WO2018212362A1 - 糖質の分解・吸収抑制剤 - Google Patents
糖質の分解・吸収抑制剤 Download PDFInfo
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- WO2018212362A1 WO2018212362A1 PCT/JP2018/019914 JP2018019914W WO2018212362A1 WO 2018212362 A1 WO2018212362 A1 WO 2018212362A1 JP 2018019914 W JP2018019914 W JP 2018019914W WO 2018212362 A1 WO2018212362 A1 WO 2018212362A1
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- extract
- glucose
- cells
- absorption
- dmso
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/13—Coniferophyta (gymnosperms)
- A61K36/15—Pinaceae (Pine family), e.g. pine or cedar
-
- 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
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
-
- 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
-
- 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
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/02—Medicinal preparations containing materials or reaction products thereof with undetermined constitution from inanimate materials
- A61K35/10—Peat; Amber; Turf; Humus
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- 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
Definitions
- the present invention relates to an ⁇ -glucosidase activity inhibitor and / or a glucose absorption inhibitor containing koji extract.
- Amber is a fossil made mainly from a resin of a pine genus plant that has been buried underground for a long period of time, and its powder has been used as a traditional Chinese medicine since ancient times. It mainly contains resin, essential oil, succinic acid, etc., and dissolves in a small amount in ethanol, diethyl ether or benzene (see, for example, Non-Patent Document 1).
- Japan it is well known as a jewelery, but in recent years, examples of using powders and extracts for cosmetics and health foods are increasing.
- a technique for improving the skin feel by blending wrinkle powder into cosmetics see, for example, Patent Document 1
- a technique for blending wrinkle extract in a skin external preparation for example, see Patent Document 2, Patent Document 3
- Technology that uses the whitening effect of hot water extract see, for example, Patent Literature 4 and Patent Literature 5
- Technology that uses a skin turnover promoting factor in the salmon extract fraction see, for example, Patent Literature 6
- a technique using the skin-farming effect of the skin in the cocoon extract see, for example, Patent Document 7
- a technique using a hyaluronic acid production promoting factor in the cocoon extract fraction see, for example, Patent Document 8
- a technique using an angiogenesis-promoting factor in a sputum extract fraction for example, see Patent Document 9 is known.
- JP 2004-83478 A JP H9-227334 JP 2001-131048 A JP 2010-235551 A JP 2012-240967 A JP 2007-314522 A JP 2008-189669 A JP 2008-266260 A JP2011-256164A JP-A-6-62798
- An object of the present invention is to provide an ⁇ -glucosidase activity inhibitor and / or a glucose absorption inhibitor that can be incorporated into foods and drinks that are easy to ingest daily.
- the present inventors have found an ⁇ -glucosidase activity inhibitory effect and / or a glucose absorption inhibitory effect in the koji extract and have completed the present invention. That is, the present invention is as follows. ⁇ 1> An ⁇ -glucosidase activity inhibitor containing a koji extract. ⁇ 2> A glucose absorption inhibitor comprising a koji extract. ⁇ 3> The agent according to ⁇ 1> or ⁇ 2>, wherein the extraction solvent for producing the koji extract is a hydrous alcohol (water content: 1% by mass to 60% by mass).
- ⁇ 4> An oral administration composition comprising one or more of the agents according to any one of ⁇ 1> to ⁇ 3>.
- ⁇ 5> The orally administered composition according to ⁇ 4>, wherein the aspect is a pharmaceutical product, quasi drug, food or drink, or food additive.
- the present invention is an ⁇ -glucosidase activity inhibitor and / or a glucose absorption inhibitor containing koji extract.
- These ⁇ -glucosidase activity inhibitors and / or glucose absorption inhibitors suppress the activity of ⁇ -glucosidase localized on the small intestinal epithelium and suppress the degradation of carbohydrates, and / or from the small intestinal epithelial cells. By suppressing glucose absorption, carbohydrate absorption can be suppressed and / or delayed.
- the ⁇ -glucosidase activity inhibitor and / or glucose absorption inhibitor of the present invention is characterized by containing a koji extract as an active ingredient.
- the cocoon extract as used in the present invention is the cocoon itself, a processed product obtained by pulverizing or chopping the cocoon, an extract obtained by adding a solvent to the cocoon or the processed product, and an extraction obtained by removing the solvent from the extract. Examples of these products include solvent-removed products, purified products thereof, and the like. Among these, extracts or their solvent-removed products are particularly preferred.
