JP2007153742A - METHOD FOR STABILIZING alpha-LIPOIC ACID AND STABILIZED alpha-LIPOIC ACID - Google Patents
METHOD FOR STABILIZING alpha-LIPOIC ACID AND STABILIZED alpha-LIPOIC ACID Download PDFInfo
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- JP2007153742A JP2007153742A JP2005346841A JP2005346841A JP2007153742A JP 2007153742 A JP2007153742 A JP 2007153742A JP 2005346841 A JP2005346841 A JP 2005346841A JP 2005346841 A JP2005346841 A JP 2005346841A JP 2007153742 A JP2007153742 A JP 2007153742A
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- lipoic acid
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- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 title claims abstract description 75
- 235000019136 lipoic acid Nutrition 0.000 title claims abstract description 73
- 229960002663 thioctic acid Drugs 0.000 title claims abstract description 73
- 238000000034 method Methods 0.000 title claims abstract description 20
- 230000000087 stabilizing effect Effects 0.000 title claims abstract description 13
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 claims abstract description 71
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical class NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000002775 capsule Substances 0.000 claims abstract description 16
- 235000005152 nicotinamide Nutrition 0.000 claims abstract description 8
- 239000011570 nicotinamide Substances 0.000 claims abstract description 8
- 235000013305 food Nutrition 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims description 14
- 150000005480 nicotinamides Chemical class 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 9
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 claims description 8
- 235000017471 coenzyme Q10 Nutrition 0.000 claims description 8
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 claims description 8
- 239000008187 granular material Substances 0.000 claims description 3
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 238000012360 testing method Methods 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
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- 238000005259 measurement Methods 0.000 description 6
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
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- 230000000052 comparative effect Effects 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
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- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- 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 description 1
- FYGDTMLNYKFZSV-URKRLVJHSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](OC2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-URKRLVJHSA-N 0.000 description 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
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- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 206010049565 Muscle fatigue Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
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- -1 acetate-phthalic acid ester Chemical class 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 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 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
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- 235000013871 bee wax Nutrition 0.000 description 1
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- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
Description
本発明は、α−リポ酸の安定化法、α−リポ酸を含有する安定化されたα−リポ酸製剤、並びに、α−リポ酸を安定に含有する医薬品、健康食品または食品に関するものである。 The present invention relates to a method for stabilizing α-lipoic acid, a stabilized α-lipoic acid preparation containing α-lipoic acid, and a pharmaceutical, health food or food containing α-lipoic acid stably. is there.
近年、α−リポ酸（チオクト酸）は、医薬として用いられるほか、二次的に生体内の抗酸化物質として有益に働くとともに、糖質の代謝に有益に働き、糖尿病の予防効果や、細胞レベルでの糖代謝促進機能によって、ダイエット、筋肉の疲労防止、抗酸化効果等を持つ物質として着目され、健康を維持するのに有益な食品ないし食品補助剤として使用されている。 In recent years, α-lipoic acid (thioctic acid) has been used not only as an anti-oxidant substance in the body, but also beneficially in the metabolism of carbohydrates, and has a preventive effect on diabetes, Due to its ability to promote sugar metabolism at the level, it is attracting attention as a substance having diet, muscle fatigue prevention, antioxidant effect, etc., and is used as a food or food supplement useful for maintaining health.
しかしながら、これまでに使用されてきたα−リポ酸含有医薬品の原料は、α−リポ酸のアミド体であるα−リポ酸（チオクト酸）アミドであり、α−リポ酸のフリータイプではなく、化学的に安定な構造を持っていた。最近、厚生労働省が食品として認めたα−リポ酸はフリー体であるため、化学的に非常に不安定な構造を有しており、α−リポ酸として製剤中に長期間安定に保つことは困難であった。このため、例えば、α−リポ酸水性製剤に亜硫酸塩またはその水和物を配合して安定化させる方法が提案されているが（特許文献１）、十分な安定化効果は得られていない。また、α−リポ酸の徐放性製剤（特許文献２）も知られているが、α−リポ酸自体を安定化することは開示されていない。
このため、市販のα−リポ酸製剤に製剤安定性試験を行うと、ほとんどの製品の１ケ月後の加速安定試験試験（温度４０℃、湿度７５％で密栓して保存）結果では、調合時に比し、１０％程度もしくはそれ以上低下する。また、２ケ月の加速安定試験では１５％程度、ひどいものでは５０％以上低下するものもあった。
For this reason, when a formulation stability test is performed on a commercially available α-lipoic acid formulation, the accelerated stability test test (stored tightly sealed at a temperature of 40 ° C. and a humidity of 75%) after one month for most products Compared to 10% or more. In addition, the accelerated stability test for 2 months showed a decrease of about 15%, and the worst case decreased by 50% or more.
