学 位 論 文 医薬品臨床使用時に生じる不快な味・においの 改善方法に関する研究 The study of improvement strategies for unpleasant taste and odor appeared in clinical usage of medicines ２０１4 原口 珠実 ┠ḟ ⥴㻌 ㄽ .............................................................................................................................................. 1 ➨ 1 ❶㻌 䜰䝭䝜䝺䝞䞁®EN 㓄ྜᩓ䛾᭹⏝ᛶホ౯ .......................................................................... 3 ➨ 1 ⠇㻌 䜰䝭䝜䝺䝞䞁®EN 㓄ྜᩓᠱ⃮ᾮ䛾ⱞ䛻ཬ䜌䛩 ᗘ䛾ᙳ㡪 ................................... 4 ➨ 1 㡯㻌 ┠ⓗ ........................................................................................................................... 4 ➨ 2 㡯㻌 ᐇ㦂᪉ἲ ................................................................................................................... 4 ➨ 3 㡯㻌 ⤖ᯝ䛸⪃ᐹ ................................................................................................................ 7 ➨ 2 ⠇㻌 䜰䝭䝜䝺䝞䞁®EN 㓄ྜᩓᠱ⃮ᾮ䛾䛻䛚䛔ホ౯ ......................................................... 12 ➨ 1 㡯㻌 ┠ⓗ ......................................................................................................................... 12 ➨ 2 㡯㻌 ᐇ㦂᪉ἲ ................................................................................................................. 12 ➨ 3 㡯㻌 ⤖ᯝ䛸⪃ᐹ .............................................................................................................. 15 ➨ 3 ⠇㻌 ᑠᣓ ............................................................................................................................ 20 I ➨ 2 ❶㻌 䝧䝅䜿䜰®㘄, 䝧䝅䜿䜰®OD 㘄⢊○䛾⢊○⛬ᗘ䛜ཬ䜌䛩ⱞ䜈䛾ᙳ㡪 ............. 21 ➨ 1 ⠇㻌 ぬ䝉䞁䝃䜢⏝䛔䛯䝋䝸䝣䜵䝘䝅䞁䝁䝝䜽㓟ሷ䛾ⱞホ౯ ..................................... 21 ➨ 1 㡯㻌 ┠ⓗ ......................................................................................................................... 21 ➨ 2 㡯㻌 ᐇ㦂᪉ἲ ................................................................................................................. 21 ➨ 3 㡯㻌 ⤖ᯝ䛸⪃ᐹ .............................................................................................................. 24 ➨ 2 ⠇㻌 ぬ䝉䞁䝃䜢⏝䛔䛯䝧䝅䜿䜰®㘄, 䝧䝅䜿䜰®OD 㘄⢊○ヨᩱ䛾ⱞホ౯ ........... 25 ➨ 1 㡯㻌 ┠ⓗ ......................................................................................................................... 25 ➨ 2 㡯㻌 ᐇ㦂᪉ἲ ................................................................................................................. 25 ➨ 3 㡯㻌 ⤖ᯝ䛸⪃ᐹ .............................................................................................................. 27 ➨ 3 ⠇㻌 䝧䝅䜿䜰®㘄, 䝧䝅䜿䜰®OD 㘄⢊○ヨᩱ䛾⸆≀⁐ฟ⋡䛾 ᐃ ............................. 29 ➨ 1 㡯㻌 ┠ⓗ ......................................................................................................................... 29 ➨ 2 㡯㻌 ᐇ㦂᪉ἲ ................................................................................................................. 29 ➨ 3 㡯㻌 ⤖ᯝ䛸⪃ᐹ .............................................................................................................. 30 ➨ 4 ⠇㻌 ᑠᣓ ............................................................................................................................ 32 II ➨ 3 ❶㻌 䝮䝁䝇䝍®Ⅼ║ᾮ UD2%Ⅼ║ᚋ䛾ⱞᢚไ䛻᭷ຠ䛺㣧㣗≀䛾᥈⣴ ......................... 33 ➨ 1 ⠇㻌 䝺䝞䝭䝢䝗䛾ⱞホ౯䛻㐺䛧䛯ぬ䝉䞁䝃⭷䛾㑅ᢥ ............................................... 33 ➨ 1 㡯㻌 ┠ⓗ ......................................................................................................................... 33 ➨ 2 㡯㻌 ᐇ㦂᪉ἲ ................................................................................................................. 33 ➨ 3 㡯㻌 ⤖ᯝ䛸⪃ᐹ .............................................................................................................. 35 ➨ 2 ⠇㻌 ぬ䝉䞁䝃䜢⏝䛔䛯䝺䝞䝭䝢䝗䛾ⱞ䛻ཬ䜌䛩㣧㣗≀䛾ᙳ㡪䛾ホ౯ ................... 36 ➨ 1 㡯㻌 ┠ⓗ ......................................................................................................................... 36 ➨ 2 㡯㻌 ᐇ㦂᪉ἲ ................................................................................................................. 36 ➨ 3 㡯㻌 ⤖ᯝ䛸⪃ᐹ .............................................................................................................. 37 ➨ 3 ⠇㻌 䝠䝖ᐁ⬟ヨ㦂䛻䜘䜛䝺䝞䝭䝢䝗䛸㣧㣗≀ΰྜヨᩱ䛾ⱞホ౯ .................................. 39 ➨ 1 㡯㻌 ┠ⓗ ......................................................................................................................... 39 ➨ 2 㡯㻌 ᐇ㦂᪉ἲ ................................................................................................................. 39 ➨ 3 㡯㻌 ⤖ᯝ䛸⪃ᐹ .............................................................................................................. 40 ➨ 4 ⠇㻌 ᑠᣓ ............................................................................................................................ 42 ➨ 4 ❶㻌 ⥲ᣓ ................................................................................................................................ 43 ㅰ㎡............................................................................................................................................... 45 ཧ⪃ᩥ⊩....................................................................................................................................... 