％が好ましい。 In the present invention, the amount of bromhexine hydrochloride added is preferably 0.2 to 5.0% by mass of the whole preparation from the viewpoint of the stability improvement effect.
本発明では、塩酸ブロムヘキシン１質量部に対するポリエチレングリコールの配合量は0.3〜50質量部、ノスカピンの配合量は1〜5質量部である。配合量が少なければ塩酸ブロムヘキシンの安定化に対する影響も小さく、配合量が多いと本発明による安定性向上効果も不十分になるからである。 In this invention, the compounding quantity of polyethyleneglycol with respect to 1 mass part of bromhexine hydrochloride is 0.3-50 mass parts, and the compounding quantity of noscapine is 1-5 mass parts. If the blending amount is small, the effect on the stabilization of bromhexine hydrochloride is small, and if the blending amount is large, the effect of improving the stability according to the present invention becomes insufficient.
本発明で用いるアミノ酸は一般的なアミノ酸を用いることができるが、特にグリシン、アスパラギン酸およびグルタミンからなる群から選ばれる１種または２種以上が好ましい。 A general amino acid can be used as the amino acid used in the present invention, and one or more selected from the group consisting of glycine, aspartic acid and glutamine are particularly preferable.
本発明でペプチドとはアスパルテーム、ポリリジン、ポリアルギニン、ポリグルタミン酸、ポリアスパラギン酸などがあげられ、特にアスパルテームが好ましい。 In the present invention, the peptide includes aspartame, polylysine, polyarginine, polyglutamic acid, polyaspartic acid, and the like, and aspartame is particularly preferable.
本発明では塩酸ブロムヘキシンに対し、アミノ酸およびペプチドから選ばれる少なくとも１種の量が、アミノ基の数で１〜５００モル当量になる量が好ましく、１０〜４００モル当量になる量がさらに好ましい。 In the present invention, the amount of at least one selected from amino acids and peptides is preferably 1 to 500 molar equivalents, more preferably 10 to 400 molar equivalents, based on the number of amino groups, relative to bromohexine hydrochloride.
ここで、アミノ基の数で１〜５００モル当量になる量とは、配合するアミノ酸またはペプチドの構造中にあるアミノ基の数で決定される量である。具体的には、塩酸ブロムヘキシン１molに対し、配合するアミノ酸またはペプチドの構造中にあるアミノ基の数が１個の場合は１〜５００mol、アミノ基の数が２個の場合は０．５〜２５０molという様に、配合する成分とその分子量によって配合量が変化するものである。 Here, the amount of 1 to 500 molar equivalents based on the number of amino groups is an amount determined by the number of amino groups in the amino acid or peptide structure to be blended. Specifically, with respect to 1 mol of bromhexine hydrochloride, 1 to 500 mol when the number of amino groups in the structure of the amino acid or peptide to be mixed is 1, and 0.5 to 250 mol when the number of amino groups is 2 In this way, the blending amount varies depending on the component to be blended and its molecular weight.
ここで、塩酸ブロムヘキシンと、ポリエチレングリコールおよびノスカピンから選ばれる１種または２種を配合した系にさらにイブプロフェンを配合すると、塩酸ブロムヘキシンの安定性がさらに低下することがわかった。しかし、その場合においても本発明により有効に安定性の向上がはかれることも同時に見出した。 Here, it was found that when ibuprofen was further added to a system in which bromhexine hydrochloride and one or two selected from polyethylene glycol and noscapine were added, the stability of bromhexine hydrochloride was further reduced. However, it was also found that even in that case, the stability can be effectively improved by the present invention.
本発明の固形製剤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薬効成分、賦形剤などを配合し、常法により、錠剤、散剤、顆粒剤などの固形製剤にすることができる。 The solid preparation of the present invention is blended with other commonly used medicinal ingredients, excipients and the like within a qualitative and quantitative range that does not impair the effects of the present invention, and in a conventional manner, solid preparations such as tablets, powders, granules, etc. It can be made into a formulation.
本発明により、塩酸ブロムヘキシンと、ポリエチレングリコールまたはノスカピンを共存させても塩酸ブロムヘキシンおよびノスカピンが安定になることがわかった。 According to the present invention, it was found that bromhexine hydrochloride and noscapine are stable even when coexisting with bromhexine hydrochloride and polyethylene glycol or noscapine.
以下、本発明を実施例および試験例によりさらに詳細に説明する。 Hereinafter, the present invention will be described in more detail with reference to examples and test examples.