本発明者らは、このような現状に鑑み、鋭意検討した結果、α−リポ酸にニコチン酸アミド誘導体を共存させることにより、α−リポ酸を安定化しうることを知見し、種々、検討を重ねて、長期間安定に維持可能な本発明のα−リポ酸の安定化法及び安定化されたα−リポ酸製剤を完成した。 As a result of intensive studies in view of the present situation, the present inventors have found that α-lipoic acid can be stabilized by coexisting a nicotinamide derivative with α-lipoic acid, and various studies have been made. The α-lipoic acid stabilization method and the stabilized α-lipoic acid preparation of the present invention that can be stably maintained for a long period of time were completed.
請求項１記載のα−リポ酸の安定化法は、α−リポ酸にニコチン酸アミド誘導体を共存させることを特徴として成るものである。 The method for stabilizing α-lipoic acid according to claim 1 is characterized in that α-lipoic acid is allowed to coexist with a nicotinamide derivative.
請求項２記載のα−リポ酸の安定化法は、前記要件に加えて、ニコチン酸アミド誘導体がニコチン酸アミドであることを特徴として成るものである。 The method for stabilizing α-lipoic acid according to claim 2 is characterized in that, in addition to the above requirements, the nicotinamide derivative is nicotinamide.
請求項３記載のα−リポ酸の安定化法は、前記要件に加えて、α−リポ酸に対して、ニコチン酸アミドとして０．５％Ｗ／Ｗ 以上のニコチン酸アミド誘導体を共存させることを特徴として成るものである。 The method for stabilizing α-lipoic acid according to claim 3, wherein, in addition to the above requirements, 0.5% W / W or more of a nicotinic acid amide derivative is allowed to coexist with α-lipoic acid as nicotinic acid amide. Is a feature.
請求項４記載のα−リポ酸の安定化法は、前記要件に加えて、α−リポ酸及びＣｏＱ１０にニコチン酸アミド誘導体を共存させることを特徴として成るものである。 The method for stabilizing α-lipoic acid according to claim 4 is characterized in that, in addition to the above requirements, α-lipoic acid and CoQ10 are allowed to coexist with a nicotinic acid amide derivative.
請求項５記載の安定化されたα−リポ酸製剤は、α−リポ酸とニコチン酸アミド誘導体を含有することを特徴として成るものである。 The stabilized α-lipoic acid preparation according to claim 5 is characterized in that it contains α-lipoic acid and a nicotinamide derivative.
請求項６記載の安定化されたα−リポ酸製剤は、前記請求項５記載の要件に加えて、α−リポ酸製剤が医薬品、健康食品または食品であることを特徴として成るものである。 The stabilized α-lipoic acid preparation according to claim 6 is characterized in that, in addition to the requirement according to claim 5, the α-lipoic acid preparation is a pharmaceutical, health food or food.
請求項７記載の安定化されたα−リポ酸製剤は、前記請求項５または６記載の要件、α−リポ酸製剤がカプセル剤、錠剤、顆粒剤、粉剤または液剤であることを特徴として成るものである。 The stabilized α-lipoic acid preparation according to claim 7 is characterized in that the requirement according to claim 5 or 6 above, the α-lipoic acid preparation is a capsule, tablet, granule, powder or liquid. Is.