46 III ⥴ ㄽ ⸆≀⒪࠾࠸࡚, ⸆ࡢ᭹⏝ᛶࡣ᭹⸆ࢥࣥࣉࣛࣥࢫࡁࡃᙳ㡪ࡍࡿ. ⸆ࡢ᭹⏝ᛶ㛵ࢃ ࡿᅉᏊࡋ࡚, ⸆⮫ᗋ⏝ࡢࡸ࠾࠸ࡀᣲࡆࡽࢀࡿ. ࡃ, ་⸆ရࡢⱞࡣ᭹⸆ࡢᝈ⪅ࡢ㈇ ᢸ࡞ࡿࡇࡀከ࠸. Dolder ࡽࡣ, ᭹⸆ࢥࣥࣉࣛࣥࢫࢆྥୖࡉࡏࡿ᪉ἲࡋ࡚, ᝈ⪅ᩍ⫱ࡀᚲせ࡛ ࠶ࡿࡇࢆ♧ࡋ࡚࠾ࡾ, ᭹⸆ࢥࣥࣉࣛࣥࢫࡢྥୖࡼࡾ, ḟⓗ࡞ධ㝔ࡢῶᑡ, ♫ᶵ⬟ࡢᨵၿ, ㆑Ḟዴࡢᨵၿࡀᮃࡵࡿࡇࢆሗ࿌ࡋ࡚࠸ࡿ 1) . ⸆ᖌࡣ, ᝈ⪅ࡢ᭹⸆ࢥࣥࣉࣛࣥࢫྥୖࡢࡓࡵ, ࢚ࣅࢹࣥࢫᇶ࡙࠸ࡓ⸆⟶⌮ᣦᑟᴗົࢆ⾜ࡗ࡚࠸ࡃࡇࡀᚲせ࡛࠶ࡿ. ࡇࢀࡲ࡛ࡢᙧูࡢ⸆ࡢ᭹⏝ᛶ㛵ࡍࡿㄪᰝ 2, 3) ࡼࡿ, ᩓࡣ, ཱྀ⭍ෆࡢᗈࡀࡾࡸṧ␃ឤ, ႃ ࡢ╔ࡢࡓࡵ᭹⏝ࡋࡃ࠸ࡇࡀሗ࿌ࡉࢀ࡚࠸ࡿ. ࡲࡓ, ᩓࡢࡣ᭹⏝ࡋࡸࡍࡉᙳ㡪ࡍࡿᅉᏊ࡛ ࠶ࡾ, L-࢝ࣝ࣎ࢩࢫࢸࣥࡢࢻࣛࢩࣟࢵࣉࡢ㣧ࡳࡸࡍࡉࡢ⌮⏤ࡢⰋࡉࡀᣲࡆࡽࢀࡓሗ࿌ࡉࢀ࡚ ࠸ࡿ 4). ࡇࡢࡼ࠺, ᩓࡣ᭹⏝ཱྀ⭍ෆᗈࡀࡿࡓࡵ, ࡑࡢࡀ᭹⏝ᛶࡁࡃᙳ㡪ࡍࡿ. ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡣ, 1 ᅇ᭹⏝㔞 50 g ࢆỈ 200 mL ᠱ⃮ࡋ࡚᭹⏝ࡍࡿ⫢⏝⤒ཱྀᰤ㣴࡛࠶ ࡿࡀ, ྵ᭷࣑ࣀ㓟≉᭷ࡢⱞࡸ࠾࠸ࢆ࿊ࡋ, 1 ᅇ᭹⏝㔞ࡀከ࠸ࡇࡽ᭹⸆ࢥࣥࣉࣛࣥࢫࡀⰋ ࡛࠶ࡿࡇࡀከ࠸ 5). ࡇࡢࡓࡵ㛗ᮇ⥅⥆᭹⏝ࡸቑ㔞ࡀᅔ㞴࡛࠶ࡗࡓࡀㄆࡵࡽࢀࡓ࠸࠺ሗ࿌ 6) ࡶ ࠶ࡾ, ࡑࡢⱞࡸ࠾࠸ࡢᨵၿࡀᚲせ࡛࠶ࡿ. ୍᪉, 㘄ࡣᄟୗࡼࡗ࡚㏿ࡸႃࢆ㏻㐣ࡍࡿࡓࡵཱྀ⭍ෆ࡛ࡢၥ㢟ࡣᑡ࡞࠸ࡉࢀ࡚࠸ࡿ. ᡂேᝈ ⪅ࢆᑐ㇟ࡋࡓ᭹⏝ᛶ㛵ࡍࡿㄪᰝ◊✲ 4) ࡛ࡣ, 㘄ࡢ㣧ࡳࡸࡍࡉࡢ⌮⏤ࡋ࡚, ႃ╔ࡋ࡞࠸ࡇ ࡸࡀ࡞࠸ࡇࡀᣲࡆࡽࢀ࡚࠾ࡾ, ཱྀ⭍ෆᗈࡀࡿᩓẚ㍑ࡋ࡚㘄ࡣ, ᭱ࡶ᭹⏝ࡋࡸࡍ࠸ᙧ࡛࠶ ࡿ࠸࠼ࡿ. ࡋࡋ, ᄟୗᅔ㞴࡞ᝈ⪅ࡸ, ⏝㔞ㄪᩚࡀᚲせ࡞ᑠඣᑐࡋ࡚, 㘄ࡀ⢊○ࡉࢀࡿࡇࡀ࠶ ࡿ 7-10). ࡇࡢሙྜ, ᩓྠᵝ⸆ࡀཱྀ⭍ෆᗈࡀࡿࡓࡵ, ࡑࡢࡀ᭹⏝ᛶᙳ㡪ࡍࡿ. 㐣άື⭤⬔⒪࡛࠶ࡿ࣋ࢩࢣ®㘄ࡣ, ῧᩥ᭩, ࠕ⸆ⱞࡀ࠶ࡿࡓࡵ᭹⏝ჶࡳ○࡞ ࠸ࡇࠖ࠸࠺ὀពࡀグ㍕ࡉࢀ࡚࠸ࡿ. ࡋࡋ, ᑠඣࡢኪᒀᑐࡋ࡚⏝㔞ㄪᩚࡢࡓࡵ⢊○ࡉࢀࡿࡇ ࡀ࠶ࡾ, ࡇࢀࢆỈ࡛᭹⏝ࡍࡿ㝿, ⸆ࡼࡿⱞࢆ࿊ࡋ, ᭹⏝ࢆᅔ㞴ࡍࡿሙྜࡀ࠶ࡿ. ࡉࡽ, ⤒ཱྀࡔࡅ࡛࡞ࡃⅬ║ᾮ࡛ࡶ⏝ᚋཱྀ⭍ෆ࡛ࡢⱞࢆ⏕ࡌ࠺ࡿ. ࢻࣛ⒪⸆࡛࠶ࡿ ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%11) ࡣ, ࣒ࢳࣥቑຍస⏝ࡼࡿࢻࣛ⒪ࡢ᪂ࡋ࠸⒪ࢥࣥࢭࣉࢺ Tear Film 1 Oriented Therapy (TFOT)12) ࢆ㋃ࡲ࠼ࡓ㔜せ࡞Ⅼ║⸆ࡋ࡚ὀ┠ࡉࢀ࡚࠸ࡿ. ࡋࡋ, Ⅼ║ᚋⅬ║ᾮࡀ 㰯ᾦ⟶ࢆ㏻㐣ࡋ࡚, ဗ㢌㒊࡛⸆ࡢࣞࣂ࣑ࣆࢻࡼࡿⱞࢆ⏕ࡌࡿࡇࡀ࠶ࡿ. ⴭ⪅ࡣ, ௨ୖࡢၥ㢟ࢆඞ᭹ࡍࡿࡓࡵ, ⱞᛌ࡞࠾࠸ࢆ࿊ࡍࡿ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ, ⸆ࡀ ⱞࢆ࿊ࡍࡿࡶࢃࡽࡎ㘄ࡀ⢊○ࡉࢀࡿࡇࡀ࠶ࡿ࣋ࢩࢣ®㘄, Ⅼ║ᚋဗ㢌㒊࡛ⱞࢆ⏕ࡌ ࡿ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%ࡘ࠸࡚, ྛ⸆ࡢ⮫ᗋ⏝⏕ࡌࡿᛌ࡞ࡸ࠾࠸ࢆホ౯ࡋ, ࡑࡢᨵ ၿ⟇ࢆ᳨ウࡋࡓ. ᮏㄽᩥࡣ, 4 ❶ࡽᡂࡾ, ➨ 1 ❶࡛ࡣ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮ༢⊂ࡲࡓࡣ, ྛᑓ⏝ࣇ࣮ࣞࣂ࣮ ࢆῧຍࡋࡓ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢⱞཬࡰࡍ ᗘࡢᙳ㡪ࡘ࠸࡚, ࣄࢺᐁ⬟ヨ㦂ࡼࡾホ ౯ࡋࡓ. ࡉࡽ, ᛌ࡞࠾࠸ࢆ࿊ࡍࡿ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ྛᑓ⏝ࣇ࣮ࣞࣂ࣮ ࡼࡿ▹⮯ຠᯝࡘ࠸࡚, ࣄࢺᐁ⬟ヨ㦂Ⴅぬࢭࣥࢧࡼࡾホ౯ࡋࡓ. ➨ 2 ❶࡛ࡣ, ⸆ࡢࢯࣜࣇ࢙ࢼࢩࣥࢥࣁࢡ㓟ሷࡀᙉ࠸ⱞࢆ࿊ࡍࡿ࣋ࢩࢣ®㘄ࡑࡢཱྀ⭍ෆᔂቯ㘄 ࡛࠶ࡿ࣋ࢩࢣ®OD 㘄ࢆ⢊○ࡍࡿሙྜࡢ⢊○⛬ᗘࡀཬࡰࡍⱞࡢᙳ㡪ࡘ࠸࡚, ぬࢭࣥࢧࢆ⏝࠸࡚ ホ౯ࡋࡓ. ➨ 3 ❶࡛ࡣ, ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%Ⅼ║ᚋ⏕ࡌࡿ, ⸆ࡢࣞࣂ࣑ࣆࢻࡼࡿⱞࢆᢚไࡍࡿຠᯝⓗ ࡞㣧㣗≀ࡢ᥈⣴ࢆ⾜࠺ࡓࡵ, ࣞࣂ࣑ࣆࢻࡢⱞཬࡰࡍ㣧㣗≀ࡢᙳ㡪ࡘ࠸࡚, ぬࢭࣥࢧࢆ⏝࠸࡚ホ ౯ࡋ, ࣄࢺᐁ⬟ヨ㦂ࡼࡿ᳨ドࢆ⾜ࡗࡓ. ➨ 4 ❶࡛ࡣ, ᮏㄽᩥࢆ⥲ᣓࡋࡓ. 2 ➨ 1 ❶ ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢ᭹⏝ᛶホ౯ ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡣ, ⫢ᛶ⬻ࢆక࠺៏ᛶ⫢ᝈ⪅ࡢᰤ㣴≧ែࡢᨵၿࢆ┠ⓗࡋ࡚㛤Ⓨࡉࢀ ࡓ⫢⏝⤒ཱྀᰤ㣴࡛࠶ࡿ. ࡑࡢ࣑ࣀ㓟⤌ᡂࡣ Fischer ࡢ⌮ㄽ‽ࡌ࡚ⰾ㤶᪘࣑ࣀ㓟㔞ࢆไ㝈ࡋ, ศᒱ㙐࣑ࣀ㓟 (L-ࣟࢩࣥ, L-ࢯࣟࢩࣥ, L-ࣂࣜࣥ) ࢆከࡃྵ᭷ࡍࡿ (Fig. 1). ⾑₢୰ࡢ࣑ࣀ㓟ࣃ ࢱ࣮ࣥࢆኚࡉࡏ Fischer ẚࢆ᭷ពቑࡉࡏࡿࡇࡼࡾ⫢ᛶ⬻≧ࢆᨵၿࡋ, ᰤ㣴ຠᯝࡶඃࢀ ࡚࠸ࡿ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢ㸯ᅇ᭹⏝㔞ࡣ 50 g (1 ໟ) ࡛, 1 ᪥ 3 ᅇ⤒ཱྀᦤྲྀࡍࡿᚲせࡀ࠶ࡿ. ࡋࡋ ࡑࡢⱞ࠾࠸ࡀᝈ⪅ࡢ᭹⸆ពḧࢆపୗࡉࡏࡿ. ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࢆ᭹⏝ࡋࡸࡍࡃࡍࡿࡓࡵ 6 ✀㢮ࡢᑓ⏝ࣇ࣮ࣞࣂ࣮ (ࢥ࣮ࣄ࣮࣑ࢵࢡࢫ, Ⲕ࣑ࢵࢡࢫ, ࢵࣉ࣑ࣝࢵࢡࢫ, ࣇ࣮ࣝࢶ࣑ࢵ ࢡࢫ, ࣉ࣒࣑ࣛࢵࢡࢫ, ࣃࢼࢵࣉ࣑ࣝࢵࢡࢫ) ࡢ⏝ࡀ᥎ዡࡉࢀ࡚࠸ࡿ. ᐑỌࡽࡣぬࢭࣥࢧ ࣄࢺᐁ⬟ヨ㦂ࡼࡾᑓ⏝ࣇ࣮ࣞࣂ࣮ࡢ⏑㓟ࡀ࣑ࣀࣞࣂࣥ ®EN 㓄ྜᩓࡢⱞࢆᢚไࡍࡿࡇࢆ ᳨ドࡋ࡚࠸ࡿ 13) . ࡋࡋ࡞ࡀࡽ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ᭹⏝ࡢᠱ⃮ᾮࡢ ᗘࡀཬࡰࡍⱞࡢᙳ㡪 ࡘ࠸࡚ࡢ᳨ドࡣ⾜ࢃࢀ࡚࠸࡞࠸. ᮏ❶࡛ࡣ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ᭹⏝ࡢᛌឤࢆࡼࡾຠᯝⓗ㍍ῶࡍࡿ᪉ἲࢆᥦࡍࡿࡇࢆ┠ ⓗࡋ᳨࡚ウࢆ⾜ࡗࡓ. ➨ 1 ⠇࡛ࡣ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢⱞཬࡰࡍ ᗘࡢᙳ㡪ࡘ࠸࡚, ࣄࢺ ᐁ⬟ヨ㦂ࡼࡾホ౯ࡋࡓ. ࡉࡽ, ➨ 2 ⠇࡛ࡣ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ࡘ࠸࡚, ࣄࢺ ᐁ⬟ヨ㦂Ⴅぬࢭࣥࢧࡼࡾホ౯ࡋࡓ. Fig. 1 Components of Aminoleban® EN and structure of BCAA (L-Leu, L-Ile, L-Val) 3 ➨ 1 ⠇ ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢⱞཬࡰࡍ ᗘࡢᙳ㡪 ➨ 1 㡯 ┠ⓗ Kadohisa ࡽࡣ, , ࠾࠸, 㣗ឤࡢ, ᗘࢆឤ▱ࡍࡿ⚄⤒ࡀ, 㣗≀ࡢ⨾ࡋࡉࢆㄆ㆑ࡍࡿ⬻㡿ᇦ࡛ ࠶ࡿ║❐๓㢌⓶㉁࠶ࡿࡇࢆⓎぢࡋ, ཱྀ⭍ෆ ᗘࡀ㣗≀ࡢᙳ㡪ࡍࡿ࠸࠺ࡇࢆሗ࿌ࡋ࡚࠸ࡿ 14). ࡇࡢࡇࡽ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ ᗘࡢ㐪࠸ࡼࡾ᭹⏝ࡢࡀኚࡍࡿྍ⬟ᛶࡀ⪃࠼ ࡽࢀࡿࡀ, ࡇࢀࢆ᳨ドࡋࡓሗ࿌ࡣ࡞࠸. ᮏ⠇࡛ࡣ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢⱞཬࡰࡍ ᗘ ࡢᙳ㡪ࡘ࠸࡚ホ౯ࡋࡓ 15). ➨ 2 㡯 ᐇ㦂᪉ἲ 1. ヨ⸆ ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ, ྛᑓ⏝ࣇ࣮ࣞࣂ࣮ (ࢥ࣮ࣄ࣮࣑ࢵࢡࢫ, Ⲕ࣑ࢵࢡࢫ, ࢵࣉࣝ ࣑ࢵࢡࢫ, ࣇ࣮ࣝࢶ࣑ࢵࢡࢫ, ࣉ࣒࣑ࣛࢵࢡࢫ, ࣃࢼࢵࣉ࣑ࣝࢵࢡࢫ) ࡣ, ሯ〇⸆ᰴᘧ♫ࡼ ࡾᥦ౪ࡉࢀࡓࡶࡢࢆ⏝࠸ࡓ. 㐣ཤࡢሗ࿌ᚑ࠸ 16), L-ࢯࣟࢩࣥ (L-Ile), L-ࣟࢩࣥ (L-Leu), L-ࣂࣜࣥ (L-Val) ࢆ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓྵ᭷ࡍࡿ⃰ᗘྠ➼࡞ࡿࡼ࠺ΰྜㄪ〇ࡋࡓヨᩱࢆ, ⱞᙉᗘ τ 3.5 ࡢ BCAA ΰྜỈ⁐ᾮࡋࡓ. ࡲࡓࡇࡢ τ 3.5 ࡢ BCAA ΰྜỈ⁐ᾮࢆᕼ㔘ࡋ࡚ τ 3.0, τ 2.5, τ 2.0, τ 1.5, τ 1.0, τ 0.5 ࡢ BCAA ΰྜỈ⁐ᾮࢆㄪ〇ࡋࡓ (Table 1). Table 1 Bitterness intensity (τ) and corresponding BCAA concentration (g/dL) 4 2. ࣄࢺᐁ⬟ヨ㦂ࡼࡿࡢホ౯ ࣄࢺᐁ⬟ヨ㦂 17)ࡼࡿࡢホ౯ࡣ, ᗣ࡞ 12 ྡࡢዪᛶ (22㸫30 ṓ) ࢆࣃࢿࣝࡋ࡚⾜ࡗࡓ. ࣃࢿࣝࡣ, ࡢᶆ‽⁐ᾮ 2 mL ࢆ 5 ⛊㛫ཱྀ⭍ෆྵࡳ, ᙉᗘࢆグ᠈ࡋࡓ. ḟྛヨ㦂ヨᩱ 2 mL ࢆ 5 ⛊㛫ཱྀ⭍ෆ ྵࡳ, ᙉᗘࢆホ౯ࡋࡓ. ཱྀ⭍ෆྵࢇࡔヨᩱࡣ, ࡢホ౯ᚋ, ㏿ࡸཱྀ⭍እྤࡁฟࡋ, တႿࡋࡓ. ⱞࡢᶆ‽⁐ᾮࡋ࡚, BCAA ΰྜỈ⁐ᾮ (Table 1), ⏑ࡢᶆ‽⁐ᾮࡋ࡚, ࢩࣙ⢾Ỉ⁐ᾮ, 㓟ࡢᶆ‽ ⁐ᾮࡋ࡚, 㓇▼㓟Ỉ⁐ᾮࢆ⏝࠸ࡓ 18) (Table 2). ᮏヨ㦂ࡣ, ṊᗜᕝዪᏊᏛ⌮ጤဨࡢᢎㄆࢆᚓࡓᚋ ⾜ࡗࡓ (ᢎㄆ␒ྕ 07-34, 12-24). Table 2 The tau scale (τ) of sweetness and sourness intensity, and corresponding concentration of sucrose and tartaric acid (g/100 mL) 2-1. ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢⱞཬࡰࡍ ᗘࡢᙳ㡪 ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮ (25 g/100 mL) ྛᑓ⏝ࣇ࣮ࣞࣂ࣮ (ࢥ࣮ࣄ࣮࣑ࢵࢡࢫ, Ⲕ࣑ ࢵࢡࢫ, ࢵࣉ࣑ࣝࢵࢡࢫ, ࣇ࣮ࣝࢶ࣑ࢵࢡࢫ, ࣉ࣒࣑ࣛࢵࢡࢫ, ࣃࢼࢵࣉ࣑ࣝࢵࢡࢫ) 3 g ࢆῧຍࡋࡓヨᩱࢆヨ㦂ヨᩱࡋ, ⱞᙉᗘࢆࣄࢺᐁ⬟ヨ㦂ࡼࡾホ౯ࡋࡓ. ࡲࡓ, ྛᑓ⏝ࣇ࣮ࣞࣂ࣮ 3 g ࢆ 100 mL ࡢ⢭〇Ỉ⁐ゎࡋࡓヨᩱࢆヨ㦂ヨᩱࡋ, ࡑࢀࡽࡢ⏑ᙉᗘ, 㓟ᙉᗘࢆࣄࢺᐁ⬟ヨ㦂ࡼ ࡾホ౯ࡋࡓ. ྛヨ㦂ࢧࣥࣉࣝࡢ ᗘ᮲௳ࡣ, 0-5Υ (௨ୗ, ప ), 25-30Υ (௨ୗ, ᖖ ) ࡢ 2 Ⅼࡋࡓ. 2-2. BCAA ΰྜỈ⁐ᾮࡢⱞཬࡰࡍ⏑ࡲࡓࡣ㓟 ᗘࡢᙳ㡪 BCAA ΰྜỈ⁐ᾮ (τ 0.5㸫τ 3.5) ࢩࣙ⢾ࢆ, ⏑ᙉᗘ τ 1, τ 2, τ 3 ࡢ⃰ᗘ࡞ࡿࡼ࠺ΰྜࡋࡓヨᩱ, BCAA ΰྜỈ⁐ᾮ (τ 0.5㸫τ 3.5) 㓇▼㓟ࢆ, 㓟ᙉᗘ τ 1, τ 2, τ 3, τ 4 ࡢ⃰ᗘ࡞ࡿࡼ࠺ΰྜࡋࡓヨᩱ ࢆヨ㦂ヨᩱࡋ, ᖖ ୗ࡛ࡢⱞᙉᗘࢆࣄࢺᐁ⬟ヨ㦂ࡼࡾホ౯ࡋࡓ. 5 ࡲࡓ, BCAA ΰྜỈ⁐ᾮ (τ 0.5㸫τ 3.5) ࢩࣙ⢾ࢆ⏑ᙉᗘ τ 3 ࡢ⃰ᗘ࡞ࡿࡼ࠺ΰྜࡋࡓヨᩱ, BCAA ΰྜỈ⁐ᾮ (τ 0.5㸫3.5) 㓇▼㓟ࢆ㓟ᙉᗘ τ 4 ࡢ⃰ᗘ࡞ࡿࡼ࠺ΰྜࡋࡓヨᩱࢆヨ㦂ヨᩱ ࡋ, ప ୗᖖ ୗ࡛ࡢⱞᙉᗘࢆࣄࢺᐁ⬟ヨ㦂ࡼࡾホ౯ࡋࡓ. 3. ⤫ィฎ⌮ ࢹ࣮ࢱࡣᖹᆒ್ ± S.D.