JP5032310B2 - 疲労回復のための医薬 - Google Patents
疲労回復のための医薬 Download PDFInfo
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- JP5032310B2 JP5032310B2 JP2007517908A JP2007517908A JP5032310B2 JP 5032310 B2 JP5032310 B2 JP 5032310B2 JP 2007517908 A JP2007517908 A JP 2007517908A JP 2007517908 A JP2007517908 A JP 2007517908A JP 5032310 B2 JP5032310 B2 JP 5032310B2
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- Prior art keywords
- vitamin
- fatigue
- adenosine triphosphate
- medicament
- physiologically acceptable
- Prior art date
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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 1
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- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 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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- 102000004196 processed proteins & peptides Human genes 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
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- ZSDSQXJSNMTJDA-UHFFFAOYSA-N trifluralin Chemical compound CCCN(CCC)C1=C([N+]([O-])=O)C=C(C(F)(F)F)C=C1[N+]([O-])=O ZSDSQXJSNMTJDA-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
ビタミンB2としては、ビタミンB2の他に、ビタミンB2の誘導体や生理学的に許容されるそれらの塩を用いてもよい。例えば、リボフラビン、リン酸リボフラビン、又はリボフラビンモノヌクレオチドなどが挙げられる。これらを2種以上組み合わせてビタミンB2として用いてもよい。これらのうち、リボフラビンが特に好ましい。
ビタミンB12としては、ビタミンB12の他に、ビタミンB12の誘導体や生理学的に許容されるそれらの塩を用いてもよい。例えば、シアノコバラミン、メチルコバラミン、ヒドロキソコバラミン、又はアデノシルコバラミンなどが挙げられる。これらを2種以上組み合わせて用いてもよい。これらのうち、シアノコバラミンが特に好ましい。
賦形剤としては、乳糖、デンプン類、結晶セルロース、蔗糖、マンニトール、又は軽質無水ケイ酸等が挙げられる。結合剤としては、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ゼラチン、アルファー化デンプン、ポリビニルピロリドン、ポリビニルアルコール、又はプルラン等が挙げられる。崩壊剤としては、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、クロスポビドン、トウモロコシ澱粉、又は低置換度ヒドロキシプロピルセルロース等が挙げられる。滑沢剤としては、ステアリン酸マグネシウム又はタルク等が挙げられる。着色剤としては、タール色素又は三二酸化鉄等が挙げられる。矯味剤としてはステビア、アスパルテーム、又は香料等が挙げられる。
製剤例1
3錠中に以下の成分及び分量を含む錠剤を通常の打錠法により調製した。
アデノシン三リン酸二ナトリウム 60.0mg
チアミンダイサルファイド 24.0mg
リボフラビン 1.5mg
塩酸ピリドキシン 24.0mg
シアノコバラミン 60μg
乳糖 301.5mg
低置換度ヒドロキシプロピルセルロース 22.5mg
ポリビニルピロリドンK30 13.5mg
ステアリン酸マグネシウム 3.0mg
合計 450.0mg(150.0mg/錠)
1日量中
アデノシン三リン酸二ナトリウム 60.0mg
硝酸チアミン 10.0mg
リボフラビン 4.0mg
塩酸ピリドキシン 10.0mg
コハク酸dl‐α‐トコフェロールカルシウム 20.7mg
アスコルビン酸ナトリウム 112.6mg
ニコチン酸アミド 25.0mg
エゾウコギ乾燥エキス(原生薬換算量300mg) 12.0mg
オウギ乾燥エキス(原生薬換算量240mg) 30.0mg
塩酸アルギニン 50.0mg
無水カフェイン 50.0mg
硬化油 30.0mg
ヒドロキシプロピルセルロース 24.0mg
結晶セルロース 125.7mg
カルメロース 30.0mg
ステアリン酸マグネシウム 6.0mg
合計 600.0mg
1日量中
アデノシン三リン酸二ナトリウム 120.0mg
ベンフォチアミン 138.3mg
リボフラビン 12.0mg
塩酸ピリドキシン 50.0mg
シアノコバラミン 60μg
ガンマ−オリザノール 10.0mg
コハク酸dl‐α‐トコフェロールカルシウム 103.6mg