（処方） 配合量（ｇ）
塩酸ブロムヘキシン １２
イブプロフェン ４５０
ノスカピン ４８
リン酸ジヒドロコデイン １３
dl−塩酸メチルエフェドリン ６０
マレイン酸カルビノキサミン ７．５
硝酸チアミン ２４
リボフラビン １２
無水カフェイン ７５
グリチルリチン酸二カリウム ３９
結晶セルロース ３００
ヒドロキシプロピルセルロース １１５
馬鈴薯デンプン ７８０
マンニトール １２９０
ポリエチレングリコール６０００ ３２０
軽質無水ケイ酸 ２５
グリシン ８００（３６６．４モル当量）
上記処方で、エタノールを適量添加して練合後、押し出し造粒法により顆粒剤を得た。
(Prescription) Compounding amount (g)
Bromhexine hydrochloride 12
Ibuprofen 450
Noscapine 48
Dihydrocodeine phosphate 13
dl-Methylephedrine hydrochloride 60
Carbinoxamine maleate 7.5
Thiamine nitrate 24
Riboflavin 12
Anhydrous caffeine 75
Dipotassium glycyrrhizinate 39
Crystalline cellulose 300
Hydroxypropyl cellulose 115
Potato starch 780
Mannitol 1290
Polyethylene glycol 6000 320
Light anhydrous silicic acid 25
Glycine 800 (366.4 molar equivalent)
In the above formulation, an appropriate amount of ethanol was added and kneaded, and then granules were obtained by extrusion granulation.
実施例1の処方のグリシンをＬ-アスパラギン酸３００ｇ（７７．５モル当量）に変えた処方で、実施例１と同様にして顆粒剤を得た。 Granules were obtained in the same manner as in Example 1 except that glycine in the formulation of Example 1 was changed to 300 g (77.5 molar equivalents) of L-aspartic acid.
実施例1の処方のグリシンをＬ-(+)-グルタミン６００ｇ（１４１．２モル当量）に変えた処方で、実施例１と同様にして顆粒剤を得た。 Granules were obtained in the same manner as in Example 1 except that the glycine in the formulation of Example 1 was changed to 600 g (141.2 molar equivalents) of L-(+)-glutamine.
比較例１
実施例１からグリシンを除いた処方で実施例１と同様にして顆粒剤を得た。
Comparative Example 1
Granules were obtained in the same manner as in Example 1 except that glycine was removed from Example 1.
試験例１[安定性試験]
実施例1〜3及び比較例1で製造した製剤を無色ガラスビンに充填、密栓した。
Test Example 1 [Stability test]
The preparations produced in Examples 1 to 3 and Comparative Example 1 were filled in colorless glass bottles and sealed.
６５℃で２週間保存した際の塩酸ブロムヘキシンおよびノスカピンの残存率をＨＰＬＣ法により測定した。直後からの残存率（％）を表に示した。 Residual rates of bromhexine hydrochloride and noscapine when stored at 65 ° C. for 2 weeks were measured by HPLC. The table shows the remaining rate (%) immediately after.
表から明らかなように本発明により塩酸ブロムヘキシンおよびノスカピンの安定性が向上することが明らかになった。 As is clear from the table, it was revealed that the present invention improves the stability of bromhexine hydrochloride and noscapine .
処方1
(処方) 配合量（ｇ）
塩酸ブロムヘキシン ４５
軽質無水ケイ酸 ４５
上記処方で配合し、ビンに充填し固形製剤を得た。
Formula 1
(Prescription) Compounding amount (g)
Bromohexine hydrochloride 45
Light anhydrous silicic acid 45
Blended in the above formulation and filled into a bottle to obtain a solid preparation.
処方２
処方１にさらにイブプロフェン ４５ｇを配合した処方でビンに充填し固形製剤を得た。
Formula 2
The formulation 1 was further filled with 45 g of ibuprofen and filled into a bottle to obtain a solid preparation.
処方３
処方１にポリエチレングリコール6000 ４５ｇを配合した処方でビンに充填し固形製剤を得た。
Formula 3
The formulation 1 was blended with 45 g of polyethylene glycol 6000 and filled into a bottle to obtain a solid preparation.
処方４
処方１の処方にイブプロフェン４５ｇとポリエチレングリコール6000 ４５ｇを添加し，ビンに充填した。
Formula 4
45 g of ibuprofen and 45 g of polyethylene glycol 6000 were added to the formulation of Formula 1 and filled into bottles.
処方１〜４について65℃１週間保存したときの塩酸ブロムヘキシンの残存量をＨＰＬＣ法により測定した。結果を表に示した。 For formulations 1 to 4, the residual amount of bromhexine hydrochloride when stored at 65 ° C. for 1 week was measured by the HPLC method. The results are shown in the table.
表から明らかなように塩酸ブロムヘキシンはイブプロフェンを配合しただけでは安定性に影響を及ぼさないものの、ポリエチレングリコールと同時配合することにより安定性が悪化し、ポリエチレングリコール存在下にイブプロフェンを配合することによりさらに安定性が悪くなることがわかった。 As is apparent from the table, bromhexine hydrochloride does not affect the stability when ibuprofen is added alone, but the stability deteriorates when it is added simultaneously with polyethylene glycol, and further by adding ibuprofen in the presence of polyethylene glycol. It was found that the stability deteriorated.