࡛⾲グࡋࡓ. Fig. 2, 3, 4, 5 ♧ࡋࡓ⤖ᯝࡘ࠸࡚ࡣ, ࢚ࢡࢭࣝ⤫ィࢆ⏝࠸࡚ Sheffe’s test ࡼࡿከ⩌㛫ࡢẚ㍑ࡲࡓࡣ Mann-whitney U test ࡼࡿ 2 ⩌㛫ࡢẚ㍑ࢆ⾜ࡗࡓ. 6 ➨ 3 㡯 ⤖ᯝ⪃ᐹ 1. ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢⱞཬࡰࡍ ᗘࡢᙳ㡪 ᖖ ୗ࡛ࡢ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢⱞᙉᗘࡣ, Ⲕ࣑ࢵࢡࢫ௨እࡢྛᑓ⏝ࣇ࣮ࣞࣂ࣮ࢆ ῧຍࡍࡿࡇࡼࡾ, ᭷ពᢚไࡉࢀࡓ (Fig. 2). Ⲕ࣑ࢵࢡࢫࡣ, ࡑࢀ⮬యⱞࡀ࠶ࡿࡓࡵ࣑ࣀ ࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢⱞࢆ㢧ⴭᢚไࡋ࡞࠸ࡇࡀ⪃࠼ࡽࢀࡓ. ࡲࡓ, ᑓ⏝ࣇ࣮ࣞࣂ࣮ῧຍࡢ᭷ ↓ࢃࡽࡎ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢⱞᙉᗘࡣ, ᖖ ୗẚ㍑ࡋ࡚ప ୗ࡛ࡣ᭷ពప ࠸್ࢆ♧ࡋࡓ. ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮ᭹⏝ࡣᠱ⃮ᾮࢆప ࡍࡿⱞࡀᑡ࡞ࡃ᭹⏝ࡋࡸ ࡍ࠸ࡇࡀ♧၀ࡉࢀࡓ. ࡉࡽ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮᑓ⏝ࣇ࣮ࣞࣂ࣮ (3 g/100 mL) ࡢ⏑ᙉᗘ, 㓟ᙉᗘࢆࣄࢺᐁ ⬟ヨ㦂ࡼࡾホ౯ࡋࡓ (Table 3). ࢵࣉ࣑ࣝࢵࢡࢫ, ࣇ࣮ࣝࢶ࣑ࢵࢡࢫ, ࣉ࣒࣑ࣛࢵࢡࢫ, ࣃ ࢼࢵࣉ࣑ࣝࢵࢡࢫࡣ, ᙉ࠸㓟ࢆ࿊ࡍࡿࡇࡀ᫂ࡽ࡞ࡗࡓ. ࡇࢀࡽࡢᑓ⏝ࣇ࣮ࣞࣂ࣮ࢆῧຍࡋࡓ ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢⱞࡣ, ప ୗ࡛ࡣᖖ ୗ࡛ࡢホ౯ẚ㍑ࡋ࡚᭷ពపࡗࡓ. ௨ୖࡼࡾ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮ㓟ࢆ࿊ࡍࡿࣇ࣮ࣞࣂ࣮ࢆῧຍࡋ࡚ప ୗ࡛᭹⏝ࡍࡿࡇ ࡀ᭱ࡶⱞᢚไ᭷ຠ࡛࠶ࡿࡇࡀ♧၀ࡉࢀࡓ. Table 3 Sweetness and sourness intensity of flavored powder measured by gustatory sensation test n=6, mean ± S.D. Fig. 2 The bitterness intensity of Aminoleban® EN with or without flavored powder * p<0.05, ** p<0.01, *** p<0.001 vs Aminoleban® EN (Sheffe’s test). †p<0.05, ††p<0.01 vs 25-30ºC (Mann-Whitney U test). n=10, mean ± S.D. 7 2. BCAA ΰྜỈ⁐ᾮࡢⱞཬࡰࡍ⏑ࡲࡓࡣ㓟 ᗘࡢᙳ㡪 ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢⱞࡢཎᅉࡉࢀࡿ BCAA ΰྜỈ⁐ᾮ (τ 0.5㸫τ 3.5) ࡢⱞࡣ, ⏑ࡢᶆ ‽≀㉁࡛࠶ࡿࢩࣙ⢾ࡲࡓࡣ㓟ࡢᶆ‽≀㉁࡛࠶ࡿ㓇▼㓟ࡢῧຍ⃰ᗘ౫Ꮡⓗᢚไࡉࢀࡓ (Fig. 3). ≀㉁ࡣ, ⯉ୖ⓶ࡢⷣᏑᅾࡍࡿぬཷᐜయཷᐜࡉࢀࡿ. 1 ಶࡢⷣࡣ⣙ 50㹼100 ಶࡢ⣽⬊ࡽᡂ ࡾ, ྂࡃࡽ㟁Ꮚ㢧ᚤ㙾ほᐹࡼࡿ⣽⬊ᙧែ⣽⬊ෆᚤ⣽ᵓ㐀ᇶ࡙࠸࡚, ⣳㗽ᙧࢆࡋࡓϨᆺ, ϩᆺ, Ϫᆺ⣽⬊, ᇶᗏ㒊Ꮡᅾࡍࡿϫᆺ⣽⬊ศ㢮ࡉࢀ࡚࠾ࡾ, ⱞ≀㉁⏑≀㉁ࡣϩᆺ⣽⬊ࡢ G ࢱࣥࣃ ࢡ㉁ඹᙺᆺཷᐜయࢆࡍࡿ୍᪉, 㓟≀㉁ࡣϪᆺ⣽⬊ࢆࡍࡿࡇࡀሗ࿌ࡉࢀ࡚࠸ࡿ. ࡇࡢࡓࡵ, 㓟 ่⃭ࡣ⏑่⃭ࡣ␗࡞ࡿ⤒㊰࡛ⱞᢚไຠᯝࢆ♧ࡍࡇࡀ⪃࠼ࡽࢀࡓ. Fig. 3 The influence of sweetness or sourness on the bitterness of BCAA solution τ 3 of sucrose significantly decreased the bitterness intensity of BCAA τ 1.5-τ 3.5 (A). τ 4 of tartaric acid significantly decreased the bitterness intensity of BCAA τ2, τ 2.5 (B). *p<0.05, **p<0.01 vs BCAA (Mann whitney U test) n=10, mean ± S.D. 8 ḟ, BCAA ΰྜỈ⁐ᾮࡢⱞཬࡰࡍ ᗘࡢᙳ㡪ࡘ࠸࡚ホ౯ࡋࡓࡇࢁ, ⱞᙉᗘ τ 2, τ 2.5, τ 3 ┦ᙜࡍࡿ BCAA ΰྜỈ⁐ᾮࡢⱞᙉᗘࡣ, ᖖ ẚ㍑ࡋ࡚ప ୗ࡛᭷ពᢚไࡉࢀࡓ (Fig. 4 (A)). ࡉࡽ , Fig. 3 ♧ࡋࡓ⤖ᯝࡽᚓࡓ BCAA ΰྜỈ⁐ᾮࡢⱞࢆ᭷ពᢚไࡍࡿ⃰ᗘ࡛࠶ࡿ 6.4%ࡢࢩࣙ⢾ (ⱞᙉᗘ τ 3) ࡲࡓࡣ 0.07%ࡢ㓇▼㓟 (㓟ᙉᗘ τ 4) ࢆྵࡴ BCAA ΰྜỈ⁐ᾮࡢⱞᙉᗘࢆ, ࡑࢀࡒࢀ ᖖ ୗప ୗ࡛ホ౯ࡋࡓ. ప ୗ࡛ࡢ BCAA ΰྜỈ⁐ᾮࡢⱞᙉᗘ, ࢩࣙ⢾ࡲࡓࡣ㓇▼㓟ࢆྵࡴᖖ ୗ࡛ࡢ BCAA ΰྜỈ⁐ᾮࡢⱞᙉᗘࡣࡰྠ⛬ᗘ࡛࠶ࡗࡓ. ࡇࡢᐇࡼࡾ, ప ࡍࡿࡇࡣ, ⏑ ≀㉁ࡸ㓟≀㉁ࢆῧຍࡍࡿࡇྠ⛬ᗘࡢⱞᢚไຠᯝࡀᚓࡽࢀࡿࡇࡀ♧၀ࡉࢀࡓ. ࡲࡓ, ࢩࣙ⢾ 6.4%ࢆྵࡴ BCAA ΰྜỈ⁐ᾮࡢప ୗ࡛ࡢⱞᙉᗘࡣ, ࢩࣙ⢾ 6.4%ࢆྵࡴ BCAA ΰྜỈ⁐ᾮࡢᖖ ୗ ࡛ࡢⱞᙉᗘࡲࡓࡣࢩࣙ⢾ࢆྵࡲ࡞࠸ BCAA ΰྜỈ⁐ᾮࡢప ୗ࡛ࡢⱞᙉᗘྠ⛬ᗘ࡛࠶ࡗࡓ (Fig. 4 (B)). ࡍ࡞ࢃࡕ, ⏑ప ࡼࡿⱞᢚไࡢ᫂☜࡞┦ຍຠᯝࡣ☜ㄆ࡛ࡁ࡞ࡗࡓ. ୍᪉, 㓇▼㓟 0.07%ࢆྵࡴ BCAA ΰྜỈ⁐ᾮࡢప ୗ࡛ࡢⱞᙉᗘࡣ, 㓇▼㓟 0.07%ࢆྵࡴ BCAA ΰྜỈ⁐ᾮࡢᖖ ୗ࡛ࡢⱞᙉᗘࡲࡓࡣ㓇▼㓟 0.07%ࢆྵࡲ࡞࠸ BCAA ΰྜỈ⁐ᾮࡢప ୗ࡛ࡢⱞᙉᗘࡼࡾ᭷ពప್ ࢆ♧ࡋࡓ (Fig. 4 (C)). ࡇࡢᐇࡼࡾ, 㓟ప ࢆ⤌ࡳྜࢃࡏࡿࡇࡼࡾ, BCAA ΰྜỈ⁐ᾮࡢⱞ ࡣ┦ຍⓗᢚไࡉࢀࡿࡇࡀ᫂ࡽ࡞ࡗࡓ. Fig. 4 Bitterness intensity of BCAA influenced by sucrose, tartaric acid and temperature Bitterness intensity of BCAA solution at 25-30ºC and 0-5ºC, *p<0.05, **p<0.01 vs BCAA 25-30ºC (Mann-Whitney U-test) (A). The influence of sweetness of sucrose and temperature (B) or sourness of tartaric acid and temperature (C) on the bitterness intensity of BCAA solution, *p<0.05, **p<0.01, ***p<0.001 vs BCAA 25-30ºC (Sheffe’s test), †p<0.05 vs BCAA+ tartaric acid τ 4 (25-30ºC), #p<0.05 vs BCAA 0-5ºC (Mann Whitney U-test). n=8, mean ± S.D. 9 ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢᑓ⏝ࣇ࣮ࣞࣂ࣮ (ࢥ࣮ࣄ࣮࣑ࢵࢡࢫ, Ⲕ࣑ࢵࢡࢫ, ࢵࣉ࣑ࣝࢵ ࢡࢫ, ࣇ࣮ࣝࢶ࣑ࢵࢡࢫ, ࣉ࣒࣑ࣛࢵࢡࢫ, ࣃࢼࢵࣉ࣑ࣝࢵࢡࢫ) ྛ 3 g/100 mL ࡢ⏑ᙉᗘࡣ, ప ୗ࡛ࡣ, ᖖ ୗ࡛ࡢ⏑ᙉᗘẚ㍑ࡋ࡚పୗࡋ, ≉ࢥ࣮ࣄ࣮, ࢵࣉࣝ, ࣉ࣒ࣛࡢࣇ࣮ࣞࣂ࣮ࡢ ⏑ᙉᗘࡢపୗࡣ㢧ⴭ࡛࠶ࡗࡓ (Fig. 5 (A)). ୍᪉, ྛᑓ⏝ࣇ࣮ࣞࣂ࣮ (3 g/100 mL) ࡢ㓟ᙉᗘࡣ, ప ୗ࡛ࡶᖖ ୗ࡛ࡢ㓟ᙉᗘྠ⛬ᗘ࡛࠶ࡗࡓ (Fig. 5 (B)). ࡍ࡞ࢃࡕᑓ⏝ࣇ࣮ࣞࣂ࣮ࡢ⏑ᙉᗘࡣ, ప ୗ࡛ࡣ, ᖖ ୗ࡛ࡢ⏑ᙉᗘࡼࡾῶᙅࡍࡿࡀ, 㓟ᙉᗘࡣప ୗ࡛ࡶ, ᖖ ୗྠ➼ࡢ㓟ᙉᗘࢆಖࡘ ࡇࡀ᫂ࡽ࡞ࡗࡓ. ᗘࡣཷᐜయάᛶᙳ㡪ࢆཬࡰࡍࡇࡀ⪃࠼ࡽࢀࡿࡀ, ᗘឤཷᛶ TRP (Transient Receptor Potential) ࢳࣕࢿࣝࡢ࠺ࡕ, 15㸫35Υࡢ ᗘ࡛άᛶࡀୖ᪼ࡍࡿ TRPM5 ࡣ, ⣽⬊Ⓨ⌧ࡋ, ⏑, ⱞ, ᪨ࡢ⣽⬊ෆࢩࢢࢼࣝఏ㐩㛵ࡍࡿࡇࡀ▱ࡽࢀ࡚࠸ࡿ 19-24) . ᮏ᳨ウ࡛, ᑓ⏝ࣇ࣮ࣞࣂ࣮ࡢ⏑ᙉᗘ ࡀప ୗ࡛ࡣᖖ ୗ࡛ࡢ⏑ᙉᗘࡼࡾ㧗್ࢆ♧ࡋࡓᐇࡣ, ᖖ ୗ࡛ࡢぬཷᐜࢩࢢࢼࣝࡼࡿ TRPM5 άᛶࡼࡿࡇࡀ᥎ ࡉࢀࡓ. Fig. 5 The influence of the temperature on sweetness intensity or sourness intensity of flavored powder Sweetness intensity of flavored powder at 0-5ºC and 25-30ºC, (A). Sourness intensity of flavored powder at 0-5ºC and 25-30ºC (B). *p<0.05 vs 25-30ºC (Mann Whitney U-test). n=6, mean ± S.D. 10 BCAA ΰྜỈ⁐ᾮࡢⱞᑐࡋ࡚, ⏑ప ࢆ⤌ࡳྜࢃࡏࡓሙྜࡣ, ⱞᢚไࡢ᭷ព࡞┦ຍຠᯝ ࡣㄆࡵࡽࢀ࡞ࡗࡓ. ୍᪉, 㓟ప ࢆ⤌ࡳྜࢃࡏࡓሙྜࡣ, ⱞᢚไࡢ┦ຍຠᯝࡀㄆࡵࡽࢀࡓ. ࡇࡢ୍ᅉࡋ࡚, ᖖ ୗ࡛ࡢ⏑ᙉᗘࡣప ୗ࡛పୗࡍࡿࡀ, ᖖ ୗ࡛ࡶ㓟ᙉᗘࡣప ୗ࡛ࡶపୗࡏ ࡎࡑࡢᙉᗘࢆಖࡘࡇࡀ⪃࠼ࡽࢀࡓ. 㓟ཷᐜయࡋ࡚ࡢ PKD2L1 (Polycystic kidney disease 2-like 1) ࡢᶵ⬟ࡀ㏆ᖺ᫂ࡽ࡞ࡗ࡚࠸ࡿࡀ 25), ᗘ PKD2L1 ࡢ㛵ಀࡘ࠸࡚ࡢヲ⣽࡞ሗ࿌ࡣ⌧ᅾ࡞࠸. ࡋࡋ, ⏑ᙉᗘ␗࡞ࡾ㓟ᙉᗘࡀ ᗘࡢ ᙳ㡪ࢆཷࡅ࡞ࡗࡓᮏ᳨ウ⤖ᯝࡢせᅉࡋ࡚ TRPM5 ࡢ㛵ࡀ⪃࠼ࡽࢀ, Ϫᆺ⣽⬊Ⓨ⌧ࡍࡿ PKD2L1 ࢆࡍࡿ㓟ࡢࢩࢢࢼࣝࡣ TRPM5 ࢆࡉࡎ, ᗘࡢᙳ㡪ࢆཷࡅ࡞ࡗࡓࡇࡀ⪃࠼ࡽࢀࡓ. ௨ୖ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ᭹⏝ࡣ, 㓟ࢆ࿊ࡍࡿࣇ࣮ࣞࣂ࣮ࢆῧຍࡋ࡚, ᠱ⃮ᾮࢆప ࡋ ࡚᭹⏝ࡍࡿ, ⱞࢆຠᯝⓗ㍍ῶ࡛ࡁࡿࡇࡀ♧၀ࡉࢀࡓ. ᮏ᳨ウ࡛ࡣ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ ᾮࡢప ୗ࡛ࡢⱞᢚไຠᯝࢆ᫂ࡽࡋࡓࡀ, ప ࡋࡍࡂࡿయㄪࢆᔂࡍࡇࡶ⪃࠼ࡽࢀࡿ. ࣄࢺ ࡀዲࡲࡋࡃ㔞㣧ࡵࡿ⁐ᾮࡢ ᗘࡣ 8㹼10Υࡉࢀ࡚࠸ࡿࡇࡽ 26) , ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ ᾮࡣ, ᖖ ࡛᭹⏝ࡍࡿࡼࡾࡶ, 8㹼10Υࡋ࡚᭹⏝ࡍࡿ᪉ࡀᝈ⪅ࡗ࡚㣧ࡳࡸࡍ࠸⪃࠼ࡽࢀࡿ. ⸆ ᖌࡣ, Ỉࡲࡓࡣ ᠱ⃮ࡋ࡚᭹⏝ࡍࡿࡇࡉࢀ࡚࠸ࡿᮏࢆ, ᐇ㝿ᝈ⪅ࡀࡢࡼ࠺᭹⏝ࡋ࡚࠸ ࡿࢆᢕᥱࡋ, ࡛ᠱ⃮ࡋ࡚࠸ࡿሙྜࡣ෭ࡲࡋ࡚ࡽ᭹⏝ࡍࡿ࠺ࡀⱞࢆ࿊ࡋࡃ࠸ࡇࢆᝈ⪅ ఏ࠼ࡿࡇ࡛, ⱞࡼࡿᝈ⪅ࡢ㈇ᢸࢆῶࡽࡍࡇࡀ࡛ࡁࡿ⪃࠼ࡽࢀࡿ. ࡲࡓ, Cola ࡽࡣ㓟෭่ ⃭ࡼࡿᄟୗㄏⓎಁ㐍ຠᯝࢆሗ࿌ࡋ࡚࠾ࡾ ®EN 27) , ᮏ᳨ウࡼࡿప ୗ࡛ࡢ㓟ࡢຠᯝࡣ, ࣑ࣀࣞࣂࣥ 㓄ྜᩓᠱ⃮ᾮࡢⱞᢚไࡔࡅ࡛࡞ࡃ, ᄟୗಁ㐍ࡶᐤࡍࡿࡇࡀᮇᚅࡉࢀࡿ. 