JP4864369B2 - Method for stabilizing thiamines - Google Patents
Method for stabilizing thiamines Download PDFInfo
- Publication number
- JP4864369B2 JP4864369B2 JP2005211545A JP2005211545A JP4864369B2 JP 4864369 B2 JP4864369 B2 JP 4864369B2 JP 2005211545 A JP2005211545 A JP 2005211545A JP 2005211545 A JP2005211545 A JP 2005211545A JP 4864369 B2 JP4864369 B2 JP 4864369B2
- Authority
- JP
- Japan
- Prior art keywords
- thiamine
- trehalose
- thiamines
- ibuprofen
- solid preparation
- 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
- 235000019157 thiamine Nutrition 0.000 title claims description 127
- 150000003544 thiamines Chemical class 0.000 title claims description 51
- 238000000034 method Methods 0.000 title claims description 25
- 230000000087 stabilizing effect Effects 0.000 title claims description 13
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 claims description 80
- 229960003495 thiamine Drugs 0.000 claims description 80
- 239000011721 thiamine Substances 0.000 claims description 78
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 claims description 76
- 238000002360 preparation method Methods 0.000 claims description 53
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 39
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 39
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 39
- 229940074410 trehalose Drugs 0.000 claims description 39
- 239000008187 granular material Substances 0.000 claims description 28
- 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 20
- 229960001680 ibuprofen Drugs 0.000 claims description 20
- 239000003826 tablet Substances 0.000 claims description 19
- 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 claims description 19
- 239000007787 solid Substances 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- DPVHGFAJLZWDOC-PVXXTIHASA-N (2r,3s,4s,5r,6r)-2-(hydroxymethyl)-6-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxane-3,4,5-triol;dihydrate Chemical group O.O.O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DPVHGFAJLZWDOC-PVXXTIHASA-N 0.000 claims description 9
- 229940074409 trehalose dihydrate Drugs 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 7
- BTNNPSLJPBRMLZ-LGMDPLHJSA-N benfotiamine Chemical compound C=1C=CC=CC=1C(=O)SC(/CCOP(O)(O)=O)=C(/C)N(C=O)CC1=CN=C(C)N=C1N BTNNPSLJPBRMLZ-LGMDPLHJSA-N 0.000 claims description 6
- 229960002873 benfotiamine Drugs 0.000 claims description 6
- GFEGEDUIIYDMOX-BMJUYKDLSA-N n-[(4-amino-2-methylpyrimidin-5-yl)methyl]-n-[(z)-3-[[(z)-2-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-5-hydroxypent-2-en-3-yl]disulfanyl]-5-hydroxypent-2-en-2-yl]formamide Chemical compound C=1N=C(C)N=C(N)C=1CN(C=O)C(\C)=C(CCO)/SSC(/CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N GFEGEDUIIYDMOX-BMJUYKDLSA-N 0.000 claims description 6
- 229960001385 thiamine disulfide Drugs 0.000 claims description 6
- YMEBNAABDXLAJE-GPAWKIAZSA-N [(e)-4-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-3-[[(e)-2-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-5-butanoyloxypent-2-en-3-yl]disulfanyl]pent-3-enyl] butanoate Chemical compound C=1N=C(C)N=C(N)C=1CN(C=O)C(\C)=C(/CCOC(=O)CCC)SS\C(CCOC(=O)CCC)=C(/C)N(C=O)CC1=CN=C(C)N=C1N YMEBNAABDXLAJE-GPAWKIAZSA-N 0.000 claims description 5
- JTLXCMOFVBXEKD-FOWTUZBSSA-N fursultiamine Chemical compound C1CCOC1CSSC(\CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N JTLXCMOFVBXEKD-FOWTUZBSSA-N 0.000 claims description 5
- 229950006836 fursultiamine Drugs 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 239000004503 fine granule Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims 1
- 239000004615 ingredient Substances 0.000 description 7
- 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 6
- -1 sazapyrine Chemical compound 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 5
- 241001411320 Eriogonum inflatum Species 0.000 description 4
- 229930003451 Vitamin B1 Natural products 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 4
- 229940088594 vitamin Drugs 0.000 description 4
- 229930003231 vitamin Natural products 0.000 description 4
- 235000013343 vitamin Nutrition 0.000 description 4
- 239000011782 vitamin Substances 0.000 description 4
- 235000010374 vitamin B1 Nutrition 0.000 description 4
- 239000011691 vitamin B1 Substances 0.000 description 4
- 239000004386 Erythritol Substances 0.000 description 3
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 3
- 229940009714 erythritol Drugs 0.000 description 3
- 235000019414 erythritol Nutrition 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 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 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
- 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
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241001106067 Atropa Species 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
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- 239000011230 binding agent Substances 0.000 description 2
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- 229910052791 calcium Inorganic materials 0.000 description 2
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- 229960000520 diphenhydramine Drugs 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、チアミン類の安定化方法およびチアミン類安定化剤、さらにチアミン類含有製剤およびその製造方法に関する。 The present invention relates to a method for stabilizing thiamines, a thiamine stabilizer, a thiamine-containing preparation and a method for producing the same.