- the solvent for the extract examples include water, alcohol such as methanol, ethanol, 1,3-butanediol, propylene glycol, and glycerin, esters such as ethyl acetate and methyl formate, nitriles such as acetonitrile, diethyl ether, Examples include ethers such as tetrahydrofuran, halogenated hydrocarbons such as chloroform and methylene chloride, ketones such as acetone and methyl ethyl ketone, and these may be used alone or in combination. Among these, water or alcohols are preferable, and water-containing alcohol is more preferable. Further, ethanol is preferable as the alcohol.
- the water content is preferably 1% by mass to 60% by mass, more preferably 10% by mass to 50% by mass. Even if it is higher or lower than this, the extraction efficiency may deteriorate.
- the extraction may be performed by adding 2 to 20 times the amount of solvent to the pulverized koji and immersing it for several days at room temperature and for several hours at a temperature near the boiling point. Thereafter, insoluble matters may be removed by filtration or the like, followed by concentration under reduced pressure. Alternatively, it may be purified by column chromatography on a column packed with silica gel, octadecylsilylated silica gel, ion exchange resin or the like.
- Production Example 1 100 g of koji powder was extracted with 50% ethanol, concentrated under reduced pressure, and lyophilized to obtain 10 g of 50% ethanol extract.
- the extract is added to a human colon cancer-derived cell (hereinafter referred to as Caco-2 cell) and cultured, and then the cell is recovered. Then, a method can be used in which the crude enzyme solution is reacted with sucrose and maltose as substrates, and the amount of glucose produced is quantified by an enzymatic method using glucose oxidase.
- glucose and an extract were simultaneously added to Caco-2 cells differentiated in the intestinal epithelium, and the amount of glucose taken into or permeated through the cells was determined using glucose oxidase.
- a method of quantifying by the enzyme method used can be used.
- beverages containing the extract of the present invention include tea beverages, coffee beverages, soft drinks, alcoholic beverages, milk beverages, carbonated beverages, health beverages, nutritional drinks, sports drinks and the like, concentrated stock solutions and prepared powders of these beverages, etc.
- food include gum, candy, jelly, tablet confectionery, health food, nutritional supplement, supplement and the like.
- the extract of the present invention When the extract of the present invention is used as a medicine such as a diabetes preventive drug, it is provided in the form of powder, granule, tablet, capsule, liquid, injection or the like.
- the extract of the present invention can be administered orally as it is or diluted with water or the like. Alternatively, it is prepared by formulating it with a known pharmaceutical carrier.
- the extract of the present invention is processed into an oral liquid preparation such as a syrup or processed into an extract or a powder and blended with a pharmaceutically acceptable carrier to obtain an oral form such as a tablet, capsule, granule or powder. It can be administered as a solid formulation.
- the pharmaceutically acceptable carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations, solvents, excipients in liquid preparations, Formulated as a suspending agent, binder, and the like.
- formulation additives such as preservatives, antioxidants, colorants, sweeteners, and the like can be used as necessary.
- the food / beverage product or the pharmaceutical composition containing the extract of the present invention can contain the extract of the present invention at an arbitrary concentration.
- the extract of the present invention is contained at a concentration of 1 to 100 ⁇ g / ml, more preferably 5 to 50 ⁇ g / ml. Effective doses can be appropriately determined depending on the age and weight of the patient, the type and severity of the disease, and the route of administration.
- Example 1 Sucrase and maltase activity inhibition test This test was based on the method of OGAWA et al. (N. Ogawa et al., The Journal Of Nutrition, 130: 507-513, 2000).
- DMEM Dulbecco's modified Eagle's medium
- FBS bovine serum
- Caco-2 cells are suspended in a culture solution (hereinafter referred to as DMEM medium) supplemented with a mixture of Wako (manufactured by wako) and a 1% non-essential amino acid mixture (MEM Non-Essential Amino Acids) (manufactured by Thermo Fisher Scientific).
- DMEM medium a culture solution
- Wako manufactured by wako
- MEM Non-Essential Amino Acids manufactured by Thermo Fisher Scientific
- DMSO dimethyl sulfoxide
- control obtained by treating a culture solution obtained by adding DMSO to a DMEM medium to a final DMSO concentration of 0.25%
- control a control obtained by adding DMSO to a DMEM medium to a final DMSO concentration of 0.25%
- ACA acarbose
- a culture solution (DMSO final concentration: 0.25%) mixed in DMEM medium was used as a positive control.
