JP2017515875A - 高血糖障害の処置のための生物学的活性物質の組み合わせ - Google Patents
高血糖障害の処置のための生物学的活性物質の組み合わせ Download PDFInfo
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- BUEBVQCTEJTADB-IGQSMMPPSA-N sambubiose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)CO1 BUEBVQCTEJTADB-IGQSMMPPSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- PCMORTLOPMLEFB-ONEGZZNKSA-N sinapic acid Chemical group COC1=CC(\C=C\C(O)=O)=CC(OC)=C1O PCMORTLOPMLEFB-ONEGZZNKSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- PZDOWFGHCNHPQD-VNNZMYODSA-N sophorose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O PZDOWFGHCNHPQD-VNNZMYODSA-N 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 150000004044 tetrasaccharides Chemical class 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- NGSWKAQJJWESNS-ZZXKWVIFSA-N trans-4-coumaric acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- LNRUEZIDUKQGRH-YZUCMPLFSA-N umbelliferose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 LNRUEZIDUKQGRH-YZUCMPLFSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- AFVLVVWMAFSXCK-UHFFFAOYSA-N α-cyano-4-hydroxycinnamic acid Chemical compound OC(=O)C(C#N)=CC1=CC=C(O)C=C1 AFVLVVWMAFSXCK-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- FYGDTMLNYKFZSV-BYLHFPJWSA-N β-1,4-galactotrioside 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]2[C@@H](O[C@@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-BYLHFPJWSA-N 0.000 description 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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Abstract
Description
OH基の1つを介してなされることが特に好ましい。フラボノール中の位置のナンバリングは、以下の式IIに示されているように、一般に公知の化学命名法に従う:
のOH基の1つを介して結合され得る。
ルチノシド(ケルセチン−3−O−グルコラムノシド)、ケンペロール−3,7−ジ−O−α−L−ラムノシド、ケンペロール−3−(2G−キシロシルルチノシド)、3−グルコシル−ケルセチン、3−グルコシル−ケンペロール、ジヒドロケンペロール−3−ラムノシド、ケルセチン−3,4−O−グルコシド、4’−メチル−ケンペロール、ケンペロ
ール−3−O−フェルロイル−ジグルコシド−7−O−グルコシド、ケンペロール−3−O−ヒドロキシフェルロイル−ジグルコシド、ケンペロール−3−O−ジシナポイル−トリグルコシド−7−O−ジグルコシド、ケンペロール−3−O−シナポイル−トリグルコシド、ケンペロール−3−O−シナポイル−ジグルコシド、ケンペロール−3−O−ジシナポイル−トリグルコシド−7−O−グルコシド、ケンペロール−3−O−ジグルコシド−7−O−ジグルコシド、ケンペロール−3−O−トリグルコシド−7−O−グルコシド、ケンペロール−3−O−グルコシド−7−O−グルコシド、ケンペロール−3−O−トリグルコシド、ケンペロール−3−O−ジグルコシド、ケンペロール−3−O−グルコシドなどの1つであり得る。
The Science and Practice of Pharmacy”,Li
ppincott Williams&Wilkins;21st Edition(2005)に記載されている。前記医薬組成物は、例えば、顆粒、粉末、錠剤、カプセル、シロップ、坐剤、注射剤、エマルジョン、懸濁液または溶液の形態を有し得る。前記組成物は、様々な投与経路のために、例えば、経口投与、非経口投与、局所投与、口腔投与、舌下投与、経粘膜投与、直腸投与、皮下投与、髄腔内投与、静脈内投与、筋肉内投与、腹腔内投与、鼻内投与、眼内投与または脳室内投与のために製剤化され得る。経口、非経口または局所用組成物としての製剤が特に好ましい。特に好ましい実施形態では、前記組成物は、経口投与のために製剤化される。前記医薬組成物はまた、徐放剤として製剤化され得る。
nce and Practice of Pharmacy”,Lippincott
Williams&Wilkins;21st Edition(2005)に記載されている。例えば、微結晶セルロース、メチルセルロース、ヒドロキシプロピルメチルセルロース、カゼイン、アルブミン、マンニトール、デキストラン、スクロース、ラクトース、ソルビトール、デンプン、寒天、アルギン酸塩、ペクチン、コラーゲン、グリセリドまたはゼラチンが、添加剤または賦形剤として使用され得る。また、経口投与のための組成物は、抗酸化剤(例えば、アスコルビン酸、トコフェロールまたはシステイン)、滑沢剤(例えば、ステアリン酸マグネシウム)、保存剤(例えば、パラベンまたはソルビン酸)、風味増強剤、崩壊剤、結合剤、増粘剤、色素および類似物質を含む。
様々なケルセチンおよびケンペロール誘導体を、ラクターゼフロリジンヒドロラーゼ(LPH)の阻害剤としてインビトロで試験した。Amiri et al.(2012,J Inherit Metab Dis,35(6):949−54)にしたがって、試験を行った。ここでは、LPHを発現するヒト小腸の組織(0.6mg/ml)を使用した。フロリジン二水和物は、基質としての役割を果たした。標準的なアッセイ(Chu&Cheung,1978,Clin Biochem,11(4):187−9)を使用して、放出されたグルコースを測定した。