ビタミン類は必須の栄養素であることはよく知られており、その中でも特にビタミンＢ１であるチアミンの欠乏症は、主に末梢神経系、消化器系および心血管系の障害として知られるいわゆる脚気の症状を呈することが知られている。また、チアミンは、特に糖のエネルギー代謝に必要であることが知られており、代謝率が上昇している甲状腺機能亢進症や、妊娠・授乳期のほか、感冒などによる肉体疲労の回復時には、より多くのチアミンの摂取が必要である。チアミンは通常の食品でも摂取できるものの、上記のような状況においては、チアミンおよびチアミン誘導体並びにこれらの塩（以下、チアミン類と称す）を含有する製剤（以下、チアミン類含有製剤と称す）、例えば、顆粒剤、液剤、錠剤などで摂取することができる。また、体力回復のためのドリンク剤やサプリメント、さらには総合感冒薬などで、チアミン類が他の薬効成分と共に配合された医薬品等が既に市販されている。 It is well known that vitamins are essential nutrients, and in particular, deficiency of thiamine, which is vitamin B1, is a so-called beriberi symptom known mainly as a disorder of the peripheral nervous system, digestive system and cardiovascular system. It is known to exhibit. In addition, thiamine is known to be necessary for energy metabolism of sugars in particular. Hyperthyroidism, which has an increased metabolic rate, pregnancy and lactation, and recovery from physical fatigue due to colds, etc. More thiamine intake is needed. Although thiamine can be ingested with ordinary foods, in the above situation, a preparation containing thiamine and a thiamine derivative and salts thereof (hereinafter referred to as thiamines) (hereinafter referred to as thiamine-containing preparation), for example, , Granules, liquids, tablets, etc. In addition, pharmaceuticals and the like in which thiamines are blended with other medicinal ingredients are already on the market, such as drinks and supplements for recovering physical fitness, and general cold medicine.
一方、チアミン類は安定性の確保が難しいことが知られている。一般的にビタミン類の安定性は、ｐＨ、光、熱、水分などの保存環境にも影響されるほか、各種添加剤や異種ビタミンなどの共存成分によっても含量低下を引き起こす。その為、チアミン類をドリンク剤などに配合する場合は、必要配合量よりも多めに配合することもある。
チアミン類の安定化方法については既にいくつか報告されている。例えば、「チアミン類配合液剤」（特許文献１参照）は、アミノ酸の１種であるタウリンを配合すると、チアミン類の液剤中における安定性の向上を図れると記載されている。
また、志望を添加することにより、ビタミンB1類を安定化させる方法を記載した「ビタミンＢ１製剤の安定化方法」（特許文献２参照）や抗酸化剤等を添加する方法なども知られている。
On the other hand, thiamines are known to be difficult to ensure stability. In general, the stability of vitamins is affected not only by the storage environment such as pH, light, heat, and moisture, but also by the coexisting components such as various additives and different types of vitamins. Therefore, when thiamines are blended in a drink or the like, they may be blended in a larger amount than necessary.