11 ➨ 2 ⠇ ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ホ౯ ➨ 1 㡯 ┠ⓗ ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡣ, ⱞࡔࡅ࡛࡞ࡃ⊂≉ࡢ࠾࠸ࢆ࿊ࡍࡿࡇࡀ▱ࡽࢀ࡚࠸ࡿ. ᮏ⠇ ࡛ࡣ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ホ౯, ࡇࡢ࠾࠸ཬࡰࡍᑓ⏝ࣇ࣮ࣞࣂ࣮ (ࢥ࣮ࣄ࣮ ࣑ࢵࢡࢫ, Ⲕ࣑ࢵࢡࢫ, ࢵࣉ࣑ࣝࢵࢡࢫ, ࣇ࣮ࣝࢶ࣑ࢵࢡࢫ, ࣉ࣒࣑ࣛࢵࢡࢫ, ࣃࢼࢵ ࣉ࣑ࣝࢵࢡࢫ) ࡢᙳ㡪ࡘ࠸࡚ࣄࢺᐁ⬟ヨ㦂ࡼࡾホ౯ࡋࡓ. ࡉࡽ, ࡇࢀࡲ࡛་⸆ရࡢ㐺⏝ࡀ ࢇ࡞ࡗࡓႥぬࢭࣥࢧ 28-30) ࢆ⏝࠸, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸, ࡇࢀཬࡰࡍྛ ᑓ⏝ࣇ࣮ࣞࣂ࣮ࡢᙳ㡪ࢆᐈほⓗホ౯ࡋࡓ 31). ➨ 2 㡯 ᐇ㦂᪉ἲ 1. ヨ⸆ ᮏ❶➨ 1 ⠇ྠᵝࡢヨ⸆ࢆ⏝࠸ࡓ. 2. ࣄࢺᐁ⬟ヨ㦂ࡼࡿ࠾࠸ホ౯ ࣄࢺᐁ⬟ヨ㦂ࡼࡿ࠾࠸ホ౯ 32)ࡣ, ᗣ࡞ 12 ྡࡢዪᛶ (22㹼30 ṓ) ࢆࣃࢿࣝࡋࡓ. ࣄࢺᐁ⬟ヨ㦂 ࡣ, ṊᗜᕝዪᏊᏛ⌮ጤဨࡢᢎㄆࢆᚓࡓᚋ⾜ࡗࡓ (ᢎㄆ␒ྕ 08-23). 2-1. ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ࡢ㆑ูホ౯ ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ 0.20, 0.39, 0.78, 1.56, 3.13, 6.25, 12.5, 25.0 g ࢆࡑࢀࡒࢀ 100 mL ࡢ⢭〇Ỉᠱ ⃮ࡋࡓᾮࢆヨ㦂ヨᩱࡋࡓ. ࣃࢿࣝࡣ, ྛヨ㦂ヨᩱࡢ࠾࠸, ⢭〇Ỉࡢ࠾࠸ࡀ㆑ูྍ⬟ྰࢆホ ౯ࡋࡓ. 㜈್ࢆ᥎ᐃࡍࡿ᪉ἲࡢ୍ࡘ࡛࠶ࡿᜏᖖἲ࡛ࡣ, ᶓ㍈ᐇ㦂ኚᩘ, ⦪㍈ṇ⟅⋡ࢆྲྀࡾ, ࠶ࡿṇ ⟅⋡ (50%ࡀ㢖⏝ࡉࢀࡿ) ᑐᛂࡍࡿᐇ㦂ኚᩘ್ࢆ㜈್ᐃ⩏ࡍࡿ 33) . ᮏ᳨ウ࡛ࡣ, ᶓ㍈ᐇ㦂ኚᩘ ࡋ࡚࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮ⃰ᗘࡢᑐᩘ, ⦪㍈ヨ㦂ヨᩱࡢ࠾࠸⢭〇Ỉࡢ࠾࠸ࢆ㆑ู࡛ࡁ ࡓࣃࢿࣝᩘࡢྜ (%) ࢆྲྀࡾ, ࣃࢿࣝᩘࡢྜ 50%ᑐᛂࡍࡿᐇ㦂ኚᩘ್ࢆ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ ࡢ࠾࠸㜈್ࡋࡓ. 12 2-2. ᑓ⏝ࣇ࣮ࣞࣂ࣮ࢆῧຍࡋࡓ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ホ౯ ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ (25 g/100 mL) ༢⊂ࡲࡓࡣ, ྛᑓ⏝ࣇ࣮ࣞࣂ࣮ (ࢥ࣮ࣄ࣮࣑ࢵࢡࢫ, Ⲕ ࣑ࢵࢡࢫ, ࢵࣉ࣑ࣝࢵࢡࢫ, ࣇ࣮ࣝࢶ࣑ࢵࢡࢫ, ࣉ࣒࣑ࣛࢵࢡࢫ, ࣃࢼࢵࣉ࣑ࣝࢵࢡࢫ) (3 g/100 mL) ࢆῧຍࡋࡓ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ (25 g/100 mL) ࡢ (1) ࠾࠸ᙉᗘ, (2) ࠾࠸ࡢႴዲ ᛶ, (3) ࠾࠸ࡼࡿ⏑ࡲࡓࡣ㓟㉳ᛶࢆホ౯ࡋࡓ. (1) ࠾࠸ᙉᗘ ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ 0.78, 1.56, 3.13, 6.25, 12.5, 25.0 g ࢆࡑࢀࡒࢀ 100 mL ࡢ⢭〇Ỉᠱ⃮ࡋࡓᾮࡢ ࠾࠸ᙉᗘ 1 ࡽ 6 ࡋ, ࡇࢀࡽヨᩱࢆ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢ࠾࠸ࡢᇶ‽ᾮࡋࡓ. ࣃࢿࣝ (12 ྡ) ࡣ, ྛᇶ‽ᾮࡢ࠾࠸ᙉᗘࢆグ᠈ࡋࡓᚋ, ヨ㦂ヨᩱࡢ࠾࠸ᙉᗘࢆホ౯ࡋࡓ. (2) ࠾࠸ࡢႴዲᛶ ࣃࢿࣝ (12 ྡ) ࡣ, ヨ㦂ヨᩱࡢ࠾࠸ࡢႴዲᛶࢆ 6 ẁ㝵 (0; ཷࡅࡅ࡞࠸, 1; ዲࡲࡋࡃ࡞࠸, 2; ࡸࡸ ዲࡲࡋࡃ࡞࠸, 3; ࡕࡽ࡛ࡶ࡞࠸, 4; ዲࡲࡋ࠸, 5; ࡞ࡾዲࡲࡋ࠸) ࡛ホ౯ࡋࡓ. (3) ࠾࠸ࡼࡿ⏑ࡲࡓࡣ㓟㉳ᛶ ࣃࢿࣝ (12 ྡ) ࡣ, ヨ㦂ヨᩱࡢ࠾࠸ࡼࡾ⏑ࢆ㉳ࡍࡿ⛬ᗘࢆ 4 ẁ㝵 (0; ࡃ࡞࠸, 1; ᑡࡋ࠶ࡿ, 2; ࠶ࡿ, 3; ࡞ࡾ࠶ࡿ) ࡛ホ౯ࡋࡓ. 3. Ⴅぬࢭࣥࢧࢆ⏝࠸ࡓ࠾࠸ホ౯ ࠾࠸㆑ูࢭࣥࢧ࣮ࢩࢫࢸ࣒ FOX 28-30) (ࣝࣇ࣭ࣔࢫ࣭ࢪࣕࣃࣥᰴᘧ♫) (௨ୗ, ࠾࠸ࢭࣥࢧ) ࢆ ⏝࠸ࡓ (Fig. 6). ࠾࠸ࢭࣥࢧࡣ, Ⓨᛶྜ≀ᛂࡍࡿࡇ࡛㟁Ẽᢠࡀኚࡍࡿ 18 ಶࡢ㔠ᒓ㓟 ≀༙ᑟయࢭࣥࢧ (LY/LG, LY/G, LY/AA, LY/GH, LY/gCTL, LY/gCT, T30/1, P10/1, P10/2, P40/1, T70/2, PA/2, P30/1, P40/2, P30/2, T40/2, T40/1, TA2) ࢆᦚ㍕ࡋ, ࡇࢀࡽࡢࢭࣥࢧᛂ⟅ࡢ⤌ࡳྜࢃࡏࣃࢱ࣮ࣥࡼࡗ࡚, ࠾࠸ࢆ㆑ูࡍࡿ. ᑓ⏝ࢭࣉࢱ࣒ࡁࣂࣝヨᩱ 1 mL ࢆධࢀᐦᑒᚋ, ࣮ࣥ࢟ࣗ࣋ࢩࣙࣥ㛫 15 ศ, ᗘ 35Υ࡛ ᐃࡋࡓ. ྛ ᐃヨᩱࡢ 18 ᮏࡢࢭࣥࢧᛂ⟅್ࢆᡂศศᯒࡋ, ᚓࡽࢀࡓ⤖ᯝࡼࡾࣉࣟࢵ ࢺࡉࢀࡓྛヨᩱࡢᗙᶆࡢ㔜ᚰ㛫ࡢ㊥㞳 (࣮ࣘࢡࣜࢵࢻ㊥㞳) ࢆ⟬ฟࡋࡓ. ࣮ࣘࢡࣜࢵࢻ㊥㞳ࡀᑠࡉ࠸ , ࡑࢀࡽࡢ࠾࠸ࡀ㢮ఝࡋ࡚࠸ࡿุ᩿ࡋࡓ. 13 Fig. 6 FOX odor analyzer (Alpha M. O. S.) 3-1. ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ࡢ㆑ูホ౯ 2-1. ࡛ㄪ〇ࡋࡓヨᩱྛ 1 mL ࢆヨ㦂ヨᩱࡋࡓ. 3-2. ᑓ⏝ࣇ࣮ࣞࣂ࣮ࢆῧຍࡋࡓ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ホ౯ 2-2. ࡛ㄪ〇ࡋࡓヨᩱྛ 1 mL ࢆヨ㦂ヨᩱࡋࡓ. 4. ⤫ィฎ⌮ Fig. 8, 9 ♧ࡋࡓ⤖ᯝࡘ࠸࡚ࡣ, ࢚ࢡࢭࣝ⤫ィࢆ⏝࠸࡚ Bonferroni/Dunnet test ࡼࡾᑐ↷⩌ࡢከ㔜 ẚ㍑᳨ᐃࢆ⾜ࡗࡓ. 14 ➨ 3 㡯 ⤖ᯝ⪃ᐹ 3-1. ࣄࢺᐁ⬟ヨ㦂ࡼࡿ࠾࠸ホ౯ ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢ࠾࠸⢭〇Ỉࡢ࠾࠸ࢆ㆑ูࡋࡓࣃࢿࣝࡢྜࡣ⃰ᗘ౫Ꮡⓗቑຍࡋ, 0.78 g/100 mL ௨ୖࡢ⃰ᗘࡢ࣑ࣀࣞࣂࣥ®EN ᠱ⃮ᾮࡣ, 80%௨ୖࡢࣃࢿࣝࡑࡢ࠾࠸ࡀ㆑ูࡉࢀࡓ (Fig. 7 (A)). ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ⃰ᗘࡢᑐᩘ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢ࠾࠸ࢆ㆑ู ࡋࡓࣃࢿࣝᩘࡢྜࡣ┦㛵ࡋ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢ࠾࠸㜈್ࡣ 0.43 g/100 mL ࡛࠶ࡗࡓ (Fig. 7 (B)). ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮ 0.78, 1.56, 3.13, 6.25, 12.5, 25.0 g/100 mL ࡘ࠸࡚, 㞄᥋ࡍࡿ⃰ᗘࡢ ␗࡞ࡿᠱ⃮ᾮࡢ࠾࠸ࡢ㆑ู⋡ࡣ࠸ࡎࢀࡶ 50%ࢆ㉸࠼, ྛᠱ⃮ᾮࡢ࠾࠸ᙉᗘࡣ⃰ᗘ౫Ꮡⓗᙉࡃ࡞ࡿ ࡇࢆ☜ㄆࡋࡓ. ࡑࡇ࡛ࡇࢀࡽࡢ࠾࠸ᙉᗘࢆࡑࢀࡒࢀ 1, 2, 3, 4, 5, 6 ࡋ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢ ࠾࠸ᙉᗘࡢᇶ‽ࡋࡓ. Fig. 7 Percentage of subjects who could recognize the odor of Aminoleban® EN at different concentrations (A) and relation between percentage of subjects who could recognize the odor of Aminoleban® EN and its concentration (0.20-1.56 g/100 mL) (B) 1: 0.20 g, 2: 0.39 g, 3: 0.78 g, 4: 1.56 g, 5: 3.13 g, 6: 6.25 g, 7: 12.5 g, 8: 25.0 g in 100 mL water (n=12). ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ (25 g/100 mL) ༢⊂ࡲࡓࡣᑓ⏝ࣇ࣮ࣞࣂ࣮3 g ࢆῧຍࡋࡓ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ (25 g/100 mL) ࡢ࠾࠸ᙉᗘࢆࣄࢺᐁ⬟ヨ㦂ࡼࡾホ౯ࡋࡓࡇࢁ, ྛᑓ⏝ࣇ࣮ࣞࣂ࣮ࡣ, ࣑ ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ࢆ᭷ពᢚไࡍࡿࡇࡀ᫂ࡽ࡞ࡗࡓ. ≉ࣃࢼࢵࣉࣝࡢࣇࣞ ࣮ࣂ࣮ࡣ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ࢆࡰ࣐ࢫ࢟ࣥࢢࡍࡿࡇࡀ᫂ࡽ࡞ࡗࡓ (Fig. 8). 15 Fig. 8 The odor intensities of Aminoleban® EN with flavoured powders A: Aminoleban® EN without flavored powder (25 g/100 mL), B-G: Aminoleban® EN with flavoured powder (B: coffee, C: green tea, D: apple, E: fruit, F: plum, G: pineapple). *p<0.05 vs A (Bonferroni/Dunnet test). n=12, mean ± S.D. ࡉࡽ, SD ἲ 34)ࢆཧ⪃, ྠヨᩱࡢ࠾࠸ࡢႴዲᛶࢆࣄࢺᐁ⬟ヨ㦂ࡼࡾホ౯ࡋࡓ. ᑓ⏝ࣇ࣮ࣞࣂ࣮ ࢆῧຍࡋ࡞࠸࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ࡣႴዲᛶࢫࢥ 1 ௨ୗࢆ♧ࡋࡓ (Fig. 9 (A)). ࣑ ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ࡣࣄࢺᛌឤࢆ࠼ࡿࡇࡀ♧၀ࡉࢀࡓ. ࡇࡢ〇ࡢ࠾࠸ࡢႴ ዲᛶࡣ, ྛᑓ⏝ࣇ࣮ࣞࣂ࣮ࢆῧຍࡍࡿࡇࡼࡾቑຍࡋ, ≉ࣃࢼࢵࣉࣝࡢࣇ࣮ࣞࣂ࣮ࡀ, ࣑ࣀࣞ ࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢᛌ࡞࠾࠸ᨵၿຠᯝⓗ࡛࠶ࡗࡓ. ྛヨ㦂ヨᩱ୰ࡢ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ ࡢ࠾࠸ᙉᗘ, ࠾࠸ࡢႴዲᛶࡣ㈇ࡢ┦㛵ࢆ♧ࡋࡓ (Fig. 9 (B)). ࡇࢀࡣ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢ ࠾࠸ࢆᢚไࡍࡿ࠾࠸ࡢႴዲᛶࡀୖ᪼ࡍࡿࡇࢆ♧ࡋ, ᛌឤࢆ࠼ࡿ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ ࡢ࠾࠸࣐ࢫ࢟ࣥࢢࡢ㔜せᛶࡀ♧၀ࡉࢀࡓ. ࡲࡓ, ྠヨ㦂ヨᩱࡢ࠾࠸ࡼࡿ⏑ࡲࡓࡣ㓟㉳ᛶࢆ ホ౯ࡋࡓ. ᯝᐇ⣔ࡢࣇ࣮ࣞࣂ࣮࡛࠶ࡿࢵࣉࣝ, ࣇ࣮ࣝࢶ, ࣉ࣒ࣛ, ࣃࢼࢵࣉࣝࡢࣇ࣮ࣞࣂ࣮ࢆῧຍ ࡋࡓヨᩱࡣ, ⏑ຍ࠼࡚㓟ࢆ㉳ࡉࡏࡿࡇࡀ᫂ࡽ࡞ࡗࡓ (Fig. 10). ⢾Ỉ⁐ᾮࡢ⏑ࡀࢫࢺ࣮ࣟ࣋ࣜࣇ࣮ࣞࣂ࣮ࣆ࣮ࢳࣇ࣮ࣞࣂ࣮ῧຍࡼࡾቑᙉࡉࢀࡿࡇ, ࢡ࢚ࣥ㓟 Ỉ⁐ᾮࡢ㓟ࡀࣞࣔࣥࣇ࣮ࣞࣂ࣮ࡼࡾቑᙉࡉࢀࡿࡇࡀሗ࿌ࡉࢀ࡚࠾ࡾ 