- sucrase and maltase activity suppression test was implemented also about the considerable amount of succinic acid contained in the koji extract.
- the succinic acid content of the koji extract of Production Example 1 is calculated using an analysis / preparative high performance liquid chromatography apparatus and a Fourier transform infrared spectrophotometer, and the succinic acid content is 2% or less. I confirmed that there was. Therefore, succinic acid was dissolved in DMSO to a final concentration of 2, 5 and 25 ⁇ g / mL and treated with DMEM medium (DMSO final concentration: 0.25%). These plates were cultured for 7 days at 37 ° C. under 95% air-5% carbon dioxide.
- Sucrase activity or maltase activity was calculated based on the amount of glucose produced. And the relative change in a sample addition sample when the enzyme activity of a control sample was set to 100 was computed. Table 1 shows the results of measuring sucrase and maltase activity.
- the sputum extract of the present invention showed a strong inhibitory action on sucrase activity and maltase activity in Caco-2 cells.
- Caco-2 cells treated with a considerable amount of succinic acid contained in the koji extract no inhibitory effect was confirmed for both sucrase activity and maltase activity.
- the sputum extract of the present invention contains a component that suppresses sucrase activity and maltase activity of Caco-2 cells, but that component is a compound or mixture other than succinic acid.
- Example 2 mRNA expression inhibition test of sucrase-isomaltase complex Caco-2 cells were suspended in DMEM medium, and a dish having a diameter of 4 cm so as to be 1.0 ⁇ 10 4 cells / cm 2 (manufactured by TPP) Sowing. The culture was carried out at 37 ° C. under 95% air-5% carbon dioxide gas, and the medium was changed every 2 to 3 days and cultured for 10 days until it became confluent.
- RNA amount was determined by absorbance at 260 nm using a nanoscale spectrophotometer (Nano 200). Subsequently, RT reaction was performed based on this total RNA using PrimeScript TM RT reagent Kit (manufactured by Takara Bio Inc.) according to the package insert. Furthermore, using SYBR (trademark) Premix Ex Taq TM II (manufactured by Takara Bio Inc.), a reaction solution was prepared according to the package insert. This reaction solution was reacted with a sucrase-isomaltase complex (hereinafter referred to as SI) and each of GAPDH primers (manufactured by Thermo Fisher Scientific) by a Quantitative RT-PCR method.
- SI sucrase-isomaltase complex
- GAPDH primers manufactured by Thermo Fisher Scientific
- Example 3 SI protein expression suppression test Caco-2 cells were suspended in DMEM medium, and seeded in a dish (manufactured by TPP) having a diameter of 4 cm so as to be 1.0 ⁇ 10 4 cells / cm 2 . The cells were cultured at 37 ° C.
- the cells were collected with RIPA Buffer (manufactured by PCC) and then centrifuged (10,000 ⁇ g) at 4 ° C. for 15 minutes, and the supernatant was collected. The total protein amount was determined from the absorbance at 595 nm using Bradford reagent (Bio-rad). Subsequently, polyacrylamide electrophoresis was performed according to a conventional method, and the protein was transferred to a polyvinylidene difluoride membrane (manufactured by Bio-rad).
- mouse anti-human SI (A-12) antibody (manufactured by Santa Cruz) was used as the primary antibody, and goat horseradish peroxidase-labeled anti-mouse antibody (manufactured by Santa Cruz) was used as the secondary antibody.
- ⁇ -actin protein as an internal standard
- a rabbit anti-human ⁇ -actin antibody (manufactured by Abcam) was used as a primary antibody, and a donkey horseradish peroxidase-labeled anti-rabbit antibody (manufactured by Jackson) was used as a secondary antibody.
- FIG. 2 (a) is a representative example of a Western blot band.
- FIG. 2B shows an average value of the signal intensity integrated value (Volume) of the band. It was confirmed that the koji extract of the present invention suppresses SI protein expression.
- Example 4 Inhibition test of glucose uptake by intestinal epithelial cells This test was according to the method of Konishi et al. (Konishi et al., Biosci. Biotechnol. Biochem., 67 (4), 856-862, 2003). Suspend Caco-2 cells in DMEM medium and transfer to Transwell-COL 12 mm Diameter 0.4 ⁇ m Pore Size (made by Corning) (hereinafter referred to as Transwell) so as to be 1.0 ⁇ 10 5 cells / cm 2. Sowing. The medium was changed every 2-3 days under 37% at 95% air-5% carbon dioxide and cultured for 3 weeks.