Several methods for stabilizing thiamines have already been reported. For example, “thiamine compounded solution” (see Patent Document 1) describes that the stability of thiamines in a solution can be improved by adding taurine, which is one of amino acids.
In addition, a method for stabilizing vitamin B1 by adding an aspiration, a method for stabilizing vitamin B1 preparation (see Patent Document 2), a method for adding an antioxidant, and the like are also known. .
上記の通り、チアミン類の安定化方法に関しては、様々な試みが為されているが、例えば、「チアミン類配合液剤」（特許文献１参照）は、対象製剤が液剤に限られていることと、チアミン類の４２日後の残存率が、７３．０％と充分に高いとはいえないという欠点がある。また、「ビタミンＢ１製剤の安定化方法」（特許文献２参照）は脂肪を製剤に配合するため、高脂血症を合併している患者に投与しにくい。また、抗酸化剤を添加する方法に関しても、安全性の面から好ましくない。 As described above, various attempts have been made to stabilize thiamines. For example, “thiamine compounding liquid” (see Patent Document 1) is that the target preparation is limited to liquids. The remaining ratio of thiamines after 42 days is 73.0%, which is not sufficiently high. In addition, the “stabilization method of vitamin B1 preparation” (see Patent Document 2) is difficult to administer to patients with hyperlipidemia because fat is added to the preparation. Also, the method of adding an antioxidant is not preferable from the viewpoint of safety.
これらの事情から、チアミン類を長期的に安定化させる新しい方法の開発が望まれていた。 Under these circumstances, development of a new method for stabilizing thiamines over the long term has been desired.
本発明は、新しいチアミン類の安定化方法およびチアミン類含有製剤を提供するものである。 The present invention provides a novel method for stabilizing thiamines and a thiamine-containing preparation.
本発明者らは鋭意研究の結果、チアミン類にトレハロースを組み合わせると、チアミン類の安定性が向上することを見出し、トレハロースをチアミン類の安定化に寄与するチアミン類安定化剤として用いることができることを見出した。また、イブプロフェンが、チアミン類の安定性に影響を与えることを見出し、チアミン類にトレハロースを配合すると、イブプロフェンのようなチアミン類の安定性に影響を及ぼす成分を配合しても、チアミン類の安定性が向上することを見出した。 As a result of diligent research, the present inventors have found that when thalamine is combined with trehalose, the stability of thiamine is improved, and trehalose can be used as a thiamine stabilizer that contributes to stabilization of thiamines. I found. In addition, we found that ibuprofen has an effect on the stability of thiamines. When trehalose is added to thiamines, the stability of thiamines can be improved even if ingredients that affect the stability of thiamines such as ibuprofen are added. It was found that the performance is improved.
すなわち本発明は、
１．トレハロースを配合することを特徴とするチアミン類の安定化方法、
２．チアミン類にトレハロースを配合することを特徴とするチアミン類含有製剤の安定化方法、
３．トレハロースを含有することを特徴とするチアミン類安定化剤、
４．トレハロースが、トレハロース２水和物またはトレハロース１／２水和物であることを特徴とする３に記載のチアミン類安定化剤、
５．チアミン類が、チアミン、チアミンジスルフィド、フルスルチアミン、ビスチアミン、ジセチアミン、ビスベンチアミン、ビスイブチアミン、ベンフォチアミンおよびこれらの塩から選ばれる１種以上である３または４に記載のチアミン類安定化剤、
６．チアミン類が、硝酸チアミンである３〜５のいずれか１に記載のチアミン類安定化剤、
７．チアミン類、イブプロフェンおよびトレハロースを含有することを特徴とするチアミン類含有製剤、
８．チアミン類およびトレハロースを含有する造粒物と、イブプロフェンを含有する造粒物を含むチアミン類含有製剤、
９．トレハロースが、トレハロース２水和物またはトレハロース１／２水和物であることを特徴とする７または８に記載のチアミン類含有製剤、
１０．チアミン類が、チアミン、チアミンジスルフィド、フルスルチアミン、ビスチアミン、ジセチアミン、ビスベンチアミン、ビスイブチアミン、ベンフォチアミンおよびこれらの塩から選ばれる１種以上である７〜９のいずれか１に記載のチアミン類含有製剤、
１１．チアミン類が、硝酸チアミンである７〜１０のいずれか１に記載のチアミン類含有製剤、
１２．剤形が錠剤、顆粒剤、細粒剤、散剤またはカプセル剤であることを特徴とする７〜１１のいずれか１に記載のチアミン類含有製剤、