α−リポ酸にニコチン酸アミド誘導体を共存させることにより、α−リポ酸を安定化し得ることを長期間安定に維持可能であり、３ないし５年間常温に保存しても、α−リポ酸の低下を５％未満に抑えることができる。 By allowing a nicotinamide derivative to coexist with α-lipoic acid, it is possible to stably maintain that α-lipoic acid can be stabilized for a long period of time, and even if stored at room temperature for 3 to 5 years, The decrease can be suppressed to less than 5%.
本発明の最良の形態は、以下の実施例に述べるとおりである。
本発明においては、α−リポ酸にニコチン酸アミド誘導体を共存させる。α−リポ酸は、必要に応じて、遊離カルボン酸もしくはナトリウム、カリウム塩等として用いられる。このようなα−リポ酸もしくは塩は、原体そのまま、あるいは、α−リポ酸もしくは塩の作用を阻害しない固形または液状であって、医薬あるいは食品に通常用いられる担体と共に用いることができる。固形担体としては、たとえば、澱粉、グルコース、乳糖、トレハロース、デキストリン、ペクチン、ベーターグルカン、セルロース、サイクロデキストリン、ベントナイト、二酸化珪素等を用いることができる。液状担体としては、水、エタノール、グリセリン、ミリスチルアルコール、オレイルアルコール、ステアリルアルコール、ラウリン酸、ミリスチン酸、パルミチン酸、オリーブ油、サフラワー油、ヒマシ油、ゴマ油、ミツロウ等を用いることができる。さらに、必要に応じて、乳化剤、増粘剤、酸化防止剤、界面活性剤、香料等を用いることもできる。また、経口的に用いる場合には、ヒドロキシプロピルメチルセルロースフタレート、メタクリル酸―メタクリル酸エステルコポリマー、ポリビニル酢酸―フタル酸エステル、酢酸フタル酸セルロース等により腸溶性コーチングしてもよい。このようなα−リポ酸は、成人一日あたり１０〜１０００ミリグラム、望ましくは６０〜３００ミリグラム摂取できるように含有させるのがよい。
The best mode of the present invention is as described in the following examples.
In the present invention, α-lipoic acid is allowed to coexist with a nicotinamide derivative. α-Lipoic acid is used as a free carboxylic acid or sodium, potassium salt or the like, if necessary. Such α-lipoic acid or salt can be used as it is or as a solid or liquid that does not inhibit the action of α-lipoic acid or salt, and can be used together with a carrier that is usually used for pharmaceuticals or foods. As the solid carrier, for example, starch, glucose, lactose, trehalose, dextrin, pectin, beta-glucan, cellulose, cyclodextrin, bentonite, silicon dioxide and the like can be used. As the liquid carrier, water, ethanol, glycerin, myristyl alcohol, oleyl alcohol, stearyl alcohol, lauric acid, myristic acid, palmitic acid, olive oil, safflower oil, castor oil, sesame oil, beeswax and the like can be used. Furthermore, an emulsifier, a thickener, an antioxidant, a surfactant, a fragrance and the like can be used as necessary. When used orally, enteric coating may be performed with hydroxypropylmethylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalic acid ester, cellulose acetate phthalate, or the like. Such α-lipoic acid is preferably contained so that it can be ingested in an amount of 10 to 1000 milligrams, preferably 60 to 300 milligrams per day for an adult.
α−リポ酸に共存させるニコチン酸アミド誘導体としては、ニコチン酸アミドのほか、モノまたはジメチル、エチル誘導体が用いられる。これらのニコチン酸アミド誘導体は、α−リポ酸に対して、ニコチン酸アミドとして０．５％Ｗ／Ｗ以上のニコチン酸アミド誘導体を共存させるのがよい。ニコチン酸アミド誘導体の添加量は一日当たりの摂取量として１０グラム以下であれば差し支えないが、ニコチン酸アミド誘導体自体の薬理作用が出ない範囲が望ましい。好ましくは、α−リポ酸に対して、ニコチン酸アミドとして０．５〜５％Ｗ／Ｗのニコチン酸アミド誘導体を共存させるのがよい。
また、必要に応じて、ビタミンＡ、Ｂ、Ｃ、Ｄ、Ｅ等のビタミン類、グリシン、アラニン、グルタミン等のアミノ酸類、ＣｏＱ１０等の酵素類、糖類、有機酸類などを配合してもよい。
本発明においては、これらを通常の方法に従って、粉剤、顆粒剤、液剤、錠剤、カプセル剤等とすることができる。
As the nicotinic acid amide derivative coexisting with α-lipoic acid, mono-, dimethyl, or ethyl derivatives are used in addition to nicotinic acid amide. These nicotinic acid amide derivatives are preferably allowed to coexist with nicotinic acid amide derivatives of 0.5% W / W or more as α-lipoic acid as nicotinic acid amide. The addition amount of the nicotinamide derivative is not particularly limited as long as the daily intake is 10 grams or less, but a range in which the pharmacological action of the nicotinamide derivative itself does not occur is desirable. Preferably, 0.5 to 5% W / W nicotinamide derivative is allowed to coexist with α-lipoic acid as nicotinamide.