D−マンニトール 106.0mg
結晶セルロース 120.1mg
ヒドロキシプロピルセルロース 37.5mg
カルメロースカルシウム 45.0mg
ステアリン酸マグネシウム 7.5mg
合計 750.0mg
1日量中
アデノシン三リン酸二ナトリウム 120.0mg
塩酸フルスルチアミン 100.0mg
塩酸ピリドキシン 100.0mg
シアノコバラミン 1500μg
ガンマ−オリザノール 10.0mg
コハク酸dl‐α‐トコフェロールカルシウム 103.6mg
パントテン酸カルシウム 30.0mg
硬化油 60.0mg
結晶セルロース 181.1mg
ヒドロキシプロピルセルロース 32.4mg
カルメロース 64.8mg
ステアリン酸マグネシウム 6.6mg
合計 810.0mg
下記の方法に従って運動負荷実験を行った。
<試験方法>
5週齢のBALB/C系雄性マウスを、34℃に維持した水を7L/分の速度で循環させた水槽内に入れ、水中に連続して7秒間沈むまで運動負荷した。続いて被験物質を動物に経口投与して30分間休息させた後、再び運動負荷を行い、水中に連続して7秒間沈むまでの時間(最大遊泳時間。以下同じ。)を測定した。
被験物質としては、アデノシン三リン酸二ナトリウム(以下、実施例において「ATP」と略す。)60mg、ビタミンB類(以下、実施例において「VBs」と略す、)としてチアミンダイサルファイド24mg、リボフラビン1.5mg、塩酸ピリドキシン24mg、及びシアノコバラミン60μgの組み合わせ、ATPとVBsとの組み合わせ(以下、実施例において「ATP+VBs」と略す)を用い、これらを0.5%メチルセルロース(以下、実施例において「MC」と略す。)に懸濁又は溶解して試験に供した。
酸化ストレスを負荷する遊泳モデル(Basic and Cli. Pharmacol. Toxicol., 97, pp.218-221, 2005、Gen. Physiol. Biophys., 23, pp.241-249, 2004)を用いて、下記方法により、精神疲労に対する本発明の医薬の効果をマイクロアレイを用いて検証した。
(a)ストレス負荷マウスの作製及び脳の採取
予め水温34℃に調整された温水を7L/minの流速で循環させた水槽内にBALB/cマウス(雄、5週齢(投与時))を投入し、水中に7秒間沈むまで遊泳させて負荷を与えると共に最大遊泳時間を測定した。遊泳終了直後に被験物質または対照物質を経口投与して30分間休息させ、再度水槽内にマウスを投入した。最大遊泳時間の50%に相当する時間、マウスを遊泳させた後、水槽より引き上げた。炭酸ガスで気絶させた後に断頭放血後、脳(中央部約5mm角)の採取を行った。
Total RNAの抽出にはRNeasy Lipid Tissue Mini kit (QIAGEN社製)を用いた。すなわち、採取した組織をチューブに入れ、QIAzol Lysis Reagentを200 μl添加し、ホモジナイザー(226AXG、有限会社アイ.エス.オー)を用いて破砕後、QIAzol Lysis Reagentを800 μl添加して混合した。室温で5分間静置した後、クロロホルムを200μl添加して15秒間激しく攪拌し、室温で2分間静置した後、12000 rpm(12000×g)、4℃、15分(Kendro,SORVALL fresco、以下、本試験例における遠心分離はすべて同機器を使用)の条件で遠心分離し、3層のうち上層を回収した。回収したサンプルに70%エタノールを600μl添加し、激しく攪拌することにより完全に混合した。混合液を、コレクションチューブをセットしたRNeasy カラム(以下カラムとする)に添加し、12000 rpm(12000×g)、20℃、15秒の条件で遠心分離した。混合液を通したカラムにBuffer RW1を700μl添加し、チューブのふたを閉めて12000 rpm(12000×g)、20℃、15秒の条件で遠心分離した。カラムを新しいコレクションチューブに移し、Buffer RPEを500 μl添加した。チューブのふたを閉めて12000 rpm(12000×g)、20℃、15秒の条件で遠心分離した。再度Buffer RPEを500μl添加し、チューブのふたを閉めて12000 rpm(12000×g)、20℃、2分の条件で遠心分離した。カラム内のメンブレンが乾燥していること確認した後、カラムを1.5 mLマイクロチューブに移し、RNaseフリー水を30μL添加した。1分間静置した後、12000 rpm(12000×g)、20℃、1分の条件で遠心分離することによりtotal RNAを溶出した。本溶出操作はカラムあたり2回行った。得られたtotal RNAサンプルについて、NanoDrop(ND-1000、NanoDrop社製)を用いて濃度測定を行った。total RNA濃度は波長260nm(以下A260とする)の吸光度を基に下記の式で算出した。
total RNA濃度(ng/μl)=(各サンプルのA260−対照のA260)×40
得られたラベル化cRNAを用いて、In situ hybridization kit plus(Agilent社製)によるmouse microarray oligo(以下マウスオリゴ)とのハイブリダイゼーションを行った。すなわち、Cy3 ラベル化cRNA 0.75μg相当とCy5ラベル化cRNA 0.75μg相当、10×コントロールターゲットを50μlとNuclease-free waterを混合して合計215μl(以降、2×ターゲットソリューションとする)とし、2×ターゲットソリューションを215μl、25×フラグメンテーションバッファを9μl添加し、60℃で30分間、遮光下でインキュベートした。2×ハイブリダイゼーションバッファを225μl添加して反応停止させた後、マイクロアレイ用チャンバー内でマウスオリゴにアプライし、60℃で17時間ハイブリダイゼーションを行った。反応終了後、マウスオリゴを0.005% TritonX-102含有6×SSC並びに0.005% TritonX-102含有0.1×SSCで洗浄し、窒素ガスで乾燥させた。乾燥したマウスオリゴをマイクロアレイスキャナー(Agilent社製)に供して画像を取り込んだ後、画像化ソフトFeature Extractionを用いてスポットの画像化並びにシグナル強度の数値化を行った。得られた数値について、Microsoft EXCEL並びにGeneSpring(Silicon Genetics社製)にて解析を行った。