１３．チアミン類、イブプロフェン、およびトレハロースを含有するチアミン類含有製剤において、（Ａ）チアミン類およびトレハロースを含有する混合物、（Ｂ）イブプロフェンを含有する混合物を、各々別に造粒することを特徴とするチアミン類含有製剤の製造方法、
１４．トレハロースが、トレハロース２水和物またはトレハロース１／２水和物であることを特徴とする１３に記載のチアミン類含有製剤の製造方法、
１５．チアミン類が、チアミン、チアミンジスルフィド、フルスルチアミン、ビスチアミン、ジセチアミン、ビスベンチアミン、ビスイブチアミン、ベンフォチアミンおよびこれらの塩から選ばれる１種以上である１３または１４に記載のチアミン類含有製剤の製造方法、
１６．チアミン類が、硝酸チアミンである１３〜１５のいずれか１に記載のチアミン類含有製剤の製造方法、である。
That is, the present invention
1. A method for stabilizing thiamines, characterized by containing trehalose,
2. A method for stabilizing a thiamine-containing preparation, characterized by blending trehalose with thiamines,
3. A thiamine stabilizer characterized by containing trehalose,
4). The thiamine stabilizer according to 3, wherein the trehalose is trehalose dihydrate or trehalose hemihydrate,
5. The thiamine stabilization according to 3 or 4, wherein the thiamine is one or more selected from thiamine, thiamine disulfide, fursultiamine, bisthiamine, dicetiamine, bisbenchamine, bisbutiamine, benfotiamine, and salts thereof. Agent,
6). The thiamine stabilizer according to any one of 3 to 5, wherein the thiamine is thiamine nitrate,
7). A thiamine-containing preparation characterized by containing thiamines, ibuprofen and trehalose;
8). A thiamine-containing preparation comprising a granulated product containing thiamines and trehalose and a granulated product containing ibuprofen;
9. The thiamin-containing preparation according to 7 or 8, wherein the trehalose is trehalose dihydrate or trehalose hemihydrate,
10. The thiamines are any one of 7 to 9, wherein the thiamine is one or more selected from thiamine, thiamine disulfide, fursultiamine, bisthiamine, dicetiamine, bisbenchamine, bisbutiamine, benfotiamine and salts thereof. Thiamine-containing preparations,
11. The thiamine-containing preparation according to any one of 7 to 10, wherein the thiamine is thiamine nitrate,
12 The thiamine-containing preparation according to any one of 7 to 11, wherein the dosage form is a tablet, granule, fine granule, powder or capsule,
13. A thiamine-containing preparation containing thiamines, ibuprofen and trehalose, wherein (A) a mixture containing thiamines and trehalose, (B) a mixture containing ibuprofen is granulated separately, A method for producing the preparation containing,
14 The method for producing a thiamine-containing preparation according to 13, wherein the trehalose is trehalose dihydrate or trehalose hemihydrate,
15. The thiamine-containing preparation according to 13 or 14, wherein the thiamine is at least one selected from thiamine, thiamine disulfide, fursultiamine, bisthiamine, discetiamine, bisbenchamine, bisbutiamine, benfotiamine, and salts thereof. Manufacturing method,
16. The method for producing a thiamine-containing preparation according to any one of 13 to 15, wherein the thiamine is thiamine nitrate.
本発明により、新しいチアミン類の安定化方法を提供することができ、この方法を利用してチアミン類含有製剤を製造し、長期安定性の優れたチアミン類含有製剤を提供することができる。 According to the present invention, a new method for stabilizing thiamines can be provided, and a thiamine-containing preparation can be produced using this method, and a thiamine-containing preparation having excellent long-term stability can be provided.