Moreover, you may mix | blend vitamins, such as vitamin A, B, C, D, and E, amino acids, such as glycine, alanine, and glutamine, enzymes, such as CoQ10, saccharides, organic acids, etc. as needed.
In the present invention, these can be made into powders, granules, liquids, tablets, capsules and the like according to ordinary methods.
[１．製品処方・配合等]
[２．保存条件] ：規格６号瓶
１）温度４０℃ 湿度７５％ＲＨ
２）常温保管
[３．保存期間] ：加速１ケ月、２ケ月、４ケ月（それぞれ常温 半年、１年、２年相当 ）
[４．試験内容] ：
（１）崩壊試験（日本薬局方１４局 試験液 水）
（２）α−リポ酸の定量（ＨＰＬＣ定量法）
＜測定条件＞
１カプセルを５ｍＭ リン酸緩衝液（ｐＨ３．５）：アセトニトリル＝１：１に溶 解して
５０ｍｌに定容
標準品による５点絶対検量線により定量
＜ＨＰＬＣ条件＞
カラム ＯＤＳ ＵＧ１２０ （資生堂カプセルパックＣ１８ ４．６ｍｍφ× ２５０ｍｍ）
流出液 メタノール：アセトニトリル（ｐＨ３．１）：５ｍＭ リン酸緩衝液＝ １１６０：１８０：９２０
流出速度 １．２ｍｌ／ｍｉｎ 検出器 ２１５ｎｍ（トーソーＰＤ−８０２０）
カラム温度 ３５℃ 注入量 ２０μｌ
（３）ＣｏＱ１０の定量（ＨＰＬＣ定量法）
＜測定条件＞
カプセル内容物をエタノールに溶解して５０ｍｌに定容
標準品による５点絶対検量線により定量
＜ＨＰＬＣ条件＞
カラム ＯＤＳ ＳＧ１２０ （資生堂カプセルパックＣ１８ ４．６ｍｍφ× ２５０ｍｍ）
流出液 メタノール：エタノール＝１３：７
流出速度 １．０ｍｌ／ｍｉｎ 検出器 ２７５ｎｍ（トーソーＰＤ−８０２０）
カラム温度 ４０℃ 注入量 ５μｌ
[2. Storage conditions]: No. 6 bottle 1) Temperature 40 ° C Humidity 75% RH
2) Room temperature storage
[3. Storage period]: Acceleration 1 month, 2 months, 4 months (Equivalent to normal temperature 6 months, 1 year, 2 years)
[4. contents of the test] :
(1) Disintegration test (14 Japanese Pharmacopoeia test solution water)
(2) Quantification of α-lipoic acid (HPLC quantification method)
<Measurement conditions>
Dissolve 1 capsule in 5 mM phosphate buffer (pH 3.5): acetonitrile = 1: 1 and constant volume to 50 ml Quantitative analysis using a 5-point absolute calibration curve with a standard product <HPLC conditions>
Column ODS UG120 (Shiseido Capsule Pack C18 4.6 mmφ x 250 mm)
Effluent Methanol: Acetonitrile (pH 3.1): 5 mM phosphate buffer = 1160: 180: 920
Outflow rate 1.2ml / min detector 215nm (Tosoh PD-8020)
Column temperature 35 ° C Injection volume 20 µl
(3) Quantification of CoQ10 (HPLC quantification method)
<Measurement conditions>
Dissolve the capsule contents in ethanol to a constant volume of 50 ml Quantitative analysis using a 5-point absolute calibration curve with a standard product <HPLC conditions>
Column ODS SG120 (Shiseido Capsule Pack C18 4.6 mmφ x 250 mm)
Effluent methanol: ethanol = 13: 7
Outflow rate 1.0 ml / min detector 275 nm (Tosoh PD-8020)
Column temperature 40 ° C Injection volume 5 μl
加速試験
まとめ
（１）崩壊試験 開口時間に遅延は見られたが、規定時間内。（２０分以内）
（２）α−リポ酸 ２ケ月で理論配合量の５％減少した。
（３）ＣｏＱ１０ ２ケ月で理論配合量の２．３％減少した。
Summary (1) Disintegration test Although there was a delay in the opening time, it was within the specified time. (Within 20 minutes)
(2) α-Lipoic acid The theoretical blending amount decreased by 5% in 2 months.