32), ࢆ㉳ࡉࡏࡿ࠾࠸ࡣ, ࡑࡢࢆቑᙉࡉࡏࡿࡇࡀ⪃࠼ࡽࢀࡿ. ᮏ❶➨ 1 ⠇࡛ࡣ, 㓟ࢆ࿊ࡍࡿᑓ⏝ࣇ࣮ࣞࣂ࣮ࡀ࣑ࣀࣞࣂࣥ ®EN 㓄ྜᩓࡢⱞࢆࡼࡃ࣐ࢫ࢟ࣥࢢࡍࡿࡇࡀ᫂ࡽ࡞ࡗࡓࡀ, 㓟ࢆ㉳ࡉࡏࡿᑓ⏝ࣇ࣮ࣞࣂ࣮ࡢ ࠾࠸ࡣ, ࣇ࣮ࣞࣂ࣮ྵࡲࢀࡿࢡ࢚ࣥ㓟ࡼࡿ㓟ࢆቑᙉࡍࡿࡇࡀ⪃࠼ࡽࢀࡿ. ࡍ࡞ࢃࡕᑓ⏝ࣇࣞ 16 ࣮ࣂ࣮ࡢ࠾࠸ࡣ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢ࠾࠸ᨵၿࡔࡅ࡛࡞ࡃ, 㓟ቑᙉࡼࡿⱞᢚไࡶᐤ ࡍࡿࡇࡀᮇᚅ࡛ࡁࡿ. Fig. 9 Preference odour levels of Aminoleban® EN with flavoured powders (A) and the correlation between odour intensity and preference odour levels of Aminoleban® EN (B) A; Aminoleban® EN without flavoured powder (25 g/100 mL), B-G; Aminoleban® EN with flavoured powder (B; coffee, C; green tea, D; apple, E; fruit, F; plum, G; pineapple). *p<0.05 vs A (Bonferroni/Dunnet test). n=12, mean ± S.D. Fig. 10 The odour image of taste (sweetness or sourness) from Aminoleban® EN containing flavoured powders A, Aminoleban® EN without flavoured powder (25 g/100 mL); B-G, Aminoleban® EN with flavoured powder (B coffee, C green tea, D apple, E fruit, F plum, G pineapple). n=12, mean ± S.D. 17 3-2. Ⴅぬࢭࣥࢧ (࠾࠸ࢭࣥࢧ) ࢆ⏝࠸ࡓ࠾࠸ホ౯ ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮ (0.20, 0.39, 0.78, 1.56, 3.13, 6.25, 12.5, 25.0 g/100 mL) ࡢỈࡢ㆑ูᣦ ᩘࢆ Table 4 ♧ࡋࡓ. ㆑ูᣦᩘࡀ 90 ௨ୖࢆ♧ࡍሙྜ, ࡑࢀࡽࡢ࠾࠸ࡀⰋዲ㆑ู࡛ࡁࡓࡇࢆ♧ࡍ. 0.39 g/100 mL ௨ୖࡢ⃰ᗘࡢ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢỈࡢ㆑ูᣦᩘࡣ࠸ࡎࢀࡶ 90 ௨ୖ࡛࠶ࡗ ࡓ. ࡇࡢᐇ, ࣄࢺᐁ⬟ヨ㦂⤖ᯝࡼࡾᚓࡽࢀࡓ࠾࠸㜈್ࡀ 0.43 g/100 mL ࡛࠶ࡗࡓࡇࡼࡾ, ᮏ᳨ウ ࡛⏝࠸ࡓ࠾࠸ࢭࣥࢧࡣ, ࣄࢺࡢႥぬྠ⛬ᗘࡢ࠾࠸ឤᗘࢆ᭷ࡍࡿࡇࡀ♧၀ࡉࢀࡓ. ࣑ࣀࣞࣂࣥ ®EN 㓄ྜᩓᠱ⃮ᾮ (0.00, 0.20, 0.39, 0.78, 1.56, 3.13, 6.25, 12.5, 25.0 g/100 mL) ࢆ࠾࠸ࢭࣥࢧ࡛ ᐃࡋ࡚ ᚓࡽࢀࡓྛࢭࣥࢧᛂ⟅್ࡢᡂศศᯒ⤖ᯝ (Fig. 11) ࡼࡾ, ࢧࣥࣉࣝ 1 (0.20 g/100 mL) ࡽ 4 (1.56 g/100 mL) ࡣ, ✵ẼࢧࣥࣉࣝỈࢧࣥࣉࣝࢆ⤖ࡪ┤⥺ୖ⨨ࡋࡓࡇࡽ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮ ୰ࡢỈࡢᙳ㡪ࡼࡿᛂ⟅࡛࠶ࡿࡇࡀ⪃࠼ࡽࢀࡓ. ࡍ࡞ࢃࡕ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢ࠾࠸Ỉࡢ ࠾࠸ࡢྜࡢ㐪࠸ࡼࡿ࠾࠸ࡢ㉁ ࡢ㐪࠸ࢆពࡍࡿࡇࡀ⪃࠼ࡽࢀࡓ. Table 4 Discrimination index between water and samples at different concentrations of Aminoleban®EN, as calculated by the electronic nose system ୍᪉, ࣄࢺᐁ⬟ヨ㦂࡛ࢧࣥࣉࣝ 4 (1.56 g/100 mL) ࡽ 8 (25.0 g/100 mL) ࡣ, ࡍ࡚ࡢࣃࢿࣝࡀ࣑ࣀࣞࣂࣥ ®EN 㓄ྜᩓࡢ࠾࠸ࢆឤࡌࡓࡇࡽ, ࢧ ࣥࣉࣝ 4 ࡽ 8 ࡢ᪉ྥࡣ, ࣑ࣀࣞࣂ ࣥ ®EN 㓄ྜᩓࡢ࠾࠸ᙉᗘࢆ♧ࡋ࡚ ࠸ࡿࡇࡀ⪃࠼ࡽࢀࡓ. ࡍ࡞ࢃࡕ, ᡂ ศ ศ ᯒ ⤖ ᯝ ࡢ ᶓ ㍈ PC1 ( ᐤ ⋡ 75.0%) ࡢྑ᪉ྥࡣ࣑ࣀࣞࣂࣥ ®EN 㓄ྜᩓࡢ࠾࠸ࡢ㉁ (ᛌ࡞࠾࠸) ࢆពࡋ, ⦪㍈ PC2 (ᐤ⋡ 24.3%) ࡢ ୗ᪉ྥࡣ࣑ࣀࣞࣂࣥ ®EN 㓄ྜᩓࡢ ࠾࠸ᙉᗘࢆពࡍࡿ⪃࠼ࡽࢀࡓ. Fig. 11 Evaluation of the odor of Aminoleban® EN at different concentrations using the electronic nose system 0.20 g, 0.39 g, 0.78 g, 1.56 g, 3.13 g, 6.25 g, 12.5 g, 25.0 g in 100 mL water. n=3. 18 ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮ (25 g/100 mL) ༢⊂ࡲࡓࡣྛᑓ⏝ࣇ࣮ࣞࣂ࣮ (3 g/100 mL) ࢆῧຍࡋ ࡓヨᩱࢆ࠾࠸ࢭࣥࢧࡼࡾ ᐃࡋ࡚ᚓࡽࢀࡓྛࢭࣥࢧᛂ⟅್ࡢᡂศศᯒ⤖ᯝ (Fig. 12 (A))ࡼࡾ, ࢥ ࣮ࣄ࣮, Ⲕࡢࣇ࣮ࣞࣂ࣮ࢆῧຍࡋࡓ࣑ࣀࣞࣂࣥ ®EN 㓄ྜᩓᠱ⃮ᾮẚ㍑ࡋ࡚, ᯝᐇ⣔ࡢࢵࣉࣝ, ࣇ࣮ࣝࢶ, ࣉ࣒ࣛ, ࣃࢼࢵࣉࣝࡢࣇ࣮ࣞࣂ࣮ࢆῧຍࡋࡓ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡣ, ࣑ࣀࣞ ࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮ༢⊂⩌ࡽ㐲࠸⨨ࢆ♧ࡋࡓ. ࡇࡢ⤖ᯝࡘ࠸࡚, Ỉྛヨᩱࡢ㛫ࡢ࣮ࣘࢡࣜ ࢵࢻ㊥㞳ࢆ⟬ฟࡋࡓࡇࢁ, ᯝᐇ⣔ࡢࣇ࣮ࣞࣂ࣮ࢆῧຍࡋࡓヨᩱ࡛ࡣ࣮ࣘࢡࣜࢵࢻ㊥㞳ࡀࡁࡃ, ࡑࡢ ୰࡛ࡶࣃࢼࢵࣉࣝࡢࣇ࣮ࣞࣂ࣮ࢆῧຍࡋࡓヨᩱ࡛ࡢ࣮ࣘࢡࣜࢵࢻ㊥㞳ࡀ᭱ࡶࡁࡗࡓ (Fig. 12 (B)). ࡇࡢᐇࡼࡾ, 㓟ࢆ࿊ࡍࡿᯝᐇ⣔ࡢᑓ⏝ࣇ࣮ࣞࣂ࣮ (ࢵࣉ࣑ࣝࢵࢡࢫ, ࣇ࣮ࣝࢶ࣑ࢵࢡࢫ, ࣉ ࣒࣑ࣛࢵࢡࢫ, ࣃࢼࢵࣉ࣑ࣝࢵࢡࢫ) ࡣ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ࢆຠᯝⓗ࣐ ࢫ࢟ࣥࢢࡋ, ࡑࡢ୰࡛ࡶࣃࢼࢵࣉ࣑ࣝࢵࢡࢫࡀ᭱ࡶຠᯝⓗ࡛࠶ࡿࡇࡀᐈほⓗ♧၀ࡉࢀࡓ. (A) (B) Fig. 12 Evaluation of odours of Aminoleban® EN (Am) with flavoured powders using the electronic nose system (A): Principal component analysis (PCA). (B): Euclidean distance from Aminoleban® EN water. n=3. 19 ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡣ, Fig. 1 ࡶ♧ࡋࡓ࠾ࡾ, ࢹ࢟ࢫࢺࣜࣥ 62%, ࢮࣛࢳࣥຍỈศゎ≀ 13%, ศᒱ㙐࣑ࣀ㓟 (BCAAs) 11%, ࡑࡢࡢ࣑ࣀ㓟 7%, ࢥ࣓Ἔ 2%ࢆྵࡳ, ࡇࡢ࠺ࡕ, BCAA ࡀ࣑ࣀࣞ ࣂࣥ®EN 㓄ྜᩓࡢⱞࡢཎᅉ࡛࠶ࡿࡇࡀ᪤᫂ࡽࡉࢀ࡚࠸ࡿ 16). ࡋࡋ, BCAA ΰྜỈ⁐ᾮࡢ ࠾࠸ࡣࢇ࡞࠸ࡇࡽ, ࡇࢀࡽ௨እࡢᡂศࡶ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢ⊂≉ࡢ࠾࠸ᐤࡋ࡚ ࠸ࡿࡇࡀ⪃࠼ࡽࢀࡿ. ≀㉁ࡢΰྜ≀ࡢ࠾࠸ࡣ, ಶࠎࡢ≀㉁ࡢ࠾࠸ࡢ⥲࡛࠶ࡿࡣ㝈ࡽ࡞࠸ࡇ ࡀሗ࿌ࡉࢀ࡚࠾ࡾ ®EN 35-37) , ྛ≀㉁ࡀΰྜࡍࡿࡇࡼࡾ, 」㞧࡞࠾࠸࡞ࡿࡇࡀ࠶ࡿ. ࣑ࣀࣞࣂࣥ 㓄ྜᩓᠱ⃮ᾮࡢ⊂≉ࡢ࠾࠸ࡣ, ྛᡂศࡢ」ྜࡼࡿࡶࡢ࡛࠶ࡿࡇࡀ⪃࠼ࡽࢀ, ࡑࡢ࠾࠸ࡀᝈ ⪅ࡢ᭹⸆ࢥࣥࣉࣛࣥࢫࢆపୗࡉࡏࡿྍ⬟ᛶࡀ࠶ࡿࡀ, ྛᑓ⏝ࣇ࣮ࣞࣂ࣮ࢆῧຍࡍࡿࡇࡼࡾ, ࡑ ࡢ࠾࠸ࡣ࣐ࢫ࢟ࣥࢢࡉࢀ, ≉, ࣃࢼࢵࣉ࣑ࣝࢵࢡࢫࡢࣇ࣮ࣞࣂ࣮ࡀ᭱ࡶຠᯝⓗ࡛࠶ࡿࡇࡀ♧ ၀ࡉࢀࡓ. ࣃࢼࢵࣉࣝࢆ㉳ࡉࡏࡿ㤶ᩱࡣ㓗㓟࢚ࢳࣝࡸ࣊࢟ࢧࣥ㓟࢚ࢳࣝࠊ࢜ࢡࢱࣥ㓟࢚ࢳࣝࡀ⏝ ࠸ࡽࢀࡿ. ࡇࢀࡽࡢ㓟㒊ࡢⅣ⣲ࡣ, ᯝᐇ⮯ࢆ࿊ࡍࡿ㓑㓟࢚ࢳࣝࡼࡾࡶከࡃ, ᙉ࠸࠾࠸࡞ࡾࡇࢀࡀ, ࣃࢼࢵࣉࣝࡢࣇ࣮ࣞࣂ࣮ࡀࡢࣇ࣮ࣞࣂ࣮ࡼࡾࡶຠᯝⓗ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ ࢆ࣐ࢫ࢟ࣥࢢࡋࡓཎᅉ࡛࠶ࡿࡇࡀ⪃࠼ࡽࢀࡓ. ➨ 3 ⠇ ᑠᣓ 1) ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢⱞࡣ, ᑓ⏝ࣇ࣮ࣞࣂ࣮ῧຍࡢ᭷↓ࢃࡽࡎ, ࣑ࣀࣞࣂࣥ ®EN 㓄ྜᩓᠱ⃮ᾮࡢ ᗘࢆపࡃࡍࡿࡇࡼࡗ࡚᭷ពᢚไࡉࢀࡿࡇࢆ᫂ࡽࡋࡓ. ࣑ࣀࣞࣂࣥ ®EN 㓄ྜᩓࡢⱞࡢཎᅉ࡛࠶ࡿ BCAA ΰྜ⁐ᾮࡢⱞࡣ, 㓟ప ࡢ⤌ࡳྜࢃࡏࡼࡾ┦ຍⓗᢚไ ࡉࢀࡿࡇࢆ᫂ࡽࡋࡓ. 2) ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢᛌ࡞࠾࠸ࡣ, ⏑ࡸ㓟ࢆ㉳ࡉࡏࡿᑓ⏝ࣇ࣮ࣞࣂ࣮ࡼࡾᢚไ ࡉࢀࡿࡇࢆࣄࢺᐁ⬟ヨ㦂ࡼࡾ᫂ࡽࡋࡓ. ࡲࡓ, ᮏ᳨ウ࡛⏝࠸ࡓ࠾࠸ࢭࣥࢧࡣ, ࣄࢺࡢႥぬྠ ⛬ᗘࡢ࠾࠸ឤᗘࢆ♧ࡍࡇࢆ᫂ࡽࡋࡓ. ᑓ⏝ࣇ࣮ࣞࣂ࣮ࡢ࠺ࡕࣃࢼࢵࣉࣝࡢࣇ࣮ࣞࣂ࣮ࡀ᭱ࡶ ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ࢆ࣐ࢫ࢟ࣥࢢࡍࡿࡇࢆ, ࣄࢺᐁ⬟ヨ㦂࠾࠸ࢭࣥࢧࢆ⏝࠸ ࡓホ౯ࡼࡾ᫂ࡽࡋࡓ. 20 ➨ 2 ❶ ࣋ࢩࢣ®㘄, ࣋ࢩࢣ®OD 㘄⢊○ࡢ⢊○⛬ᗘࡀཬࡰࡍⱞࡢᙳ㡪 㘄ࡣ, ᭹⏝㏿ࡸᄟୗࡉࢀ, ཱྀ⭍ෆᗈࡀࡿࡇࡣ࡞࠸ࡓࡵ᭹⏝ᛶࡀᙳ㡪ࡍࡿࡇࡣ ࢇ࡞࠸. ࡋࡋ, ᄟୗᅔ㞴࡞ᝈ⪅ࡸ⏝㔞ㄪᩚࡀᚲせ࡞ᑠඣᑐࡋ࡚㘄ࡀ⢊○ࡉࢀࡿሙྜࡣ, ᭹⏝ ⸆ࡀཱྀ⭍ෆᗈࡀࡾ, ᩓྠᵝ, ᭹⏝ᛶᙳ㡪ࢆ࠼ࡿྍ⬟ᛶࡀ࠶ࡿ. 㐣άື⭤⬔⒪࣋ࢩࢣ ®㘄ࡣ, ᙉ࠸ⱞࢆ࿊ࡍࡿࢯࣜࣇ࢙ࢼࢩࣥࢥࣁࢡ㓟ሷ (Fig. 13) ࢆ⸆ࡋ, ᑠඣࡢኪᒀ⏝࠸ࡿࡓ ࡵ㘄ࡀ⢊○ࡉࢀࡿࡇࡀ࠶ࡿ. ࡑࡢⱞࡣ᭹⏝ᛶᙳ㡪ࢆཬࡰࡋ᭹⸆ࢥࣥࣉࣛࣥࢫࢆపୗࡉࡏ ࡿᜍࢀࡀ࠶ࡿ. 2006 ᖺᢎㄆ㈍ࡉࢀࡓ࣋ࢩࢣ®㘄ᘬࡁ⥆ࡁ, 2010 ᖺࡣ࣋ࢩࢣ®ཱྀ⭍ෆᔂቯ㘄 (OD 㘄) ࡀᢎㄆ㈍ࡉࢀࡓ. ࣋ࢩࢣ®OD 㘄ࡣ, ⸆≀ࢥሷᯒᒙỈධ㔞ไᚚᒙࢆ⿕そࡋࡓᶵ⬟ᛶ ᚤ⢏Ꮚࢆྵࡴࡓࡵ, ࡑࡢሷᯒຠᯝࢆ⏝ࡋࡓ⸆≀⁐ฟࣛ ࢢࢱ࣒ࡼࡿⱞ࣐ࢫ࢟ࣥࢢࢩࢫࢸ࣒ࡀᵓ⠏ࡉࢀ࡚࠸ ࡿ 38-41). ࡋࡋ, ࡇࡢ࣋ࢩࢣ®OD 㘄ࢆ⢊○ࡋࡓሙྜࡣ ᶵ⬟ᛶᚤ⢏Ꮚࡀ◚ቯࡉࢀ, ࣋ࢩࢣ®㘄ྠᵝⱞࢆ࿊ࡍ Fig. 13 Solifenacin succinate ࡿྍ⬟ᛶࡀ࠶ࡿ. ᮏ❶࡛ࡣ࣋ࢩࢣ®㘄, ࣋ࢩࢣ®OD 㘄 ࢆ⢊○ࡋࡓሙྜࡢⱞࡘ࠸࡚ホ౯ࡋࡓ 42). ➨ 1 ⠇ ぬࢭࣥࢧࢆ⏝࠸ࡓࢯࣜࣇ࢙ࢼࢩࣥࢥࣁࢡ㓟ሷࡢⱞホ౯ ➨ 1 㡯 ┠ⓗ ᮏ⠇࡛ࡣ, ࣋ࢩࢣ®㘄, ࣋ࢩࢣ®OD 㘄ࡢ⸆࡛࠶ࡿࢯࣜࣇ࢙ࢼࢩࣥࢥࣁࢡ㓟ሷࡢⱞࢆホ౯ࡍࡿ ࡓࡵ᭱㐺࡞ぬࢭࣥࢧ⭷ࢆ㑅ᢥࡍࡿࡇࢆ┠ⓗࡋࡓ. ➨ 2 㡯 ᐇ㦂᪉ἲ 1. ヨ⸆ ࣋ࢩࢣ®㘄 5 mg (ࢫࢸࣛࢫ〇⸆ᰴᘧ♫), ࢯࣜࣇ࢙ࢼࢩࣥࢥࣁࢡ㓟ሷ (Tronto Research Chemicals Inc.), ࢟ࢽ࣮ࢿሷ㓟ሷ (Shigma Chemical Co.) ࢆ⏝࠸ࡓ. 