本発明にかかるチアミン類は、チアミン、チアミンジスルフィド、フルスルチアミン、ビスチアミン、ジセチアミン、ビスベンチアミン、ビスイブチアミン、ベンフォチアミンおよびこれらの塩などが挙げられるが、特にこれらに限定されない。上記チアミン類の塩としては、硝酸塩、塩酸塩、硫酸塩、リン酸塩などが挙げられる。本発明においては、硝酸チアミンが最も好ましい。これらのチアミン類は公知の化合物であり、市販のものを用いても良く、また公知の方法を用いて製造することも可能である。 Examples of the thiamine according to the present invention include, but are not limited to, thiamine, thiamine disulfide, fullsultiamine, bisthiamine, dicetiamine, bisbenchamine, bisibutiamine, benfotiamine, and salts thereof. Examples of the thiamine salts include nitrates, hydrochlorides, sulfates and phosphates. In the present invention, thiamine nitrate is most preferred. These thiamines are known compounds, which may be commercially available, or can be produced using known methods.
本発明は、上記チアミン類を安定化させるために、トレハロースを配合することを特徴とする。このトレハロースは特に限定されないが、トレハロース１／２水和物、トレハロース２水和物が好ましい。これらトレハロースは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。 The present invention is characterized by blending trehalose in order to stabilize the thiamines. The trehalose is not particularly limited, but trehalose hemihydrate and trehalose dihydrate are preferable. These trehalose is a known compound, and a commercially available one may be used, or it can be produced using a known method.
本発明のチアミン類含有製剤は、上記のチアミン類およびトレハロースを含有されていれば良く、また、当該チアミン類含有製剤に含有されるチアミン類の量にも、特に制限はない。また、本発明のチアミン類含有製剤の投与量は、患者の病状に応じて適宜調節が可能であるが、例えば経口剤の場合、チアミン類の１日あたりの投与量として、通常０．１〜５００ｍｇであり、１〜５０ｍｇが好ましく、１〜２５ｍｇがより好ましい。
なお、チアミン類を安定化させるために必要なトレハロースの配合量は、チアミン類１重量部に対して、トレハロースを０．０１〜１００重量部、好ましくは０．１〜５０重量部である。
The thiamine-containing preparation of the present invention only needs to contain the above-mentioned thiamines and trehalose, and the amount of thiamines contained in the thiamine-containing preparation is not particularly limited. The dosage of the thiamine-containing preparation of the present invention can be appropriately adjusted according to the patient's medical condition. For example, in the case of an oral preparation, the daily dosage of thiamine is usually 0.1 to 500 mg, preferably 1 to 50 mg, more preferably 1 to 25 mg.
In addition, the compounding quantity of the trehalose required in order to stabilize thiamines is 0.01-100 weight part with respect to 1 weight part of thiamines, Preferably it is 0.1-50 weight part.
本発明のチアミン類含有製剤は、チアミン類以外の薬効成分を配合することができる。具体的には、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剤、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、塩酸ブロムヘキシン、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、ビタミンＡ、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などのビタミン剤、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、これらに限定されるべきものではない。これらの薬効成分は、単一成分を配合しても良く、２種以上のものを組み合わせて配合しても良い。
本発明により製造されるチアミン類含有製剤の剤形は、固形製剤、特に錠剤、顆粒剤、細粒剤、散剤またはカプセル剤であることが好ましく、特に錠剤または顆粒剤が好ましい。
The thiamine-containing preparation of the present invention can contain medicinal ingredients other than thiamines. Specifically, antipyretic analgesics such as aspirin, aspirin aluminum, sazapyrine, etenzamide, salicylamide, ibuprofen, acetaminophen, isopropylantipyrine, central nervous stimulants such as caffeine, anhydrous caffeine, sodium benzoate caffeine, Sedatives such as bromovaleryl urea and allyl isopropyl acetyl urea, chlorpheniramine maleate, diphenhydramine, diphenhydramine salicylate, carbinoxamine maleate, mequitazine, alimemazine tartrate, diphenylpyraline hydrochloride, triprolidine hydrochloride, clemastine fumarate and other antihistamine drugs Lysozyme, bromelain, serrapeptase, semi-alkaline proteinase, glycyrrhizinate, dipotassium glycyrrhizinate, glycyrrhizinate Anti-inflammatory agents such as monium, glycyrrhetinic acid, sodium azulene sulfonate, antiplasmin agents 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 Expectorants such as potassium sulfonate, potassium cresolate, guaifenesin, bromhexine hydrochloride, carbocysteine, ambroxol hydrochloride, theophylline, aminophylline, di Tracheodilators such as lofilin, belladonna (total) alkaloids, belladonna extract, isopropamide iodide, scopolamine hydrobromide, funnel extract, antiacetylcholine drugs such as scopolamine bromide, methylbenactidium bromide, pirenzepine, cetyl Pyridinium, 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, aminobenzoic acid Local anesthetics such as ethyl, lidocaine, lidocaine