(3) CoQ10 Reduced by 2.3% of the theoretical blending amount in 2 months.
〔比較例１〕
[１．製品処方・配合等]
[1. Product prescription and formulation]
[２．保存条件] ：規格６号瓶
温度４０℃ 湿度７５％ＲＨ
[３．保存期間] ：加速１ケ月、２ケ月、４ケ月（それぞれ常温 半年、１年、２年相当 ）
[４．試験内容] ：
(1）崩壊試験（日本薬局方１４局 試験液 水）
(2）α−リポ酸の定量（ＨＰＬＣ定量法）
＜測定条件＞
１カプセルを５ｍＭ リン酸緩衝液（ｐＨ３．５）：アセトニトリル＝１：１に溶 解して５０ｍｌに定容
標準品による５点絶対検量線により定量
＜ＨＰＬＣ条件＞
カラム ＯＤＳ ＵＧ１２０ （資生堂カプセルパックＣ１８ ４．６ｍｍφ× ２５０ｍｍ）
流出液 メタノール：アセトニトリル（ｐＨ３．１）：５ｍＭ リン酸緩衝液＝ １１６０：１８０：９２０
流出速度 １．２ｍｌ／ｍｉｎ 検出器 ２１５ｎｍ（トーソーＰＤ−８０２０）
カラム温度 ３５℃ 注入量 ２０μｌ
(3）ＣｏＱ１０の定量（ＨＰＬＣ定量法）
＜測定条件＞
カプセル内容物をエタノールに溶解して５０ｍｌに定容
標準品による５点絶対検量線により定量
＜ＨＰＬＣ条件＞
カラム ＯＤＳ ＳＧ１２０ （資生堂カプセルパックＣ１８ ４．６ｍｍφ× ２５０ｍｍ）
流出液 メタノール：エタノール＝１３：７
流出速度 １．０ｍｌ／ｍｉｎ 検出器 ２７５ｎｍ（トーソーＰＤ−８０２０）
カラム温度 ４０℃ 注入量 ５μｌ
[2. Storage conditions]: Standard No. 6 bottle
Temperature 40 ℃ Humidity 75% RH
[3. Storage period]: Acceleration 1 month, 2 months, 4 months (Equivalent to normal temperature 6 months, 1 year, 2 years)
[4. contents of the test] :
(1) Disintegration test (Japanese Pharmacopoeia 14th Test Solution Water)
(2) Determination of α-lipoic acid (HPLC determination method)
<Measurement conditions>
Dissolve 1 capsule in 5 mM phosphate buffer (pH 3.5): acetonitrile = 1: 1 and constant volume to 50 ml Quantitative analysis using a 5-point absolute calibration curve with a standard product <HPLC conditions>
Column ODS UG120 (Shiseido Capsule Pack C18 4.6 mmφ x 250 mm)
Effluent Methanol: Acetonitrile (pH 3.1): 5 mM phosphate buffer = 1160: 180: 920
Outflow rate 1.2ml / min detector 215nm (Tosoh PD-8020)
Column temperature 35 ° C Injection volume 20 µl
(3) CoQ10 determination (HPLC determination method)
<Measurement conditions>
Dissolve the capsule contents in ethanol to a constant volume of 50 ml. Quantitative analysis using a 5-point absolute calibration curve with a standard product
Column ODS SG120 (Shiseido Capsule Pack C18 4.6 mmφ x 250 mm)
Effluent methanol: ethanol = 13: 7
Outflow rate 1.0 ml / min detector 275 nm (Tosoh PD-8020)
Column temperature 40 ° C Injection volume 5 μl
[５．試験結果]
加速試験
Accelerated test
まとめ
(1) 崩壊試験 開口時間に遅延は見られたが、規定時間内。（２０分以内）
(2) α−リポ酸 ２ケ月で理論配合量の１５．７％の減少。
(3) ＣｏＱ１０ ２ケ月で理論配合量の４．６％の減少。
Summary
(1) Disintegration test Although there was a delay in the opening time, it was within the specified time. (Within 20 minutes)
(2) α-Lipoic acid A decrease of 15.7% of the theoretical amount in two months.