㐣ཤࡢሗ࿌ᚑ࠸ 43, 44), ⱞࡢᶆ‽≀㉁࡛࠶ࡿ 21 ࢟ࢽ࣮ࢿሷ㓟ሷỈ⁐ᾮ 0.01, 0.03, 0.10, 0.30, 1.00 mM ࡢⱞᙉᗘࢆྛࠎ τ 0, τ 1, τ 2, τ 3, τ 4 ࡋࡓ. 2. ぬࢭࣥࢧ ぬࢭࣥࢧࡣ, ࣥࢸࣜࢪ࢙ࣥࢺࢭࣥࢧ࣮ࢸࢡࣀࣟࢪ࣮ᰴᘧ♫ࡢ SA402B ࢆ⏝࠸ࡓ 45-47) . ࡇࡢぬ ࢭࣥࢧࡣ, ࣄࢺࡢぬჾࢆᶍࡋ࡚㛤Ⓨࡉࢀࡓ⨨࡛࠶ࡿ. ࣟ࣎ࢵࢺ࣮࣒ྲྀࡾࡅࡽࢀࡓࢭࣥࢧ࣊ࢵ ࢻཧ↷㟁ᴟ⬡㉁⭷ࢭࣥࢧ㟁ᴟࢆྲྀࡾࡅ, ࡇࡢ㟁ᴟ㒊ࢆࢧࣥࣉࣝ⁐ᾮ୰ᾐࡍ, ᐃ≀㉁⬡㉁ ⭷ࡢᏛ⤖ྜࡸ㟼㟁┦స⏝, ≀⌮ⓗ྾╔➼ࡼࡾ, ⬡㉁⭷㟁ࡀኚࡋ, ཧ↷㟁ᴟ⬡㉁⭷ࢭࣥࢧ 㟁ᴟ㛫ࡢ㟁ᕪࡀฟຊ࡞ࡾ, ࣟ࣎ࢵࢺ࣮࣒ࢆ㏻ࡌ࡚ࢥࣥࣆ࣮ࣗࢱ㏦ࡽࢀࡿ. ཧ↷㟁ᴟࡣ, ෆ㒊ᾮ (3.3 M KCl+㣬 AgCl) ࡀධࡗࡓ୰✵Წ㖟࣭ሷ㖟㟁ᴟࡽᵓᡂࡉࢀ, ඛ➃ࡢᏍࡣ KCl ࢆΰධࡋࡓᐮኳ ࡛ሰࡀࢀ࡚࠸ࡿ. ⬡㉁⭷ࢭࣥࢧ㟁ᴟࡶྠᵝࡢᵓᡂ࡛࠶ࡿࡀ, ඛ➃ࡢᏍࡣ㟁ᴟࡈࡑࢀࡒࢀ≉ᛶࡢ␗ ࡞ࡿ⬡㉁⭷ࡀ㈞ࡾࡅ࡚࠶ࡿ. ⬡㉁⭷ࡢཌࡉࡣ⣙ 0.2 mm ࡛, ⬡㉁ᮦᩱྍረࡽᡂࡿ. 㟁ᴟ㒊ࢆ, ၚ ᾮ┦ᙜࡍࡿᇶ‽ᾮ (0.3 mM 㓇▼㓟ࢆྵࡴ 30 mM KCl) ᾐࡋ࡚⭷㟁 (Vr) ࢆ ᐃᚋ, ࢭࣥࢧࢆࢧࣥ ࣉࣝᾐࡋ࡚⭷㟁 (Vs) ࢆ ᐃࡋ, ⭷㟁ኚ (Vs㸫Vr) ࢆࢭࣥࢧฟຊ್ (Relative value) ࡋ࡚ࡢ ホ౯⏝࠸ࡓ (Fig. 14). Fig. 14 Taste sensor system (Intelligent Sensor Technology Inc.) 22 ⱞࡣࣄࢺ࡛ࡣ 25 ✀㢮ࡢ T2R ࣇ࣑࣮࡛ࣜㄆ㆑ࡉࢀࡿࡇࡀ▱ࡽࢀ࡚࠸ࡿ. ࣄࢺࡢ⯉ࢆᶍೌࡋࡓ⬡ ㉁⭷ࢭࣥࢧࡣ⬡㉁ྍረࡽᡂࡾ, ⌧ᅾ, ሷᇶᛶࡢⱞᛂ⟅ࡍࡿ BT0, AN0, AC0, 㓟ᛶࡢⱞᛂ⟅ ࡍࡿ C00, AE1 ࡀ㛤Ⓨࡉࢀ࡚࠸ࡿ 47) (Table 5). ࡇࢀࡽࡢ⬡㉁⭷ࢭࣥࢧࡢ࠺ࡕ, ྛ་⸆ရ᭱ࡶᛂ⟅ᛶࡀ㧗 ࠸⬡㉁⭷ࢭࣥࢧࢆ⏝࠸࡚ⱞࡢホ౯ࢆ⾜ࡗࡓ. Table 5 Taste sensor lipid-baced membrane 3. ⤫ィฎ⌮ Fig. 15 ♧ࡋࡓ⤖ᯝ࡛ࡣ, ⸆≀⃰ᗘࢭࣥࢧฟຊ್ࡢ┦㛵ᛶࢆ☜ㄆࡍࡿࡓࡵ, ࢚ࢡࢭࣝ⤫ィࢆ⏝࠸ ࡚ Spearman’s test ࢆ⾜ࡗࡓ. 23 ➨ 3 㡯 ⤖ᯝ⪃ᐹ ࢟ࢽ࣮ࢿሷ㓟ሷỈ⁐ᾮࡣ, ሷᇶᛶⱞ⭷ࢭࣥࢧ AC0 ⃰ᗘ౫Ꮡⓗᛂ⟅ࡋࡓ (Fig. 15 (A)). ࡢᙉᗘ ࡣᑐ㇟≀㉁ࡢ⃰ᗘࡢᑐᩘẚࡍࡿ࠸࠺࢙࣮࢘ࣂ࣮࣭ࣇ࢙ࣄࢼ࣮ࡢἲ๎ 48) ᚑ࠺ࡇࡀ▱ࡽࢀ࡚࠸ ࡿࡀ, ࢭࣥࢧฟຊ್ࡣ࢟ࢽ࣮ࢿሷ㓟ሷࡢ⃰ᗘࡢᑐᩘẚࡋࡓ (r = 0.973, Pearson’s correlation test) (Fig. 15 (B)). ୍᪉, ࢯࣜࣇ࢙ࢼࢩࣥࢥࣁࢡ㓟ሷỈ⁐ᾮ (0.08, 0.32, 0.65, 1.30 mM) ࢆ AC0 ⭷ࢭࣥࢧ࡛ ᐃࡋࡓ ⤖ᯝ, ࢟ࢽ࣮ࢿሷ㓟ሷỈ⁐ᾮྠᵝࡢ, ⸆≀⃰ᗘ㸫ࢭࣥࢧฟຊ್ࣉࣟࣇࣝࡀᚓࡽࢀࡓ (Fig. 15 (C)). ࢟ࢽ࣮ࢿሷ㓟ሷỈ⁐ᾮࡢⱞᙉᗘ AC0 ࢭࣥࢧฟຊ್ࡢ㛵ಀࡣ Fig. 15 (D) ⾲ࡉࢀ, (AC0 ࢭࣥࢧฟຊ ್)㸻31.581× (ⱞᙉᗘ) ࠸࠺ᅇᖐᘧࡀᚓࡽࢀࡓ. ௨ୗࡢ᳨ウ࡛ࡣ, ࡇࡢᘧࢭࣥࢧฟຊ್ࢆ௦ධࡋ, ࢯࣜࣇ࢙ࢼࢩࣥࢥࣁࢡ㓟ሷࡼࡿⱞᙉᗘࢆண ࡋࡓ (ண ⱞᙉᗘ). ࣋ࢩࢣ®㘄ࡣ, ㏻ᖖ, ᡂேࡢ 㐣άື⭤⬔ᝈ⪅ࡣ 1 ᪥ 1 ᅇ 1 㘄 (ࢯࣜࣇ࢙ࢼࢩࣥࢥࣁࢡ㓟ሷ 5 mg) ࡀ㐺ᛂࡉࢀࡿࡀ, ᑠඣࡣ༙㘄 (ࢯ ࣜࣇ࢙ࢼࢩࣥࢥࣁࢡ㓟ሷ 2.5 mg) ๓ᚋࡀ⏝࠸ࡽࢀࡿ. ࣄࢺࡢⱞ㜈್࡛࠶ࡿ τ 1 ẚ㍑ࡋ࡚, ࢯࣜࣇ࢙ࢼ ࢩࣥࢥࣁࢡ㓟ሷ 2.5 mg/20 mL (0.32 mM) ࡢண ⱞᙉᗘࡣ⣙ τ 3 ࡛࠶ࡾ, ᙉ࠸ⱞࢆ࿊ࡍࡿࡇࡀண ࡉࢀࡓ. Fig. 15 AC0 taste sensor output (relative value) of quinine hydrochloride (A), correlation between logarithm of quinine hydrochloride concentration and AC0 taste sensor output (relative value) (B), AC0 taste sensor output (relative value) of solifenacin (C), and correlation between bitterness score of quinine hydrochloride and AC0 taste sensor output (relative value) (D) n=4, mean ± S.D., rs=0.985 (Spearman’s test) (B, D). 24 ➨ 2 ⠇ ぬࢭࣥࢧࢆ⏝࠸ࡓ࣋ࢩࢣ®㘄, ࣋ࢩࢣ®OD 㘄⢊○ヨᩱࡢⱞホ౯ ➨ 1 㡯 ┠ⓗ ࣋ࢩࢣ®㘄, ࣋ࢩࢣ OD®㘄ࡀ⢊○ㄪࡉࢀࡓሙྜࡢ᭹⏝ࡢⱞࢆண ࡍࡿࡇࢆ┠ⓗࡋࡓ. ཱྀ⭍ෆ⎔ቃࢆᶍࡋࡓ⡆᫆⁐ฟヨ㦂 49)ࡼࡾ, ࣋ࢩࢣ®㘄, ࣋ࢩࢣ OD®㘄⢊○ヨᩱࡢ, ཱྀ⭍ෆ࡛ࡢⱞ ᙉᗘࡢண ࢆ⤒ⓗ⾜ࡗࡓ. ࡇࡢ㝿, ྛ㘄ࢆ 2 ㏻ࡾࡢ᪉ἲ࡛⢊○ࡋ, ⢊○⛬ᗘࡀཬࡰࡍⱞࡢᙳ 㡪ࢆホ౯ࡋࡓ. ➨ 2 㡯 ᐇ㦂᪉ἲ 1. ヨ⸆ ᮏ❶➨ 1 ⠇ྠᵝࡢヨ⸆, ࣋ࢩࢣ®OD 㘄 5 mg (ࢫࢸࣛࢫ〇⸆ᰴᘧ♫) ࢆ⏝࠸ࡓ. 2. ヨᩱࡢㄪ〇 㘄ࡢ⢊○ࡣ, 㘄ࢆங㖊ࡢ୰࡛ஙᲬࢆ⏝࠸࡚ࡍࡾࡘࡪࡋ, ⢏ᚄ 100 μm ᮍ‶࡞ࡿࡼ࠺⢊○ࡍࡿሙ ྜ, 㘄ࢆ⸆ໟ⣬ᣳࡳ, ⸆ໟ⣬ࡢୖࡽஙᲬ࡛ᢲࡋࡘࡪࡋ, ⢏ᚄ 500 μm ᮍ‶࡞ࡿࡼ࠺⢊○ࡍࡿ ሙྜࡢ 2 ㏻ࡾࡢ᪉ἲ࡛⾜ࡗࡓ. ࣋ࢩࢣ®㘄 5 mg ࢆ, ⢏ᚄ 100 μm ᮍ‶࡞ࡿࡼ࠺ᙉࡃ⢊○ࡋࡓヨᩱࢆ CTS (Conventional Tablet Crushed Strongly), ࣋ࢩࢣ®㘄 5 mg ࢆ, ⢏ᚄ 500 μm ᮍ‶࡞ࡿࡼ࠺ᙅࡃ⢊○ ࡋࡓヨᩱࢆ CTL (Conventional Tablet Crushed Lightly), ࣋ࢩࢣ®OD 㘄 5 mg ࢆ, ⢏ᚄ 100 μm ᮍ‶࡞ࡿ ࡼ࠺ᙉࡃ⢊○ࡋࡓヨᩱࢆ ODTS (OD Tablet Crushed Strongly), ࣋ࢩࢣ®OD 㘄 5 mg ࢆ, ⢏ᚄ 500 μm ᮍ ‶࡞ࡿࡼ࠺ᙅࡃ⢊○ࡋࡓヨᩱࢆ ODTL (OD Tablet Crushed Lightly) ࡋࡓ. 3. ⡆᫆⁐ฟヨ㦂 ᜏ ࠺ᵴ࡛ 37Υಖࡗࡓ⢭〇Ỉ 40 mL ࢆධࢀࡓࣅ࣮࣮࢝ࢆ 25 rpm ࡛࠺ࡉࡏ, ⢭〇Ỉ୰ྛ 㘄 1 㘄ศࡢ⢊○ヨᩱ (CTS, CTL, ODTS, ODTL) ࢆᢞධࡋ࡚ࡽ 5, 10, 30, 60, 90, 120 ⛊ᚋ 0.45 μm ࣇ ࣝࢱ࣮࡛ࢁ㐣ࡋࡓ. 25 4. ぬࢭࣥࢧ ᐃ 4-1. SA402B (ࣥࢸࣜࢪ࢙ࣥࢺࢭࣥࢧ࣮ࢸࢡࣀࣟࢪ࣮ᰴᘧ♫) ⡆᫆⁐ฟヨ㦂ࡼࡾᚓࡽࢀࡓྛヨᩱࢆ, ぬࢭࣥࢧ SA402B ࢆ⏝࠸࡚ ᐃࡋࡓ. ࢭࣥࢧ⭷ࡣ, ᮏ❶➨ 1 ⠇ ࡛ࢯࣜࣇ࢙ࢼࢩࣥࢥࣁࢡ㓟ሷࡢⱞࢆホ౯ࡋ࠺ࡿࡇࡀ᫂ࡽ࡞ࡗࡓ AC0 ⭷ࢆ⏝࠸ࡓ. 4-2. α-ASTREE (α-MOS) ぬࢭࣥࢧ α-ASTREE (α-MOS) ࡣ, CHEMFET (Ꮫⓗ㟁⏺ຠᯝࢺࣛࣥࢪࢫࢱ) ᢏ⾡ᇶ࡙ࡃ㟁ẼᏛ ࢭࣥࢧ࡛࠶ࡾ, 7 ᮏࡢࢭࣥࢧ (ZZ, AB, GA, BB, CA, DA JE) ࡢ⤌ࡳྜࢃࡏࡼࡿࣃࢱ࣮ࣥࡼࡗ࡚ࢆ㆑ ูࡍࡿ. ྛࢭࣥࢧᛂ⟅್ࡽ Alpha Soft (α-MOS) ࢆ⏝࠸࡚ᡂศศᯒࡋ, ᚓࡽࢀࡓ࣐ࢵࣉୖࣉࣟࢵࢺ ࡉࢀࡓྛࢧࣥࣉࣝ㛫ࡢ㊥㞳 (࣮ࣘࢡࣜࢵࢻ㊥㞳) ࡀᑠࡉ࠸ࡀ㢮ఝࡋ࡚࠸ࡿุ᩿ࡋࡓ 49). 5. ⤫ィฎ⌮ Fig. 16 ♧ࡋࡓ⤖ᯝ࡛ࡣ, ᖹᆒ್ ± S. D.࡛⾲グࡋ, ࢚ࢡࢭࣝ⤫ィࢆ⏝࠸࡚ Sheffe’s test ࡼࡿከ㔜ẚ ㍑᳨ᐃࢆ⾜ࡗࡓ. 26 ➨ 3 㡯 ⤖ᯝ⪃ᐹ CTS, CTL, ODTS ࡣ, ⡆᫆⁐ฟヨ㦂 5 ⛊ᚋ࡛ࡣண ⱞᙉᗘࡣ⣙ τ 3 ࡛࠶ࡿࡇࡀண ࡉࢀࡓ. ୍᪉ ODTL ࡣ, ⡆᫆⁐ฟヨ㦂 120 ⛊ᚋ࡛ࡶ τ 2 ᮍ‶ࢆಖࡗ࡚࠸ࡓ (Fig. 16). ࣋ࢩࢣ®㘄ࡣ⢊○ࡑࡢ⢊○ ⛬ᗘᙳ㡪ࡉࢀࡎⱞࢆ࿊ࡍࡿࡀ, ࣋ࢩࢣ®OD 㘄ࡣ, ⢏ᚄ 500 μm ᮍ‶࡞ࡿࡼ࠺ᙅࡃ⢊○ࡍࡿሙ ྜ, ⢏ᚄ 100 μm ᮍ‶࡞ࡿࡼ࠺ᙉࡃ⢊○ࡍࡿሙྜẚ㍑ࡋ࡚ⱞࡀᑡ࡞࠸ࡇࡀ♧၀ࡉࢀࡓ. ࣋ࢩࢣ®㘄, ࣋ࢩࢣ®OD 㘄ࢆ⢏ᚄ 500 μm ᮍ‶࡞ࡿࡼ࠺ᙅࡃ⢊○ࡋࡓヨᩱ (CTL, ODTL) ࢟ ࢽ࣮ࢿሷ㓟ሷỈ⁐ᾮ (0.03, 0.10, 0.30 mM) ࢆぬࢭࣥࢧ αASTREE ࡛ ᐃࡋ࡚ᚓࡽࢀࡓྛࢭࣥࢧฟຊ್ ࡢᡂศศᯒ⤖ᯝࢆ Fig.17 (A) ♧ࡋ, ྛヨᩱỈࡢ㛫ࡢ࣮ࣘࢡࣜࢵࢻ㊥㞳ࢆ Fig. 17 (B) ♧ࡋࡓ. ᐤ⋡ࡣᶓ㍈ PC1: 89.5%, ⦪㍈ PC2: 7.3%࡛࠶ࡾ, ᶓ㍈ࡢᐤ⋡ࡀ㧗ࡗࡓ. ࢟ࢽ࣮ࢿሷ㓟ሷỈ⁐ᾮࡣ, ᡂศศᯒ࣐ࢵࣉୖ࡛⃰ᗘ౫Ꮡⓗᶓ㍈ྑ᪉ྥ⨨ࡀࢩࣇࢺࡋࡓࡇࡼࡾ, ࣐ࢵࣉୖࡢྑࣉࣟࢵࢺ ࡉࢀࡓヨᩱⱞࢆ࿊ࡍࡿࡇࡀ♧၀ࡉࢀࡓ. CTL ࡣ, ⡆᫆⁐ฟヨ㦂ᚋࡢ㛫ࢃࡽࡎ, ⱞᙉ ᗘ τ 3 ┦ᙜࡍࡿ࢟ࢽ࣮ࢿሷ㓟ሷỈ⁐ᾮ 0.30 mM ㏆࠸⨨ࢆ♧ࡋࡓ. ୍᪉ ODTL ࡣ, 5 ⛊ᚋࡢヨᩱࡣⱞ ᙉᗘ τ 1 ┦ᙜࡍࡿ࢟ࢽ࣮ࢿሷ㓟ሷỈ⁐ᾮ 0.03 mM ㏆࠸⨨ࢆ♧ࡋ, 120 ⛊ᚋࡢヨᩱ࡛ࡶⱞᙉᗘ τ 2 ┦ᙜࡍࡿ࢟ࢽ࣮ࢿሷ㓟ሷỈ⁐ᾮ 0.10 mM ㏆࠸⨨ࢆ♧ࡋࡓ. ࡇࡢࡇࡽࡶ, ⢏ᚄࡀ 500 μm ᮍ‶ ࡞ࡿࡼ࠺ᙅࡃ⢊○ࡍࡿሙྜ, ࣋ࢩࢣ®OD 㘄ࡣ࣋ࢩࢣ®㘄ࡼࡾࡶ, ⢊○ࡢⱞࡀᑡ࡞࠸ࡇࡀ♧ ၀ࡉࢀࡓ. Fig. 16 Predicted bitterness intensity (τ) of Vesicare®; CT(intact), ODT (intact), CT crushed strongly (CTS), CT crushed lightly (CTL), ODT crushed strongly (ODTS), ODT crushed lightly (ODTL) *p<0.05 vs CT (intact) (Scheffe’s test) n=4, mean ± S.D. 27 Fig. 17 Comparison of 5, 30 and 120 s samples of CT and ODT crushed lightly (CTL and ODTL) using the taste sensor α-ASTREE (A): Principal component analysis (PCA). (B): Euclidean distance from water. n=3. 