hydrochloride, oxesecasein, vitamin A, vitamin B2, vitamin B6, vitamin B12, vitamin C, calcium ascorbate, vitamin D, Vitamin E, vitamins such as tocophenol calcium succinate, pantothenic acid, panthenol, calcium pantothenate, sodium pantothenate, panthetin, nicotinic acid, nicotinamide, glucuronic acid, glucuronolactone, aminoethylsulfonic acid, biotin, Metabolic components such as γ-oryzanol, crude drugs such as earth dragon, keihi, gooh, gyoza, kyoukyo, maou, licorice, kyounin, hange, sensou, senegal, psycho, bucurium, shinnyi and extracts of these herbal medicines (extract, Tincture etc.) can be mentioned, but should not be limited to these. These medicinal components may be blended with a single component or in combination of two or more.
The dosage form of the thiamine-containing preparation produced according to the present invention is preferably a solid preparation, particularly a tablet, granule, fine granule, powder or capsule, and particularly preferably a tablet or granule.
さらに、本発明の効果に影響を及ぼさない範囲内で、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、滑沢剤など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、トウモロコシデンプン、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、白糖、Ｄ−マンニトール、エリスリトール、ブドウ糖、果糖などを挙げることができる。
Furthermore, an appropriate additive can be added to the preparation within a range not affecting the effects of the present invention. Specific examples include excipients, binders, disintegrants, and lubricants.
Examples of the excipient include crystalline cellulose, powdered cellulose, corn starch, potato starch, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, calcium lactate and silicic acid. Examples include calcium, magnesium aluminate metasilicate, synthetic hydrotalcite, synthetic aluminum silicate, lactose, sucrose, D-mannitol, erythritol, glucose, fructose and the like.
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、メチルセルロース、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、ポリビニルアルコール、ポビドン、マクロゴール、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、ポリアクリル酸ナトリウム、プルラン等を挙げることができる。
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 methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, povidone, macrogol, gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, pullulan and the like. be able to.
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、ポリエチレングリコール、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。 Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, polyethylene glycol, sodium lauryl sulfate, and hardened oil.
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良い。 These additives may be used alone or in combination of two or more.
本発明のチアミン類含有製剤は、上記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、造粒、圧縮、乾燥など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、溶融造粒法など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 thiamine-containing preparation of the present invention can be obtained by formulating the above components by a known production method. For example, pulverization, mixing, granulation, compression, drying and the like 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.
チアミン類またはトレハロースの安定性に影響を及ぼすような成分を、本発明の製剤に含有させる場合には、その製造工程において、チアミン類およびトレハロースを含有する混合物を造粒し、別にチアミン類またはトレハロースの安定性に影響を及ぼす成分を含有する混合物を造粒することが望ましい。チアミン類の安定性に影響を及ぼす成分の例として、イブプロフェンを挙げることができる。本発明のチアミン類含有製剤にイブプロフェンを含有させる際には、（Ａ）チアミン類とトレハロースを含有する混合物、（Ｂ）イブプロフェンを含有する混合物を、各々別に造粒し、（Ａ）を含有する造粒物と、（Ｂ）を含有する造粒物を含有する混合物を必要に応じて圧縮し、本発明の製剤を得ることができる。 When a component that affects the stability of thiamines or trehalose is contained in the preparation of the present invention, a mixture containing thiamines and trehalose is granulated in the production process, and thiamines or trehalose is separately prepared. It is desirable to granulate a mixture containing components that affect the stability of the. An example of a component that affects the stability of thiamines is ibuprofen. When containing ibuprofen in the thiamines-containing preparation of the present invention, (A) a mixture containing thiamines and trehalose and (B) a mixture containing ibuprofen are granulated separately, and contain (A). The granule and the mixture containing the granule containing (B) may be compressed as necessary to obtain the preparation of the present invention.