(3) CoQ10 Decreased by 4.6% of theoretical amount in 2 months.
[１．製品処方・配合等]
[２．保存条件] ：温度４０℃ 湿度７５％ＲＨ ・ 規格６号瓶
[３．保存期間] ：
(1) １ケ月、２ケ月、４ケ月
(2) 常温半年
[４．試験内容] ：
(1）色調 （ＪＩＳ ２８７２１の色表 光沢版）
(2）崩壊試験（日本薬局方１４局 試験液 水・１液・２液）
(3）水分（加熱乾燥式）
(4）臭気評価（官能試験）
(5）α−リポ酸の定量（ＨＰＬＣ定量法：カラムＯＤＳ ＵＧ１２０）
＜測定条件＞
１カプセルを５ｍＭ リン酸緩衝液（ｐＨ３．５）：アセトニトリル＝１：１に溶 解して５０ｍｌに定容
標準品による５点絶対検量線により定量
＜ＨＰＬＣ条件＞
カラム ＯＤＳ ＵＧ１２０ （資生堂カプセルパックＣ１８ ４．６ｍｍφ× ２５０ｍｍ）
流出液 メタノール：５ｍＭ リン酸緩衝液：アセトニトリル（ｐＨ３．１）＝ １１６０：１８０：９２０
流出速度 １．２ｍｌ／ｍｉｎ 検出器 ２１５ｎｍ（トーソーＰＤ−８０２０）
カラム温度 ３５℃ 注入量 ２０μｌ
[2. Storage conditions]: Temperature 40 ° C Humidity 75% RH Standard 6 bottle
[3. Retention period]:
(1) 1 month, 2 months, 4 months
(2) Normal temperature half year
[4. contents of the test] :
(1) Color tone (JIS 28721 color chart glossy version)
(2) Disintegration test (Japanese Pharmacopoeia, 14th test solution, water, 1 liquid, 2 liquids)
(3) Moisture (heat drying type)
(4) Odor evaluation (sensory test)
(5) Quantification of α-lipoic acid (HPLC quantification method: column ODS UG120)
<Measurement conditions>
Dissolve 1 capsule in 5 mM phosphate buffer (pH 3.5): acetonitrile = 1: 1 and constant volume to 50 ml Quantitative analysis using a 5-point absolute calibration curve with a standard product <HPLC conditions>
Column ODS UG120 (Shiseido Capsule Pack C18 4.6 mmφ x 250 mm)
Effluent Methanol: 5 mM Phosphate buffer: Acetonitrile (pH 3.1) = 1160: 180: 920
Outflow rate 1.2ml / min detector 215nm (Tosoh PD-8020)
Column temperature 35 ° C Injection volume 20 µl
[５．試験結果]
まとめ
（１）色調 経時変化なし。
（２）崩壊試験 ６０分以内に被膜は全溶解で、問題なし。
（３）水分 問題なし。
（４）臭気評価 経時変化なし。
（５）α−リポ酸 経時変化は認められるが、許容範囲内。
Summary (1) Color tone No change over time.
(2) Disintegration test The coating was completely dissolved within 60 minutes and there was no problem.