マウスオリゴに搭載されているプローブのうち、コントロールプローブ並びにノイズにより測定値の信頼性が低いプローブを除去し、残りの約20000遺伝子について解析を行った。無処置の群とMC投与群の比較から、ストレス負荷により発現量が2倍以上増加した遺伝子が27遺伝子、逆に発現量が1/2以下に減少した遺伝子が68遺伝子確認された。また、無処置の群とATP+VBs投与群の比較から、ATP+VBsの投与後、ストレス負荷を行ったことにより発現量が2倍以上に増加した遺伝子が69遺伝子、逆に発現量が1/2以下に減少した遺伝子が112遺伝子確認された。これらのうち、ストレス負荷時並びにATP+VBs投与後ストレス負荷時に発現量が2倍以上増加した遺伝子にvasoactive intestinal polypeptide遺伝子が含まれていた。各群におけるvasoactive intestinal polypeptide遺伝子のシグナル値、及び、MC投与群とATP+VBs投与群のシグナル値の、無処置の群のシグナル値に対する比率(対control比)を表2に示す。
Claims (4)
- 疲労回復のための経口投与用の医薬であって、アデノシン5'−三リン酸又は生理学的に許容されるその塩とビタミンB 1 、ビタミンB 2 、ビタミンB 6 、及びビタミンB 12 の組み合わせとを同時に投与するための組み合わせを含む医薬。
- アデノシン5'−三リン酸又は生理学的に許容されるその塩1重量部に対して、ビタミンB1を0.0003〜20重量部、ビタミンB2を0.0005〜8重量部、ビタミンB6を0.001〜20重量部、及びビタミンB12を0.0000003〜0.3重量部の割合で含む請求項1に記載の医薬。
- ビタミンB 1 がチアミンダイサルファイドであり、ビタミンB 2 がリボフラビンであり、ビタミンB 6 が塩酸ピリドキシンであり、ビタミンB 12 がシアノコバラミンである請求項1又は2に記載の医薬。
- 疲労が、身体的負荷に伴う疲労である、請求項1ないし3のいずれか1項に記載の医薬。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01308232A (ja) * | 1988-06-03 | 1989-12-12 | Takeda Chem Ind Ltd | 固型医薬およびその製造法 |
JPH06305963A (ja) * | 1993-04-21 | 1994-11-01 | Taisho Pharmaceut Co Ltd | 疲労改善剤 |
JPH10287560A (ja) * | 1997-04-11 | 1998-10-27 | Taisho Pharmaceut Co Ltd | 医薬組成物 |
JP2003040793A (ja) * | 2001-07-24 | 2003-02-13 | Arie:Kk | シートパック化粧料、飲用カプセル及び飲用錠剤 |
JP2003119139A (ja) * | 2001-10-12 | 2003-04-23 | Ss Pharmaceut Co Ltd | 疲労回復医薬組成物 |
JP2004535417A (ja) * | 2001-06-04 | 2004-11-25 | テクニカル ソーシング インターナショナル インコーポレイテッド | アデノシン三リン酸の投与により筋疲労を低減させる方法 |
JP2005023008A (ja) * | 2003-07-01 | 2005-01-27 | Sankyo Co Ltd | ビタミンb群を含有する内服液剤組成物 |
-
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01308232A (ja) * | 1988-06-03 | 1989-12-12 | Takeda Chem Ind Ltd | 固型医薬およびその製造法 |
JPH06305963A (ja) * | 1993-04-21 | 1994-11-01 | Taisho Pharmaceut Co Ltd | 疲労改善剤 |
JPH10287560A (ja) * | 1997-04-11 | 1998-10-27 | Taisho Pharmaceut Co Ltd | 医薬組成物 |
JP2004535417A (ja) * | 2001-06-04 | 2004-11-25 | テクニカル ソーシング インターナショナル インコーポレイテッド | アデノシン三リン酸の投与により筋疲労を低減させる方法 |
JP2003040793A (ja) * | 2001-07-24 | 2003-02-13 | Arie:Kk | シートパック化粧料、飲用カプセル及び飲用錠剤 |
JP2003119139A (ja) * | 2001-10-12 | 2003-04-23 | Ss Pharmaceut Co Ltd | 疲労回復医薬組成物 |
JP2005023008A (ja) * | 2003-07-01 | 2005-01-27 | Sankyo Co Ltd | ビタミンb群を含有する内服液剤組成物 |
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