28 ➨ 3 ⠇ ࣋ࢩࢣ®㘄, ࣋ࢩࢣ®OD 㘄⢊○ヨᩱࡢ⸆≀⁐ฟ⋡ࡢ ᐃ ➨ 1 㡯 ┠ⓗ ᮏ❶➨ 2 ⠇࡛࣋ࢩࢣ OD®㘄ࡀ⢊○ㄪࡉࢀࡓሙྜࡢⱞᙉᗘࡣ⢊○⛬ᗘࡼࡾ␗࡞ࡿࡇࡀண ࡉ ࢀࡓࡇࡽ, ᮏ⠇࡛ࡣ, ᮏ❶➨ 2 ⠇࡛⾜ࡗࡓ⡆᫆⁐ฟヨ㦂ᚋࡢࢁᾮヨᩱ୰ࡢࢯࣜࣇ࢙ࢼࢩࣥࢥࣁࢡ㓟 ሷࡢ⃰ᗘࢆ HPLC ࡚ ᐃࡋ, ⤒ⓗ࡞⸆≀⁐ฟࢆ☜ㄆࡋࡓ. ࡉࡽ, ࣋ࢩࢣ®㘄, ࣋ࢩࢣ OD®㘄⢊ ○ヨᩱࡢ⢏Ꮚࡢᙧ≧ࢆ☜ㄆࡋࡓ. ➨ 2 㡯 ᐇ㦂᪉ἲ 1. ヨ⸆ ᮏ❶➨ 2 ⠇ྠᵝࡢヨ⸆ࢆ⏝࠸ࡓ. 2. HPLC ࢯࣜࣇ࢙ࢼࢩࣥࢥࣁࢡ㓟ሷࡢ⃰ᗘࢆ HPLC ⨨࡚ ᐃࡋࡓ. ⛣ື┦ࡣ, pH 3 ㄪᩚࡋࡓ 0.1% Triethylamine ࢆྵࡴ 10 mM ࣜࣥ㓟Ỉ⣲࣒࢝ࣜ࢘⁐ᾮࢭࢺࢽࢺࣜࣝࢆయ✚ẚ 60:40 ࡛ΰྜࡋࡓヨᩱ ࢆ⏝࠸, 4.6 mm×250 mm ࡢ࣒࢝ࣛ (Capcell Pak C18 UG120, ㈨⏕ᇽ), ᗘ 25Υ, ὶ㏿ 1 mL/min, ᐃἼ㛗 210 nm ࡚ ᐃࡋࡓ 50). ᮏ❶➨ 2 ⠇࡛⾜ࡗࡓ⡆᫆⁐ฟヨ㦂ᚋࡢヨᩱ୰ࡢࢯࣜࣇ࢙ࢼࢩࣥࢥࣁࢡ㓟ሷࡢ⃰ ᗘࢆ ᐃࡋࡓ. 3. ࣋ࢩࢣ®㘄, ࣋ࢩࢣ®OD 㘄⢊○ヨᩱࡢ⢏Ꮚࡢほᐹ ࣋ࢩࢣ®㘄, ࣋ࢩࢣ®OD 㘄⢊○ヨᩱ CTS, CTL, ODTS, ODTL ࡢ⢏ᚄ⢏Ꮚࡢᙧ≧ࢆ, 㟁Ꮚ㢧ᚤ㙾 (OLYMPUS SZX10) ࢆ⏝࠸࡚ほᐹࡋࡓ. 4. ⤫ィฎ⌮ Fig. 18 ♧ࡋࡓ⤖ᯝ࡛ࡣ, ᖹᆒ್ ± S. D. ࡛⾲グࡋ, ࢚ࢡࢭࣝ⤫ィࢆ⏝࠸࡚ Sheffe’s test ࡼࡿከ㔜ẚ 29 ㍑᳨ᐃࢆ⾜ࡗࡓ. ➨ 3 㡯 ⤖ᯝ⪃ᐹ CTS ࡣ 5 ⛊ᚋࡣࡍ࡛ 80%௨ୖࡢ⁐ฟ⋡ࢆ♧ࡋࡓࡇᑐࡋ, ODTL ࡣ, ⸆≀⁐ฟࡀᢚไࡉࢀ࡚࠾ࡾ, 120 ⛊ᚋ࡛ࡶ 20%ᮍ‶ࡢ⸆≀⁐ฟ⋡ࢆ♧ࡋࡓ. ࣋ࢩࢣ®OD 㘄ࡣ, ⢏ᚄ 500 μm ᮍ‶࡞ࡿࡼ࠺⢊○ࡍ ࡿࡇࡼࡾ, ⢏ᚄ 100 μm ᮍ‶࡞ࡿࡼ࠺⢊○ࡍࡿሙྜẚ㍑ࡋ࡚⸆≀⁐ฟࡀᢚไ࡛ࡁࡿࡇࡀ᫂ ࡽ࡞ࡾ, ࡇࡢࡇࡀⱞᢚไᐤࡍࡿࡇࡀ♧၀ࡉࢀࡓ㸦Fig. 18㸧. ࡇࢀࡽࡢ⢊○ࡢ⢏Ꮚࡢᙧ≧ࢆ㟁Ꮚ㢧ᚤ㙾࡛ほᐹࡋࡓࡇࢁ, ODTL ࡛ࡣ, ⣙ 200 μm ࡢ⌫≧ࡢ⢏Ꮚࡀ☜ ㄆࡉࢀࡓ (Fig. 19). ࣋ࢩࢣ®OD 㘄ࡢ〇㐀ᕤ⛬ࡣ, ᶵ⬟ᛶᚤ⢏Ꮚᕤ⛬ WOWTAB ᕤ⛬ࡽᡂࡾ❧ࡗ࡚ ࠸ࡿࡀ, ᚤ⢏Ꮚᕤ⛬࡛ࡣሷᯒຠᯝࢆ♧ࡍⱞ࣐ࢫ࢟ࣥࢢᢏ⾡ࡼࡿࢥ࣮ࢸࣥࢢࡀࡉࢀ࡚࠸ࡿ 38-41) . ⢏ᚄࡀ 100 μm ᮍ‶࡞ࡿࡼ࠺⢊○ࡋࡓሙྜࡣࡇࡢࢥ࣮ࢸࣥࢢࡀ◚ቯࡉࢀ࡚⸆≀ࡀᨺฟࡍࡿࡀ, ⢏ ᚄ 100 μm ௨ୖ 500 μm ᮍ‶࡞ࡿࡼ࠺⢊○ࡍࡿሙྜࡣࢥ࣮ࢸࣥࢢᚤ⢏Ꮚࡀಖࡓࢀ࡚࠸ࡿࡇࡀ᫂ࡽ ࡞ࡗࡓ (Fig. 20). Fig. 18 Serial evaluation of solifenacin release from Vesicare®; CT (intact), ODT (intact), CT crushed strongly (CTS), CT crushed lightly (CTL), ODT crushed strongly (ODTS), ODT crushed lightly (ODTL) *p<0.05, **p<0.01 vs CTS (Sheffe’s test). n=5, mean ± S.D. 30 Fig. 19 Particle size and morphology of crushed Vesicare® tablets viewed microscopically CTS (A), CTL (B), ODTS (C), ODTL (D). Fig. 20 Summary of the study Lightly crushed ODT would be prevented the expression of bitterness because of functioning the salting-out taste masking system. 31 ➨ 4 ⠇ ᑠᣓ ࣋ࢩࢣ®㘄ࢆ⢊○ࡋࡓሙྜࡣ, ⢊○⛬ᗘࢃࡽࡎ⸆ࡢࢯࣜࣇ࢙ࢼࢩࣥࡢ⁐ฟࡼࡾཱྀ⭍ෆ࡛ ᙉ࠸ⱞࢆ࿊ࡍࡿྍ⬟ᛶࡀ♧၀ࡉࢀࡓ. ୍᪉, ࣋ࢩࢣ®OD 㘄ࡣ, ⢏ᚄࡀ 100 μm ᮍ‶࡞ࡿࡼ࠺ᙉࡃ ⢊○ࡍࡿሙྜࡣᚤ⢏Ꮚࢥ࣮ࢸࣥࢢࡀ◚ቯࡉࢀࡿࡀ, ⢏ᚄ 100 μm ௨ୖ 500 μm ᮍ‶࡞ࡿࡼ࠺ᙅࡃ ⢊○ࡍࡿሙྜࡣࢥ࣮ࢸࣥࢢࡀಖࡓࢀ, ཱྀ⭍ෆ࡛ࡢ⸆≀⁐ฟక࠺ⱞࡀᢚไࡉࢀᚓࡿࡇࡀ᫂ࡽ ࡞ࡗࡓ. 32 ➨ 3 ❶ ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%Ⅼ║ᚋࡢⱞᢚไ᭷ຠ࡞㣧㣗≀ࡢ᥈⣴ ᩓࡸ㘄➼ࡢෆ᭹⸆ࡣ, ࡑࡢࡀ᭹⏝ᛶࡁࡃᙳ㡪ࡋ࠺ࡿࡀ, Ⅼ║ࡶ, Ⅼ║ᚋ㰯ᾦ⟶ࢆ㏻㐣 ࡋ࡚ဗ㢌㒊㐩ࡍࡿࡁࢆ࿊ࡍࡿࡇࡀ࠶ࡾ, ᙉ࠸ⱞࢆ࿊ࡍࡿ⸆≀ࢆྵ᭷ࡍࡿⅬ║⏝ࡢⅬ ║ᚋࡢⱞࡣ, ᝈ⪅ࡢࢥࣥࣉࣛࣥࢫపୗࡢཎᅉ࡞ࡾ࠺ࡿ. ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%ࡢᡂศ࡛࠶ ࡿࣞࣂ࣑ࣆࢻ (Fig. 21) ࡣ, 㰯ᾦ⟶ࢆ㏻㐣ࡋ࡚ဗ㢌㒊࡛ⱞࢆ࿊ࡍࡿࡇࡀ▱ࡽࢀ࡚࠾ࡾ, ࣥࢱࣅࣗ ࣮ࣇ࢛࣮࣒ࡣ⮫ᗋヨ㦂࡛Ⅼ║ᚋ 670 ୰ 105 (15.7%) ࡀⱞࢆ♧ࡋࡓࡇࡀグ㍕ࡉࢀ࡚࠸ࡿ. ࡋ ࡋࡇࡢⱞᑐࡍࡿ᭷ຠ࡞ᢚไ᪉ἲࡘ࠸࡚ࡢሗ࿌ࡣ࡞࠸. ᮏ❶࡛ࡣ, ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%Ⅼ║ᚋ㌟㏆࡞㣧㣗≀ࢆ ᦤྲྀࡍࡿࡇࡼࡾ, ࣞࣂ࣑ࣆࢻࡼࡿⱞࢆᢚไࡍࡿࡇ ࢆ┠ⓗࡋ, ࡇࢀ᭷ຠ࡞㣧㣗≀ࡢ᥈⣴ࢆ⾜ࡗࡓ 51). Fig. 21 Chemical structure of Rebamipide ➨ 1 ⠇ ࣞࣂ࣑ࣆࢻࡢⱞホ౯㐺ࡋࡓぬࢭࣥࢧ⭷ࡢ㑅ᢥ ➨ 1 㡯 ┠ⓗ ᮏ⠇࡛ࡣ, ࣞࣂ࣑ࣆࢻࡢⱞࢆホ౯ࡍࡿࡓࡵ᭱㐺࡞ぬࢭࣥࢧ⭷ࢆ㑅ᢥࡍࡿࡇࢆ┠ⓗࡋࡓ. ➨ 2 㡯 ᐇ㦂᪉ἲ 1. ヨ⸆ ࣞࣂ࣑ࣆࢻ (LKT Laboratories Inc.) ࢆࣜࣥ㓟⦆⾪⏕⌮㣗ሷᾮ (Phosphate bufferd saline: PBS) ⁐ゎࡋ, 62.5, 125, 250, 500 μg/mL ࡢࣞࣂ࣑ࣆࢻ⁐ᾮࢆㄪ〇ࡋࡓ. PBS ࡣ, PBS Tablets (T900, Takara) 10 㘄ࢆ⢭〇Ỉ ⁐ゎࡋ, 㔞ࢆ 1000 mL ࡋ࡚ㄪ〇ࡋࡓ (pH 7.35-7.65). 33 2. ぬࢭࣥࢧ ➨ 2 ❶࡛⏝࠸ࡓぬࢭࣥࢧ SA402B ࢆ⏝࠸ࡓ. ࣞࣂ࣑ࣆࢻࡣ㓟ᛶ་⸆ရ࡛࠶ࡿࡓࡵ, 㓟ᛶࡢⱞᛂ ⟅ࡍࡿ⬡㉁⭷ C00 ⭷, AE1 ⭷ࢆ⏝࠸࡚, ࣞࣂ࣑ࣆࢻ⁐ᾮࡢぬࢭࣥࢧᛂ⟅ࢆ☜ㄆࡋࡓ. C00 ⭷, AE1 ⭷ࡣ, ࣉࣛࢫᖏ㟁ࡋ࡚࠸ࡿࡓࡵ, 㓟ᛶⱞ≀㉁ࡣ࣐ࢼࢫഃฟຊࡍࡿ (Fig. 22). Fig. 22 C00, AE1 taste sensor output 3. ⤫ィฎ⌮ Fig. 23 ♧ࡋࡓ⤖ᯝ࡛ࡣ, ⸆≀⃰ᗘࡢᑐᩘࢭࣥࢧฟຊ್ࡢ㛫ࡢ┦㛵ᛶࢆ☜ㄆࡍࡿࡓࡵ, ࢚ࢡࢭࣝ⤫ ィࢆ⏝࠸࡚ Pearson’s correlation test ࢆ⾜ࡗࡓ. 34 ➨ 3 㡯 ⤖ᯝ⪃ᐹ 㓟ᛶࡢⱞᛂ⟅ࡍࡿ⬡㉁⭷ࢭࣥࢧ C00 ⭷, AE1 ⭷ࢆ⏝࠸࡚, ࣞࣂ࣑ࣆࢻ⁐ᾮ (⁐፹: PBS) ࢆ ᐃࡋ ࡓࡇࢁ, C00 ⭷ࡣᛂ⟅ࡏࡎ, AE1 ⭷ࡣ⃰ᗘ౫Ꮡⓗᛂ⟅ࡋࡓ (Fig. 23). ࡉࡽ, ぬ (ᙉᗘ) ࡣᑐ ㇟≀㉁ࡢ⃰ᗘࡢᑐᩘẚࡍࡿ࠸࠺࢙࣮࢘ࣂ࣮࣭ࣇ࢙ࣄࢼ࣮ࡢἲ๎ᇶ࡙ࡁ, ࣞࣂ࣑ࣆࢻࡢ⃰ᗘࡢᑐ ᩘ AE1 ࢭࣥࢧฟຊ್ࡣⰋዲ࡞┦㛵ᛶࢆ♧ࡍࡇࢆ☜ㄆࡋࡓ (r =㸫0.988, Pearson’s correlation test). ࡇ ࢀࡼࡾ, ࣞࣂ࣑ࣆࢻࡢⱞࡣ AE1 ⭷ࢆ⏝࠸࡚ホ౯ࡋ࠺ࡿࡇࡀ♧၀ࡉࢀࡓ. Fig. 23 AE1 taste sensor output of rebamipide n=3, mean ± S.D. 35 ➨ 2 ⠇ ぬࢭࣥࢧࢆ⏝࠸ࡓࣞࣂ࣑ࣆࢻࡢⱞཬࡰࡍ㣧㣗≀ࡢᙳ㡪ࡢホ౯ ➨ 1 㡯 ┠ⓗ ᮏ⠇࡛ࡣ, ᮏ❶➨ 1 ⠇࡛㑅ᢥࡋࡓࣞࣂ࣑ࣆࢻࡢⱞホ౯᭷⏝࡛࠶ࡿࡇࡀ♧၀ࡉࢀࡓぬࢭࣥࢧ AE1 ⭷ࢆ⏝࠸࡚, ࣞࣂ࣑ࣆࢻࡢⱞࢆᢚไࡋ࠺ࡿ㣧㣗≀ࢆ᥈⣴ࡍࡿࡇࢆ┠ⓗࡋࡓ. ➨ 2 㡯 ᐇ㦂᪉ἲ 1. ヨ⸆ ࣞࣂ࣑ࣆࢻ⁐ᾮࡣ, ᮏ❶➨ 1 ⠇ྠᵝ, PBS ࢆ⁐፹ࡋ࡚ㄪ〇ࡋࡓ. ࣞࣂ࣑ࣆࢻ⁐ᾮΰྜࡍࡿ㣧㣗 ≀ࡋ࡚, ᕷ㈍ࡢ⥳Ⲕ (⏕Ⲕ; ࢟ࣜࣥᰴᘧ♫), ࢥࢥ (ࣂ࣮ࣥ࣍ࢸࣥࢥࢥࢡ࢜ࣜࢸ࣮ࢸࢫࢺ; ᰴᘧ♫᫂), ࢥ࣮ࣄ࣮ (࣎ࢫ㉕ἑᚤ⢾; ࢧࣥࢺ࣮࣮ࣜ࣍ࣝࢹࣥࢢࢫᰴᘧ♫), ჯỒ (࠶ࡉࡆ; ᰴ ᘧ♫Ọ㇂ᅬ) ࢆ⏝࠸ࡓ. 600 μg/mL ࡢࣞࣂ࣑ࣆࢻ⁐ᾮ, ྛ㣧㣗≀ࢆ⢭〇Ỉ࡛ 10, 5, 1 ಸᕼ㔘ࡋࡓヨᩱ ࢆయ✚ẚ 1:1 ࡢྜ࡛ΰྜࡋࡓヨᩱ (᭱⤊⃰ᗘ㸸ࣞࣂ࣑ࣆࢻ 300 μg/mL, ྛ㣧㣗≀ 5%, 10%, 50%) ࢆぬ ࢭࣥࢧ AE1 ⭷ࢆ⏝࠸࡚ ᐃࡋࡓ. 2. ぬࢭࣥࢧ ᮏ❶➨ 1 ⠇࡛, ࣞࣂ࣑ࣆࢻࡢⱞࡀぬࢭࣥࢧ AE1 ⭷ࡢ┦ᑐ್࡛ホ౯ࡋ࠺ࡿࡇࢆ♧ࡋࡓࡓࡵ, ᮏ⠇ ࡛ࡣ AE1 ⭷ࢆ⏝࠸࡚ࣞࣂ࣑ࣆࢻ㣧㣗≀ΰྜヨᩱࡢⱞࢆホ౯ࡋࡓ. ⱞᢚไホ౯ࡣ, 㣧㣗≀༢⊂࡛ ࡢࢭࣥࢧฟຊ್ࢆᇶ‽ࡋࡓ⿵㛫ᕪศ್ࢆ⏝࠸ࡓ. 3. ⤫ィฎ⌮ Fig. 24, 25 ♧ࡋࡓ⤖ᯝ࡛ࡣ, ࢹ࣮ࢱࡣᖹᆒ್ ± S.D.࡛⾲グࡋ, ࢚ࢡࢭࣝ⤫ィࢆ⏝࠸࡚ Tukey test ࡼ ࡿከ㔜㛫ࡢẚ㍑ࢆ⾜ࡗࡓ. 36 ➨ 3 㡯 ⤖ᯝ⪃ᐹ ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%୰ࡣࣞࣂ࣑ࣆࢻࡣ⣙ 300 μg/mL ⁐ゎࡋ࡚࠸ࡿࡇࡀ HPLC ἲࡼࡾ☜ㄆࡉ ࢀࡓࡓࡵ, ᮏ⠇࡛ࡣ, ࣞࣂ࣑ࣆࢻ⁐ᾮ 300 μg/mL ࡢⱞࡘ࠸࡚, 㣧㣗≀ࡼࡿⱞᢚไຠᯝࡢホ౯ࢆ ⾜ࡗࡓ. ྛ㣧㣗≀ࢆ, ᭱⤊⃰ᗘ 50%࡞ࡿࡼ࠺ࣞࣂ࣑ࣆࢻ⁐ᾮ (᭱⤊⃰ᗘ 300 μg/mL) ΰྜࡋࡓሙྜ, ⥳Ⲕࢆΰྜࡋࡓࣞࣂ࣑ࣆࢻ⁐ᾮࡢ⿵㛫ᕪศ್ࡣ, ࣞࣂ࣑ࣆࢻ⁐ᾮࡢࢭࣥࢧฟຊ್ࡰྠ➼ࡢ್ࢆ♧ࡋ ࡓࡀ, ჯỒ, ࢥࢥ, ࢥ࣮ࣄ࣮ࢆࡑࢀࡒࢀΰྜࡋࡓࣞࣂ࣑ࣆࢻ⁐ᾮࡢ⿵㛫ᕪศ್ࡣ, ࣞࣂ࣑ࣆࢻ⁐ᾮ ࡢࢭࣥࢧฟຊ್ẚ㍑ࡋ࡚᭷ពప࠸್ࢆ♧ࡋࡓ (Fig. 24). ྛ㣧㣗≀ (᭱⤊⃰ᗘ 50%) ࢆΰྜࡋࡓࣞࣂ ࣑ࣆࢻ⁐ᾮࡢ⿵㛫ᕪศ್, ࣞࣂ࣑ࣆࢻ⁐ᾮࡢࢭࣥࢧฟຊ್ࢆẚ㍑ࡋࡓ⤖ᯝ, ࢥ࣮ࣄ࣮, ჯỒ, ࢥࢥ , ⥳Ⲕࡢ㡰, ࡇࢀࡽࡣࣞࣂ࣑ࣆࢻ⁐ᾮࡢࢭࣥࢧฟຊ್ࢆᢚไࡍࡿࡇࡀ᫂ࡽ࡞ࡗࡓ (Fig. 25). Fig. 24 AE1 taste sensor output (vs each refreshments as control) of rebamipide (300 μg/mL) mixed with green tea (A), cocoa (B), coffee (C), miso soup (D) (0, 5, 10, 50%) **p<0.01, ***p<0.001 vs control (0%), ††p<0.01 (Tukey test). n=3, mean ± S.D. 37 Fig. 25 AE1 taste sensor output (vs each refreshments as control) of rebamipide (300 μg/mL) mixed with 50% refreshments *p<0.05, **p<0.01, ***p<0.001 vs control (water), ††p<0.01 (Tukey test). n=3, mean ± S.D. 38 ➨ 3 ⠇ ࣄࢺᐁ⬟ヨ㦂ࡼࡿࣞࣂ࣑ࣆࢻ㣧㣗≀ΰྜヨᩱࡢⱞホ౯ ➨ 1 㡯 ┠ⓗ ᮏ❶➨ 2 ⠇࡛, ぬࢭࣥࢧࢆ⏝࠸࡚ࣞࣂ࣑ࣆࢻࡢⱞࡀࢥ࣮ࣄ࣮ࡼࡾᢚไࡉࢀࡿࡇࡀண ࡉࢀࡓ ࡀ, ࡇࢀࢆ᳨ドࡍࡿࡓࡵࣄࢺᐁ⬟ヨ㦂ࢆ⾜ࡗࡓ. ➨ 2 㡯 ᐇ㦂᪉ἲ 1. ヨ⸆ ᮏ❶➨ 2 ⠇ྠᵝࡢヨ⸆ࢆ⏝࠸ࡓ. 2. ࣄࢺᐁ⬟ヨ㦂 ⱞࡢᶆ‽≀㉁࡛࠶ࡿ࢟ࢽ࣮ࢿሷ㓟ሷỈ⁐ᾮ 0.01, 0.03, 0.10, 0.30 mM ࡢⱞࢆࡑࢀࡒࢀⱞᙉᗘ τ 0, 1, 2, 3 ࡋࡓ. ࣃࢿ࣮ࣛ (4 ྡ) ࡣ, ⱞᙉᗘ τ 0㹼3 ࡢ࢟ࢽ࣮ࢿሷ㓟ሷỈ⁐ᾮࢆྛ 2 mL ཱྀ 5 ⛊㛫ྵࡳ, ⱞࢆグ᠈ࡋࡓ. ḟ, ヨ㦂ࢧࣥࣉࣝࢆྛ 2 mL ཱྀྵࡳ, ⱞᙉᗘࢆホ౯ࡋࡓ. ヨ㦂ࢧࣥࣉࣝࡣ, ࣞࣂ ࣑ࣆࢻ⁐ᾮ 600 μg/mL ྛ㣧㣗≀ (ᕼ㔘࡞ࡋ) ࢆయ✚ẚ 1:1 ࡛ΰྜࡋࡓヨᩱ (᭱⤊⃰ᗘ㸸ࣞࣂ࣑ࣆࢻ 300 μg/mL, ྛ㣧㣗≀ 50%) ࡋࡓ. ࣄࢺᐁ⬟ヨ㦂ࡣ, ṊᗜᕝዪᏊᏛ⌮ጤဨࡢᢎㄆࢆᚓࡓᚋ⾜ࡗࡓ (ᢎㄆ␒ྕ 12-37). 3. ⤫ィฎ⌮ Fig. 26 ♧ࡋࡓ⤖ᯝ࡛ࡣ, ࢹ࣮ࢱࡢᖹᆒ್ ± S.D.