以下に実施例を示して本発明を説明するが、本発明はこれのみに限定されるべきものではない。 Hereinafter, the present invention will be described with reference to examples. However, the present invention should not be limited to these examples.
（実施例１）
表１に記載されている成分を混合攪拌造粒後、解砕、乾燥後、さらに整粒して、Ａ顆粒を得た。
Example 1
The ingredients listed in Table 1 were mixed and stirred, granulated, crushed, dried, and further sized to obtain A granules.
表１
表２に記載されている成分を、混合、溶融造粒後に冷却し、さらに整粒してＢ顆粒を得た。 The components listed in Table 2 were mixed and cooled after melt granulation, and further sized to obtain B granules.
表２
表３に記載されている成分を混合、攪拌造粒後に解砕、乾燥し、さらに整粒してＣ顆粒を得た。 The ingredients listed in Table 3 were mixed, stirred and granulated, then crushed and dried, and further sized to obtain C granules.
表３
上記の工程により得られたＡ顆粒、Ｂ顆粒、Ｃ顆粒を混合、整粒し、表４に示した成分をあわせて、混合、次いで圧縮を行い、チアミン類含有錠剤を得た。 A granule, B granule, and C granule obtained by the above steps were mixed and sized, and the components shown in Table 4 were mixed, mixed, and then compressed to obtain a thiamine-containing tablet.
表４
得られた錠剤をビン密栓にて５０℃で保存し、保存開始から３０日後の硝酸チアミンの残存率を測定した。結果を表ａに示す。 The obtained tablets were stored in a bottle stopper at 50 ° C., and the residual rate of thiamine nitrate was measured 30 days after the start of storage. The results are shown in Table a.
（比較例１）
実施例１のＡ顆粒の成分中のトレハロース２水和物をエリスリトールに換えて、実施例１と同様の操作を行い、得られた錠剤をビン密栓にて５０℃で保存し、保存開始から３０日後の硝酸チアミンの残存率を測定した。結果を表ａに示す。
(Comparative Example 1)
The trehalose dihydrate in the ingredients of the granule A in Example 1 was changed to erythritol, and the same operation as in Example 1 was performed. The obtained tablets were stored at 50 ° C. in a bottle stopper, and 30 The residual ratio of thiamine nitrate after the day was measured. The results are shown in Table a.
（比較例２）
下記の表５の成分から、実施例１に記載した方法と同様に各々Ｄ顆粒、Ｅ顆粒、Ｆ顆粒を製造した。
(Comparative Example 2)
D granules, E granules, and F granules were produced from the components shown in Table 5 in the same manner as in the method described in Example 1.
表５
これらのＤ顆粒、Ｅ顆粒、Ｆ顆粒に下記の表６の成分を加え、実施例１と同様の方法にてチアミン類含有錠剤の素錠を得た。 The components shown in Table 6 below were added to these D granules, E granules, and F granules, and uncoated tablets of thiamine-containing tablets were obtained in the same manner as in Example 1.
表６
さらに、表７の成分を用いて、得られた素錠をフィルムコーティングし、チアミン類含有錠剤を得た。 Furthermore, the obtained uncoated tablet was film-coated using the components in Table 7 to obtain thiamine-containing tablets.
表７
得られた錠剤をビン密栓にて５０℃で保存し、保存開始から３０日後の硝酸チアミンの残存率を測定した。結果を表ａに示す。 The obtained tablets were stored in a bottle stopper at 50 ° C., and the residual rate of thiamine nitrate was measured 30 days after the start of storage. The results are shown in Table a.