比較例２
(処方) 配合量（ｇ）
塩酸ブロムヘキシン １２
ポリエチレングリコール６０００ ３００
上記処方で配合し、ビンに充填し固形製剤を得た。
Comparative Example 2
(Prescription) Compounding amount (g)
Bromhexine hydrochloride 12
Polyethylene glycol 6000 300
Blended in the above formulation and filled into a bottle to obtain a solid preparation.
比較例２の処方にＬ-アスパラギン酸３００g（７７．５モル当量）を配合した処方で配合し、ビンに充填し固形製剤を得た。 The formulation of Comparative Example 2 was blended with a formulation in which 300 g (77.5 molar equivalents) of L-aspartic acid was blended, and filled into a bottle to obtain a solid preparation.
試験例２
比較例２および実施例４の固形製剤を６５℃２週間で保存し、塩酸ブロムヘキシンの残存量をＨＰＬＣ法により測定して対直後の残存率（％）を求めた。結果を表に示した。
Test example 2
The solid preparations of Comparative Example 2 and Example 4 were stored at 65 ° C. for 2 weeks, and the residual amount of bromhexine hydrochloride was measured by the HPLC method to determine the residual rate (%) immediately after. The results are shown in the table.
表から明らかなようにポリエチレングリコールの配合により低下した塩酸ブロムヘキシンの残存率が、Ｌ-アスパラギン酸を配合することにより改善することがわかった。 As is apparent from the table, it was found that the residual ratio of bromhexine hydrochloride decreased by the addition of polyethylene glycol was improved by adding L-aspartic acid.
比較例３
（処方） 配合量（ｇ）
塩酸ブロムヘキシン １２
ノスカピン ４８
上記処方で配合し、ビンに充填し固形製剤を得た。
Comparative Example 3
(Prescription) Compounding amount (g)
Bromhexine hydrochloride 12
Noscapine 48
Blended in the above formulation and filled into a bottle to obtain a solid preparation.
比較例３の処方にアスパルテーム９０ｇ（１０．５モル当量）を添加し、ビンに充填し固形製剤を得た。 90 g (10.5 molar equivalent) of aspartame was added to the formulation of Comparative Example 3 and filled into a bottle to obtain a solid preparation.
試験例３
比較例１および実施例１の６５℃２週間での塩酸ブロムヘキシンの残存量をＨＰＬＣ法により測定し、対直後の残存率（％）を求めた。結果を表に示した。
The residual amount of bromhexine hydrochloride in Comparative Example 1 and Example 1 at 65 ° C. for 2 weeks was measured by the HPLC method, and the residual rate (%) immediately after the measurement was obtained. The results are shown in the table.
表から明らかなように、ノスカピンを配合することにより低下した塩酸ブロムヘキシンの残存率が、アスパルテームを配合することにより改善することがわかった。 As is clear from the table, it was found that the residual ratio of bromhexine hydrochloride decreased by adding noscapine was improved by adding aspartame.
本発明により、塩酸ブロムヘキシンと、ポリエチレングリコールまたはノスカピンを同時配合しても簡便な方法で安定に配合することが可能になったので、去痰薬、感冒薬などの医薬品に利用可能である。 According to the present invention, even when bromohexine hydrochloride and polyethylene glycol or noscapine are simultaneously blended, it can be stably blended by a simple method, and thus can be used for pharmaceuticals such as expectorants and cold remedies.
Claims (4)
アスパラギン酸およびグルタミンからなる群から選ばれる１種または２種以上であるアミ
ノ酸並びにアスパルテームから選ばれる少なくとも１種、を同時配合かつ共存させたことを特徴とする固形製剤（ただし、プロラミンを含有する固形製剤を除く）。 (1) bromhexine hydrochloride, (2) polyethylene glycol, and (3) glycine,
A solid preparation characterized in that at least one amino acid selected from the group consisting of aspartic acid and glutamine and at least one selected from aspartame are simultaneously blended and coexisted (however, a solid containing prolamin Excluding formulations).
る群から選ばれる１種または２種以上であるアミノ酸並びにアスパルテームから選ばれる
少なくとも１種の量が、アミノ基の数で１〜５００モル当量になる量である請求項１に記
載の固形製剤。 The amount of at least one amino acid selected from the group consisting of (3) glycine, aspartic acid and glutamine, at least one amino acid selected from the group consisting of glycine, aspartic acid and glutamine, and aspartame is 1 to 500 in terms of the number of amino groups. The solid preparation according to claim 1, which is an amount that provides a molar equivalent.
製剤。 Furthermore, ibuprofen was mix | blended, The solid formulation in any one of Claims 1-2 characterized by the above-mentioned.
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