(3) Moisture No problem.
(4) Odor evaluation No change over time.
(5) α-Lipoic acid Although change with time is observed, it is within the allowable range.
〔比較例２〕
[１．製品処方・配合等]
[1. Product prescription and formulation]
[２．保存条件] ：温度４０℃ 湿度７５％ＲＨ ・ 規格６号瓶
[３．保存期間] ：
(1) １ケ月、２ケ月、４ケ月
(2) 常温半年
[４．試験内容] ：
(1) 色調 （ＪＩＳ ２８７２１の色表 光沢版）
(2) 崩壊試験（日本薬局方１４局 試験液 水・１液・２液）
(3) 水分（加熱乾燥式）
(4) 臭気評価（官能試験）
(5) α−リポ酸の定量（ＨＰＬＣ定量法：カラムＯＤＳ ＵＧ１２０）
＜測定条件＞
１カプセルを５ｍＭ リン酸緩衝液（ｐＨ３．５）：アセトニトリル＝１：１に溶 解して５０ｍｌに定容
標準品による５点絶対検量線により定量
＜ＨＰＬＣ条件＞
カラム ＯＤＳ ＵＧ１２０ （資生堂カプセルパックＣ１８ ４．６ｍｍφ× ２５０ｍｍ）
流出液 メタノール：５ｍＭ リン酸緩衝液：アセトニトリル（ｐＨ３．１）＝ １１６０：１８０：９２０
流出速度 １．２ｍｌ／ｍｉｎ 検出器 ２１５ｎｍ（トーソーＰＤ−８０２０）
カラム温度 ３５℃ 注入量 ２０μｌ
[2. Storage conditions]: Temperature 40 ° C Humidity 75% RH Standard 6 bottle
[3. Retention period]:
(1) 1 month, 2 months, 4 months
(2) Normal temperature half year
[4. contents of the test] :
(1) Color tone (JIS 28721 color chart glossy version)
(2) Disintegration test (Japanese Pharmacopoeia 14th test solution water, 1 liquid, 2 liquids)
(3) Moisture (heat drying type)
(4) Odor evaluation (sensory test)
(5) Quantification of α-lipoic acid (HPLC quantification method: column ODS UG120)
<Measurement conditions>
Dissolve 1 capsule in 5 mM phosphate buffer (pH 3.5): acetonitrile = 1: 1 and constant volume to 50 ml Quantitative analysis using a 5-point absolute calibration curve with a standard product <HPLC conditions>
Column ODS UG120 (Shiseido Capsule Pack C18 4.6 mmφ x 250 mm)
Effluent Methanol: 5 mM Phosphate buffer: Acetonitrile (pH 3.1) = 1160: 180: 920
Outflow rate 1.2ml / min detector 215nm (Tosoh PD-8020)
Column temperature 35 ° C Injection volume 20 µl
[５．試験結果]
崩壊試験結果
まとめ
（１）色調 経時変化なし。
（２）崩壊試験 加速品は、内容物が１２０分以上経過しても分散せず残るが、規定 ６０分以内に被膜は全溶解。
（３）水分 経時変化なし。
（４）臭気評価 変化なし。
（５）α−リポ酸 経時的に、減少がみられた。
Summary (1) Color tone No change over time.
(2) Disintegration test Although the accelerated product remains undispersed even after 120 minutes, the coating dissolves completely within 60 minutes.
(3) Moisture No change with time.
(4) Odor evaluation No change.
(5) α-Lipoic acid A decrease was observed with time.
Claims (7)
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040044046A1 (en) * | 2002-06-07 | 2004-03-04 | Ames Bruce N. | Stability of lipoic acid |
| JP2005002096A (en) * | 2003-05-21 | 2005-01-06 | Oga Research:Kk | AQUEOUS PREPARATION CONTAINING alpha-LIPOIC ACID |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040044046A1 (en) * | 2002-06-07 | 2004-03-04 | Ames Bruce N. | Stability of lipoic acid |
| JP2005002096A (en) * | 2003-05-21 | 2005-01-06 | Oga Research:Kk | AQUEOUS PREPARATION CONTAINING alpha-LIPOIC ACID |
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