表ａ
表ａの結果より、硝酸チアミンと同一の顆粒に配合する賦形剤をＤ−マンニトール、エリスリトール、トレハロース２水和物にて比較したところ、トレハロース２水和物が、硝酸チアミンを安定化させることを見出した。 From the results in Table a, when excipients blended in the same granules as thiamine nitrate were compared with D-mannitol, erythritol, and trehalose dihydrate, trehalose dihydrate stabilized thiamine nitrate. I found.
（試験例１）
下記の表８の成分から、実施例１に記載した方法と同様に各々Ｇ顆粒、Ｈ顆粒、Ｉ顆粒を製造した。
(Test Example 1)
From the components shown in Table 8 below, G granules, H granules and I granules were produced in the same manner as in the method described in Example 1.
表８
これらのＧ顆粒、Ｈ顆粒、Ｉ顆粒に下記の表９の成分を加え、実施例１と同様の方法にてチアミン類含有錠剤の素錠を得た。 The components shown in Table 9 below were added to these G granules, H granules, and I granules, and uncoated tablets of thiamine-containing tablets were obtained in the same manner as in Example 1.
表９
さらに、表１０の成分を用いて、得られた素錠をフィルムコーティングし、チアミン類含有錠剤を得た。 Furthermore, the obtained uncoated tablets were film-coated using the components shown in Table 10 to obtain thiamine-containing tablets.
表１０
得られた錠剤をビン密栓にて４０℃または５０℃で保存し、保存開始から３０日後の硝酸チアミンの残存率を測定した。結果を表ｂに示す。 The obtained tablets were stored in a bottle stopper at 40 ° C. or 50 ° C., and the residual ratio of thiamine nitrate was measured 30 days after the start of storage. The results are shown in Table b.
表ｂ
硝酸チアミンに他の薬効成分を組み合わせ、賦形剤としてＤ―マンニトールを添加して造粒処理、次いで圧縮処理を行い、得られた錠剤を瓶に密閉し、長期安定性を検討した。４０℃で３０日間の密閉保存では、硝酸チアミンの残存率に影響は無かったものの、高温度下の５０℃で３０日間密閉保存を行なった場合、硝酸チアミンの残存率は７１．５％と、硝酸チアミンの含量低下が認められた（試験例１）。 Other medicinal ingredients were combined with thiamine nitrate, D-mannitol was added as an excipient, granulated, and then compressed, and the resulting tablets were sealed in a bottle to examine long-term stability. In the sealed storage at 40 ° C. for 30 days, the residual rate of thiamine nitrate was not affected, but when the sealed storage was performed at 50 ° C. for 30 days under high temperature, the residual rate of thiamine nitrate was 71.5%. A decrease in thiamine nitrate content was observed (Test Example 1).
（参考例１）
硝酸チアミン０．５ｇに、表１１に記載の各成分を加え、さらに結晶セルロースを加えて４５．０ｇにしたものを７０℃で５日間保存し、硝酸チアミンと各成分の配合変化試験を行なった。
(Reference Example 1)
Each component listed in Table 11 was added to 0.5 g of thiamine nitrate, and further 45.0 g of crystalline cellulose was added and stored at 70 ° C. for 5 days, and a blending change test of thiamine nitrate and each component was performed. .
表１１
結果を表ｃに示す。 The results are shown in Table c.
表ｃ
表ｃから、イブプロフェンが硝酸チアミンの含量低下の起因物質であることが認められた。 From Table c, it was confirmed that ibuprofen was a causative substance for the decrease in thiamine nitrate content.
本発明により、新しい地アミン類を安定化させる方法を提供することができ、本発明を利用して、チアミン類を含有する製剤、例えば、風邪薬や肉体疲労回復のための栄養補給剤などを提供することができる。
According to the present invention, it is possible to provide a method for stabilizing new ground amines. By using the present invention, a preparation containing thiamines such as a cold medicine and a nutritional supplement for recovery from physical fatigue can be provided. Can be provided.
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| CN103804368A (en) * | 2012-11-07 | 2014-05-21 | 江苏兄弟维生素有限公司 | Recovery method of thiamine nitrate in thiamine nitrate mother liquor |
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