࡛⾲グࡋ, ࢚ࢡࢭࣝ⤫ィࢆ⏝࠸࡚ Tukey test ࡼࡾ ከ⩌㛫ࡢẚ㍑ࢆ⾜ࡗࡓ. Fig. 27 ♧ࡋࡓ⤖ᯝ࡛ࡣ, ࣄࢺᐁ⬟ヨ㦂⤖ᯝࢭࣥࢧฟຊ್ࡢ┦㛵ᛶࢆ☜ㄆࡍ ࡿࡓࡵ, ࢚ࢡࢭࣝ⤫ィࢆ⏝࠸࡚ Pearson’s correlation test ࢆ⾜ࡗࡓ. 39 ➨ 3 㡯 ⤖ᯝ⪃ᐹ ࣞࣂ࣑ࣆࢻ⁐ᾮࡢⱞᙉᗘࡣ τ 2.00 ± 0.70 ࡛࠶ࡗࡓ. ྛ㣧㣗≀ࢆΰྜࡋࡓࣞࣂ࣑ࣆࢻ⁐ᾮࡢⱞᙉᗘ ࡣ, ⥳Ⲕΰྜᾮ࡛ࡣ τ 2.50 ± 0.41, ࢥࢥΰྜᾮ࡛ࡣ τ 2.00 ± 0.00, ࢥ࣮ࣄ࣮ΰྜᾮ࡛ࡣ τ 1.88 ± 0.25 ࡛࠶ ࡗࡓ. ྛ㣧㣗≀ࢆΰྜࡋࡓࣞࣂ࣑ࣆࢻ⁐ᾮࡢⱞᙉᗘྛ㣧㣗≀ࡢࡳࡢⱞᙉᗘࡢᕪࡣ, 㣧㣗≀ࡀ⥳Ⲕ ࡢሙྜ 1.63 ± 0.48, ࢥࢥࡢሙྜ 1.50 ± 0.58, ࢥ࣮ࣄ࣮ࡢሙྜ 0.75 ± 0.87, ჯỒࡢሙྜ 1.25 ± 0.65 ࡛࠶ ࡗࡓ (Fig. 26). ぬࢭࣥࢧࡽᚓࡽࢀࡓྛ㣧㣗≀ࢆΰྜࡋࡓࣞࣂ࣑ࣆࢻ⁐ᾮࡢ⿵㛫ᕪศ್, ᐁ⬟ヨ㦂 ࡼࡿⱞᙉᗘ (τ) ࡢᕪ㹙㣧㣗≀ࢆΰྜࡋࡓࣞࣂ࣑ࣆࢻ⁐ᾮࡢⱞᙉᗘ (τ) 㸫㣧㣗≀ (50%) ࡢⱞᙉ ᗘ (τ)㹛 ࡢ㛫ࡣ㧗࠸┦㛵ࡀㄆࡵࡽࢀࡓ (r = 㸫0.989, Pearson’s correlation test) (Fig. 27). ᮏ᳨ウ࡛⏝࠸ࡓ 4 ✀ࡢ㣧㣗≀ࡢ࠺ࡕ, ࢥ࣮ࣄ࣮ࡀ᭱ࡶࣞࣂ࣑ࣆࢻࡢⱞࢆᢚไࡍࡿྍ⬟ᛶࡀ♧ࡉࢀࡓ. Fig. 26 Bitterness intensity of rebamipide with refreshments by human sensation test *p<0.05 vs control (water) (Tukey test). n=3, mean ± S.D. Fig. 27 Correlation between bitterness intensity of rebamipide with refreshments by human sensation test and taste sensor output ⱞࡣᇶᮏⓗᚷ㑊ࡉࢀࡿࡀ, ࢝ࣇ࢙ࣥࡢⱞࡣ㐺ᗘ࡞⃰ᗘ࡛࠶ࢀࡤࣄࢺႴዲࡉࢀࡿ࠸࠺ᛶ㉁ ࢆࡶࡘ 52) . ᮏ᳨ウ࠾ࡅࡿࣄࢺᐁ⬟ヨ㦂ࡢ⤖ᯝ, ࢥ࣮ࣄ࣮⮬యࡀⱞࢆ᭷ࡋ, ࢥ࣮ࣄ࣮ΰྜࡋࡓࣞࣂ ࣑ࣆࢻ⁐ᾮࡢⱞᙉᗘࢥ࣮ࣄ࣮༢⊂ࡢⱞᙉᗘࡢᕪࡀ 1 ᮍ‶࡛࠶ࡗࡓࡇࡽ, ࣞࣂ࣑ࣆࢻࡢⱞࡣ ࢥ࣮ࣄ࣮ࡢႴዲࡉࢀࡿⱞࡼࡾຠᯝⓗ࣐ࢫ࢟ࣥࢢࡉࢀࡿࡇࡀ⪃࠼ࡽࢀࡓ. ࡲࡓ, ࢥ࣮ࣄ࣮ࡢᡂศ 40 ࡢࢡࣟࣟࢤࣥ㓟ࡣ, ⱞࡔࡅ࡛࡞ࡃ㓟ࢆ࿊ࡍࡿࡇࡀ▱ࡽࢀ࡚࠾ࡾ 53) , ࡇࡢ㓟ࡼࡿࣞࣂ࣑ࣆࢻࡢ ⱞᢚไࡢྍ⬟ᛶࡶ⪃࠼ࡽࢀࡿ. ࡲࡓ, ࢥࢥࡸჯỒࡼࡿࣞࣂ࣑ࣆࢻࡢⱞᢚไຠᯝࡶ☜ㄆࡉࢀࡓ. ࢥࢥࣃ࢘ࢲ࣮ࡣ, ⸆ࡢⱞࢆ࣐ࢫ࢟ࣥࢢࡍࡿຠᯝࡀ⮫ᗋ࡛⤒㦂ⓗ☜ㄆࡉࢀ࡚࠸ࡿࡇࡽ, ཱྀ⭍ ෆᔂቯ㘄ࣞࣂ࣑ࣆࢻࢳࣙࢥࣞࢵࢺࡢㄪ〇ࡶ⏝ࡉࢀ࡚࠸ࡿ 54) . ჯỒࡣ, ⱞᢚไຠᯝࡀሗ࿌ࡉࢀ࡚ ࠸ࡿ㇋ᡂศࡢࣞࢩࢳࣥࡸ NaCl ࡀྵࡲࢀ, ࡇࢀࡽࡀࣞࣂ࣑ࣆࢻࡢⱞᢚไᐤࡍࡿࡇࡀ⪃࠼ࡽࢀ ࡿ. ࡋࡋ, ࢥ࣮ࣄ࣮ࡣࡇࢀࡽࢥࢥࡸჯỒࡼࡾࡶຠᯝࡀ࠶ࡿྍ⬟ᛶࡀ♧၀ࡉࢀࡓ. ᮏ᳨ウ࡛ࡣ, ᕼ㔘ࡋࡓ㣧㣗≀ࢆ⏝ࡋࡓࡓࡵ, 㣧㣗≀ࡢ࠾࠸ࡀཬࡰࡍࡢᙳ㡪ࡣᑡ࡞࠸⪃࠼ࡿ. ࡋࡋᐇ㝿ࡣ㣧㣗≀ࡼࡿ࠾࠸ࡶ, ࣞࣂ࣑ࣆࢻࡢⱞᢚไᐤࡍࡿࡇࡀ⪃࠼ࡽࢀࡿ. ཱྀ⭍ෆ ᗈࡀࡗࡓໝ࠸ศᏊࡀⓎࡋ࡚㰯⭍ෆ㐩ࡋࡓࡶࡢࡣ, ぬࡁࡃ㛵ࡍࡿゝࢃࢀ࡚࠾ࡾ ࣃ࢘ࢲ࣮ࡢໝ࠸ศᏊࡀࣞࣂ࣑ࣆࢻࡢⱞࢆᢚไࡍࡿࡇ ࢫຠᯝ, ࣐࢘ࢫ࡛ࡢࢫࢺࣞࢫ⦆స⏝ࢆ♧ࡋࡓࡇ 55) , ࢥࢥ 56) , ࢥ࣮ࣄ࣮ࡢⓎᡂศࡀ, ࣄࢺ࡛ࡢࣜࣛࢵࢡ 57) ࡀሗ࿌ࡉࢀ࡚࠸ࡿ. ࡲࡓ, 㤶ࡾࡀ㉳ࡉࡏࡿࡀ, ࡑࡢࢆቑᙉࡍࡿࡇࡶሗ࿌ࡉࢀ࡚࠸ࡿ 32, 58). ᮏ᳨ウ࡛⏝࠸ࡓ㣧㣗≀ࡢ࠺ࡕࣞࣂ࣑ࣆࢻࡢⱞࢆ᭱ࡶຠ ᯝⓗᢚไࡋࡓࢥ࣮ࣄ࣮ࡘ࠸࡚, ࡑࡢ㤶ࡾࡀࡉࡽࢥ࣮ࣄ࣮ࡢႴዲࡉࢀࡿࢆቑᙉࡍࡿࡇࡶ⪃࠼ࡽ ࢀ, 㤶ࡾࡢ୧㠃ࡽࡢࣞࣂ࣑ࣆࢻࡢⱞᢚไຠᯝࡀᮇᚅࡉࢀࡿ. ௨ୖ, ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%Ⅼ║ᚋࡢࣞࣂ࣑ࣆࢻࡼࡿⱞࢆ㍍ῶࡍࡿ㣧㣗≀ࡋ࡚, ᮏ᳨ウ࡛⏝ ࠸ࡓ 4 ✀ࡢ㣧㣗≀ࡢ୰࡛ࡣࢥ࣮ࣄ࣮ࡀ᭱ࡶ᭷ຠ࡛࠶ࡿࡇࡀ♧ࡉࢀࡓ. ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%ࡣ 1 ᪥ 4 ᅇⅬ║ࡍࡿᚲせࡀ࠶ࡿࡀ, Ⅼ║ࡋ࡚ࡽⱞࡀ⌧ࢀࡿࡲ࡛ࡢ㛫ࡣ ಶேᕪࡀ࠶ࡾ, Ⅼ║┤ᚋࡽᩘ㛫ゝࢃࢀ࡚࠸ࡿ. Ⅼ║ᚋ㛢▛ࡋ࡚ 1㹼5 ศ㛫ᾦᄞ㒊ࢆᅽ㏕ࡋ, ⸆ᾮ ࡀဗ㢌㒊ὶࢀࡿ㔞ࢆᢚไࡍࡿࡇࡼࡾⱞࢆ㜵ࡄࡇࡀ࡛ࡁࡿࡇࡀ᪤▱ࡽࢀ࡚࠸ࡿ. ᮏ᳨ウ⤖ ᯝࡼࡾ, ဗ㢌㒊ὶࢀ࡚ࡁࡓ୍㒊ࡢ⸆ᾮࡢⱞࢆᢚไࡍࡿࡓࡵࡣ, Ⅼ║ᚋࢥ࣮ࣄ࣮ࢆ㣧⏝ࡍࡿࡇ ࡀ᥎ዡࡉࢀࡿ. ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%Ⅼ║ᚋࢥ࣮ࣄ࣮ࢆ㣧⏝ࡍࢀࡤ, ဗ㢌㒊㐩ࡋࡓ⸆ࡀࢥ࣮ࣄ ࣮ΰྜࡉࢀ, ⸆ࡢⱞࡀࢥ࣮ࣄ࣮ࡼࡾᢚไࡉࢀࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀࡿ. 41 ➨ 4 ⠇ ᑠᣓ ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%ࡢ⸆࡛࠶ࡿࣞࣂ࣑ࣆࢻࡢⱞࡣぬࢭࣥࢧ AE1 ࢆ⏝࠸࡚ ᐃࡋ࠺ࡿࡇࢆ ᫂ࡽࡋࡓ. ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%⁐ゎࡋ࡚࠸ࡿࣞࣂ࣑ࣆࢻྠ➼⃰ᗘ࡛࠶ࡿ 300 μg/mL ࡢࣞࣂ࣑ ࣆࢻ⁐ᾮࡢ AE1 ࢭࣥࢧᛂ⟅್ࡣ, ⥳Ⲕ, ࢥࢥ, ࢥ࣮ࣄ࣮, ჯỒࡢ࠺ࡕ, ࢥ࣮ࣄ࣮ࡼࡗ࡚᭱ࡶᢚไࡉ ࢀࡿࡇࢆ᫂ࡽࡋࡓ. ࡉࡽ, ࣄࢺᐁ⬟ヨ㦂ࡼࡾࢥ࣮ࣄ࣮ࡼࡿࣞࣂ࣑ࣆࢻࡢⱞᢚไຠᯝࢆ☜ ㄆࡋࡓ. ࣞࣂ࣑ࣆࢻࡢⱞཬࡰࡍ㣧㣗≀ࡢᙳ㡪ࡘ࠸࡚ࡢぬࢭࣥࢧ ᐃ⤖ᯝࣄࢺᐁ⬟ヨ㦂⤖ᯝࡢ 㛫ࡣ㧗࠸┦㛵ᛶࢆㄆࡵࡓ. ௨ୖ, ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%Ⅼ║ࡣ, ࢥ࣮ࣄ࣮ࢆ㣧⏝ࡍࡿࡇࡼࡾ Ⅼ║ᚋࡢࣞࣂ࣑ࣆࢻࡼࡿⱞࢆ㍍ῶࡋ࠺ࡿࡇࢆ♧ࡋࡓ. 42 ➨ 4 ❶ ⥲ᣓ ᮏ◊✲࡛ࡣ, ་⸆ရ⮫ᗋ⏝⏕ࡌࡿᛌ࡞ࡸ࠾࠸ࡘ࠸࡚ホ౯ࡋ, ࡑࡢᨵၿ⟇ࢆ᳨ウࡋ࡚௨ୗ ࡢ⤖ᯝࢆᚓࡓ. 㸦㸯㸧 ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢⱞࡣ, 㓟ࢆ࿊ࡍࡿᯝᐇ⣔ࡢᑓ⏝ࣇ࣮ࣞࣂ࣮ (ࢵࣉ࣑ࣝࢵࢡ ࢫ, ࣇ࣮ࣝࢶ࣑ࢵࢡࢫ, ࣉ࣒࣑ࣛࢵࢡࢫ, ࣃࢼࢵࣉ࣑ࣝࢵࢡࢫ) ࡼࡾຠᯝⓗᢚไࡉࢀࡿࡀ, ᑓ⏝ࣇ࣮ࣞࣂ࣮ࡢ᭷↓ࢃࡽࡎ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ ᗘࢆపࡃࡍࡿࡇࡼࡗ࡚ࡶ ⱞࡣ᭷ពᢚไࡉࢀࡿࡇࢆ᫂ࡽࡋࡓ. ࣑ࣀࣞࣂࣥ ®EN 㓄ྜᩓᠱ⃮ᾮࡢⱞࡢཎᅉ࡛࠶ࡿ BCAA ΰྜỈ⁐ᾮࡢⱞࡣ, 㓟ప ࢆ⤌ࡳྜࢃࡏࡿࡇࡼࡾ, ┦ຍⓗᢚไࡉࢀࡿࡇࢆ᫂ࡽ ࡋࡓ. ௨ୖ, ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓ᭹⏝ࡣ, 㓟ࡢ࠶ࡿᑓ⏝ࣇ࣮ࣞࣂ࣮ࢆ㑅ᢥࡋ, ᠱ⃮ᾮࢆ෭ ࡸࡋ࡚᭹⏝ࡍࡿࡇࡀ, ᭹⏝ࡢᛌ࡞ⱞࢆ㍍ῶࡍࡿࡓࡵ᭱ࡶຠᯝⓗ࡛࠶ࡿࡇࢆ᫂ࡽࡋࡓ. 㸦㸰㸧 ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ࡣᛌឤࢆ࠼ࡿࡇࡀ♧၀ࡉࢀ, ᭹⏝ᛶࢆᝏࡃࡍࡿ せᅉ࡞ࡾ࠺ࡿࡇࡀ⪃࠼ࡽࢀࡓ. ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢ࠾࠸ࡣ, ⏑ࡸ㓟ࢆ㉳ࡉࡏࡿᑓ⏝ ࣇ࣮ࣞࣂ࣮ࡼࡾᢚไࡉࢀࡿࡇࢆ᫂ࡽࡋࡓ. ࡲࡓ, ࠾࠸ࢭࣥࢧࡣࣄࢺࡢႥぬྠ⛬ᗘࡢ࠾࠸ ឤᗘࢆ♧ࡍࡇࢆ᫂ࡽࡋࡓ. ᑓ⏝ࣇ࣮ࣞࣂ࣮ࡢ࠺ࡕ, 㓟ࢆ㉳ࡉࡏࡿࣃࢼࢵࣉࣝࡢࣇ࣮ࣞࣂ࣮ ࡀ᭱ࡶ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓᠱ⃮ᾮࡢ࠾࠸ࢆ࣐ࢫ࢟ࣥࢢࡍࡿࡇࢆ, ࣄࢺᐁ⬟ヨ㦂࠾࠸ࢭࣥࢧ ࢆ⏝࠸ࡓホ౯ࡼࡾ᫂ࡽࡋࡓ. 㸦㸱㸧 ࣋ࢩࢣ®㘄, ࣋ࢩࢣ®OD 㘄⢊○ࡢⱞࡘ࠸࡚, ࣋ࢩࢣ®㘄ࡣ, ⢊○⛬ᗘࢃࡽࡎ ⱞࢆ࿊ࡍࡿࡇࢆ♧ࡋࡓ. ୍᪉࣋ࢩࢣ®OD 㘄ࡣ, ⢏ᚄ 100 μm ௨ୖ 500 μm ᮍ‶࡞ࡿࡼ࠺ᙅࡃ⢊ ○ࡍࡿሙྜ, ⸆≀ࢥࢆྵࡴᚤ⢏Ꮚࢥ࣮ࢸࣥࢢࡣ◚ቯࡉࢀࡎⱞ࣐ࢫ࢟ࣥࢢࢩࢫࢸ࣒ࡀಖࡓࢀࡿࡇ ࢆ᫂ࡽࡋࡓ. 43 㸦㸲㸧 ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%Ⅼ║ᚋࡢⱞᢚไ᭷ຠ࡞㣧㣗≀ࡢ᥈⣴ࢆ⾜࠺ࡓࡵ, ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%ࡢ⸆࡛࠶ࡿࣞࣂ࣑ࣆࢻࡢⱞࢆ, ぬࢭࣥࢧࢆ⏝࠸࡚ホ౯ࡋࡓ. ࣞࣂ࣑ࣆࢻࡢⱞࡣぬࢭࣥ ࢧ AE1 ࢆ⏝࠸࡚ホ౯ࡋ࠺ࡿࡇࡀ♧၀ࡉࢀ, ࡇࡢࢭࣥࢧࢆ⏝࠸ࡓⱞホ౯ࣄࢺᐁ⬟ヨ㦂⤖ᯝࡼࡾ, ࣞ ࣂ࣑ࣆࢻࡢⱞࡣ⥳Ⲕ, ࢥࢥ, ࢥ࣮ࣄ࣮, ჯỒࡢ୰࡛ࡣ, ࢥ࣮ࣄ࣮ࡼࡾ᭱ࡶ࣐ࢫ࢟ࣥࢢࡉࢀࡿࡇ ࢆ᫂ࡽࡋࡓ. ࣑ࣀࣞࣂࣥ®EN 㓄ྜᩓࡢࡼ࠺, ᭹⏝ཱྀ⭍ෆᗈࡀࡿᩓࡢࡣ᭹⏝ᛶࡁࡃᙳ㡪ࡍࡿ. ᭹ ⸆ࢥࣥࣉࣛࣥࢫࢆ㧗ࡵࡿࡓࡵࡣ, ⸆ᖌഃࡽ, ⸆ࡢຠᯝࡔࡅ࡛࡞ࡃ, ࣇ࣮ࣞࣂ࣮ࡢῧຍࡸ᭹ ⏝ࡢᠱ⃮ᾮ ᗘὀពࡍࡿࡇ࡛, 〇ࡢⱞࢆ㍍ῶ࡛ࡁࡿࡇ➼, ᭹⸆ୖࡢᕤኵࡘ࠸࡚ࡢሗᥦ ౪ࢆ⾜࠺ࡇࡀᚲせ࡛࠶ࡿ. ࡲࡓ࣋ࢩࢣ®OD 㘄ࡢࡢࡼ࠺, 㘄ࡢ⢊○⛬ᗘࡀ᭹⸆ࡢⱞࡢ⛬ᗘᙳ㡪ࡍࡿࡇࡀ࠶ࡿࡓࡵ, ⸆ᖌࡀㄪୖࡢᕤኵࢆ⾜࠺ࡇࡼࡾ, ᝈ⪅ࡢ᭹⸆ࢥࣥࣉࣛࣥࢫࢆྥୖࡉࡏࡿࡇࡀ࡛ࡁࡿሙྜ ࡶ࠶ࡿ. ࡉࡽ, ᩓࡸ㘄➼ࡢෆ᭹⸆ࡔࡅ࡛࡞ࡃ, ࣒ࢥࢫࢱ®Ⅼ║ᾮ UD2%ࡢࡼ࠺࡞Ⅼ║ࡶ, Ⅼ║ᚋⱞ ࢆ࿊ࡍࡿࡇࡀ࠶ࡿ. ⸆ᖌࡣࡇࡢࡼ࠺࡞⸆ሗࢆᢕᥱࡋ࡚࠾ࡃᚲせࡀ࠶ࡾ, ࡉࡽࡑࡢᑐฎἲࢆᥦ ࡛ࡁࡿࡇࡀᮃࡲࢀࡿ. ་⸆ရ⮫ᗋ⏝ࡢ᭹⏝ᛶᙳ㡪ࡋ, ࡑࡢ᭹⸆ࢥࣥࣉࣛࣥࢫࢆపୗࡉࡏࡿཎᅉ࡛࠶ࡿ⸆ࡢࡸ ࠾࠸ࡘ࠸࡚ホ౯ࡋࡓᮏ◊✲ࡽᚓࡽࢀࡓሗࡣ, ⸆ᖌࡀᝈ⪅ࡢ᭹⸆ࢥࣥࣉࣛࣥࢫྥୖࡢࡓࡵ ࡢ࢚ࣅࢹࣥࢫᇶ࡙࠸ࡓ⸆⟶⌮ᣦᑟᴗົࢆ⾜ࡗ࡚࠸ࡃୖ࡛᭷⏝࡛࠶ࡿ⪃࠼ࡿ. 44 ㅰ㎡ ◊✲ࢆ㐍ࡵ, ᮏㄽᩥࢆࡲࡵࡿ࠶ࡓࡾ, ࡈ᠓⠜࡞ࡿࡈᩍ♧, ࡈ㧗㓄ࢆ㈷ࡾࡲࡋࡓ ṊᗜᕝዪᏊᏛ ⸆Ꮫ㒊 ⮫ᗋ〇Ꮫ◊✲ᐊ ෆ⏣ ாᘯ ᩍᤵ῝⏒࡞ࡿឤㅰࡢពࢆ⾲ࡋࡲࡍ㸬 ࡲࡓ, ᮏㄽᩥࢆࡲࡵࡿ࠶ࡓࡾ, ᩘࠎࡢ᭷┈࡞ࡈᣦᑟ, ࡈᩍ♧ࢆ㈷ࡾࡲࡋࡓ ṊᗜᕝዪᏊᏛ ⸆Ꮫ㒊 ⮫ᗋ⸆Ꮫᩍ⫱ࢭࣥࢱ࣮ ∦ᒸ ୕㑻 ᩍᤵ, ṊᗜᕝዪᏊᏛ ⸆Ꮫ㒊 ⮫ᗋ⸆Ꮫ◊✲ᐊ ᒸᮧ ᪼ ᩍᤵ, ṊᗜᕝዪᏊᏛ ⸆Ꮫ㒊 ែ⏕⌮Ꮫ◊✲ᐊ ୕ᮌ ▱༤ ᩍᤵ, ṊᗜᕝዪᏊᏛ ⸆Ꮫ㒊 ⮫ᗋែゎᯒᏛ◊✲ᐊ ᳃ᒣ ㈼ ᩍᤵ῝⏒࡞ࡿឤㅰࡢពࢆ⾲ࡋࡲࡍ. ࡲࡓ, ᮏ◊✲㐙⾜࠶ࡓࡾ, ⤊ጞࡈ༠ຊࢆ㈷ࡾ, ᩘࠎࡢ᭷┈࡞ࡈຓゝ,ࡈᨭࢆ㈷ࡾࡲࡋࡓ ṊᗜᕝዪᏊᏛ ⸆Ꮫ㒊 ⮫ᗋ〇Ꮫ◊✲ᐊ ྜྷ⏣ 㒔 ㅮᖌ, Ḁᕝ ⯙ ຓᩍ῝⏒࡞ࡿឤㅰࡢពࢆ ⾲ࡋࡲࡍ. ࡉࡽ, ᐇ㦂࠾ࡼࡧ㆟ㄽࢆඹࡋ, ᮏㄽᩥసᡂ㝿ࡋ࡚ከ࡞ࡈ༠ຊ࠸ࡓࡔࡁࡲࡋࡓ ṊᗜᕝዪᏊᏛ ⸆Ꮫ㒊 ⮫ᗋ〇Ꮫ◊✲ᐊࡢ㝔⏕, Ꮫ⏕, ◊✲⏕, ༞ᴗ⏕ࡢⓙᵝ῝ㅰ࠸ࡓࡋࡲࡍ. 45 ཧ⪃ᩥ⊩ 1) Dolder C R, Lacro J P, Leckband S, Jeste D V, J Clin Psychopharmacol, 23, 389-399 (2003) 2) Tensho M, Saitoh K, Hashimoto Y, Sawa Y, ᪥⸆ㄅ, 44, 767-769 (2008) 3) Natori N, Hanawa K, Suzuki M, Hanawa T, Oguchi T, Jpn. 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