試験したケルセチンおよびケンペロール誘導体は、LPHに対する高い阻害活性を示し、LPHを濃度依存的に阻害することができた(表1)。ケルセチン−7−グルコシドおよびケンペロール−7−O−グルコシドは、50mg/mlの濃度で、特に強い約70%のLPH阻害を示した。
SGLT1トランスポーターによるグルコース取り込みに対するフロリジンおよびLPH阻害剤の組み合わせの効果を、ヒト腸内の状況をシミュレートするエクスビボモデルを用いて試験した。エクスビボ試験モデルは、ラクターゼフロリジンヒドロラーゼ(LPH)を発現するヒト小腸由来の組織を使用するので、フロリジンおよび他のグリコシドを切断することができる。続いて、このように前処理した反応バッチを、インビトロアッセイにおいて、SGLT1トランスポーターに対する阻害効果について試験した。
フロリジンおよび試験LPH阻害剤は、SGLTの活性を相乗的に減少させることが示された。表2は、元の活性の阻害率に対する各値によって、試験化合物による阻害を示す。驚くべきことに、フロリジンおよび試験LPH阻害剤ケンペロール−7−O−グルコシドまたはケルセチン−7−グルコシドの組み合わせはそれぞれ、個々の物質の合計よりも有意に強く、SGLTの活性を減少させることができた(例えば、バッチAを参照のこと)。各場合において、フロリジン、ケルセチン−7−グルコシドおよびケンペロール−7−O−グルコシドは単独で、グルコース取り込みを32%、2%または2.5%減少させた一方、フロリジンおよびケルセチン−7−グルコシドの組み合わせ、ならびにフロリジンおよびケンペロール−7−O−グルコシドの組み合わせはそれぞれ、グルコース取り込みを48%および52%減少させることができた。
Claims (13)
- 前記阻害剤のグリコシド結合基が、前記フラボノールの3位または7位に位置し、前記グリコシド結合基が、好ましくはβ−グリコシド結合である、請求項1に記載の組成物。
- 前記糖基がグルコース基である、請求項1〜2に記載の組成物。
- 前記フラボノールの3位または7位のグリコシド結合基の他に、さらなるグリコシド結合基が存在しない、請求項2〜3に記載の組成物。
- 前記ラクターゼフロリジンヒドロラーゼ阻害剤が、ケルセチン−7−O−グルコシドおよびケンペロール−7−O−グルコシドからなる群より選択される、請求項4に記載の組成物。
- 0.01〜10gのフロリジンを含む、請求項1〜5のいずれか一項に記載の組成物。
- 0.01〜10gの前記ラクターゼフロリジンヒドロラーゼ阻害剤を含む、請求項1〜6のいずれか一項に記載の組成物。
- 高血糖疾患の処置および/または予防のための方法に使用するための請求項1〜7のいずれかに記載の組成物であり、前記疾患が、好ましくは、肥満症、糖尿病、または糖尿病によって引き起こされる二次疾患からなる群より選択される、組成物。
- 医薬組成物、ダイエットフードまたはフードサプリメントを調製するための、請求項1〜7のいずれか一項に記載の組成物の使用。
- 請求項1〜7のいずれかに記載の組成物を含む、医薬組成物、ダイエットフードまたはフードサプリメント。
- 請求項1〜7のいずれかに記載の組成物を含み、好ましくは肥満、糖尿病、糖尿病によって引き起こされる二次疾患からなる群より選択される高血糖疾患の処置および/または予防のための方法に使用するための医薬組成物、ダイエットフードまたはフードサプリメント。
- 前記糖尿病がII型糖尿病である、請求項8に記載の使用のための組成物、または請求項11に記載の医薬組成物、ダイエットフードもしくはダイエットサプリメント。
- 経口投与、非経口投与または局所投与のために製剤化されていることを特徴とする、請求項10に記載の医薬組成物、または請求項11もしくは12に記載の医薬組成物。
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- 2014-05-16 EP EP14168754.1A patent/EP2944311A1/de not_active Withdrawn
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2015
- 2015-05-15 EP EP15724579.6A patent/EP3142671B1/de active Active
- 2015-05-15 CA CA2963025A patent/CA2963025A1/en not_active Abandoned
- 2015-05-15 ES ES15724579T patent/ES2908961T3/es active Active
- 2015-05-15 CN CN201580036496.0A patent/CN107073026B/zh active Active
- 2015-05-15 US US15/311,747 patent/US10213450B2/en active Active
- 2015-05-15 JP JP2016568550A patent/JP6711763B2/ja active Active
- 2015-05-15 WO PCT/EP2015/060743 patent/WO2015173383A1/de active Application Filing
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KR101939151B1 (ko) * | 2017-09-05 | 2019-01-16 | 대구대학교 산학협력단 | 플라즈마 처리된 플로리진 반응물을 유효성분으로 함유하는 대사성 질환의 예방, 개선 또는 치료용 조성물 |
Also Published As
Publication number | Publication date |
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ES2908961T3 (es) | 2022-05-04 |
CN107073026A (zh) | 2017-08-18 |
WO2015173383A1 (de) | 2015-11-19 |
EP3142671A1 (de) | 2017-03-22 |
EP3142671B1 (de) | 2021-12-22 |
EP2944311A1 (de) | 2015-11-18 |
US20170080005A1 (en) | 2017-03-23 |
CN107073026B (zh) | 2020-09-25 |
CA2963025A1 (en) | 2015-11-19 |
US10213450B2 (en) | 2019-02-26 |
JP6711763B2 (ja) | 2020-06-17 |
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