- control a solution obtained by treating a 0.5% glucose solution with DMSO added to a final DMSO concentration of 1%
- phlorizin phlorizin n hydrate, derived from apple
- a positive control was treated with a solution (DMSO final concentration: 1%) mixed with 0.5% glucose solution dissolved in DMSO to a volume of mL.
- a glucose permeation suppression test was also conducted for a considerable amount of succinic acid contained in the koji extract.
- the succinic acid content of the koji extract of Production Example 1 is calculated using an analysis / preparative high performance liquid chromatography apparatus and a Fourier transform infrared spectrophotometer, and the succinic acid content is 2% or less. It was confirmed that there was. Therefore, succinic acid was dissolved in DMSO to a final concentration of 0.02, 0.05 and 0.1 mg / mL, and a solution mixed with PBS (+) (DMSO final concentration: 1%) was treated. Moreover, 500 ⁇ L of PBS (+) was added to each basolatal side. After culturing these Transwells at 37 ° C.
- the amount of glucose permeated to the basolataral side was quantified using a glucose CII test Wako. And the relative change in the sample addition sample when the glucose permeation amount of the control sample was set to 100 was calculated. Further, it was confirmed that the TER value was 350 ⁇ ⁇ cm 2 or more after the test.
- the results of glucose permeability are shown in Table 2. It was confirmed that the extract of the present invention suppresses glucose uptake by intestinal epithelial cells. On the other hand, the glucose permeation inhibitory effect was not confirmed in Caco-2 cells treated with a considerable amount of succinic acid contained in the koji extract. That is, it was found that the sputum extract of the present invention contains a component that suppresses glucose permeation in Caco-2 cells, but that component is a compound or mixture other than succinic acid.
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Abstract
Description
日本では宝飾品としてよく知られているが、近年では、粉末や抽出物を化粧品や健康食品に用いる例が増えている。例えば、琥珀粉末を化粧品に配合し、肌感触を改善する技術(例えば、特許文献1を参照)、琥珀抽出物を皮膚外用剤に配合する技術(例えば、特許文献2、特許文献3を参照)、琥珀熱水抽出物の美白効果を利用する技術(例えば、特許文献4、特許文献5を参照)、琥珀抽出画分中の皮膚ターンオーバー促進因子を利用する技術(例えば、特許文献6を参照)、琥珀抽出物中の皮膚のスキンファーミング効果を利用する技術(例えば、特許文献7を参照)、琥珀抽出画分中のヒアルロン酸産生促進因子を利用する技術(例えば、特許文献8を参照)、琥珀抽出画分中の血管新生促進因子を利用する技術(例えば、特許文献9を参照)などが知られている。
このように、琥珀には様々な物理化学的、生物学的効果が知られており、非常に有用な素材として様々な分野で用いられてきており、無限の可能性を秘める素材として期待されている。
一方、近年急増している糖尿病は、慢性高血糖をはじめとする様々な代謝異常が現れる疾患である。糖尿病の90%以上を占めるII型糖尿病は生活習慣と密接に関連しており、食事や運動等による予防・軽減が可能と言われている。従来、糖尿病治療薬としてインクレチン関連薬、ピグアナイド薬、スルホニルウレア薬、インスリン感受性増強薬、チアゾリジン薬、α−グルコシダーゼ阻害薬などが用いられてきたが、いずれも医師の管理下での使用が必須である上、副作用が心配されるものも多い。これらのことから、日常的な摂取が簡便である飲食品によって日ごろから血糖値を良好に調節し、糖尿病を予防及び改善することが望ましい。そこで、飲食品に添加可能な、食後の血糖値上昇を抑制する作用を有する食品素材の開発が強く望まれている。
食事から摂取した糖質は、小腸上皮上に局在するα−グルコシダーゼによってグルコースなどの単糖に分解され、その後小腸上皮細胞が単糖を取込むことで血液中に運ばれる。よって、α−グルコシダーゼの働きやグルコースの取込みを抑制することによって、食事に含まれる糖質の吸収を抑制又は遅らせることが可能であり、それによって食後の血糖値上昇を抑制することができる。
これまでにα−グルコシダーゼ活性抑制作用を有する食品素材としては、例えば、グアバ葉熱水抽出物(例えば、非特許文献2を参照)などが知られている。グルコース吸収抑制作用を有する食品素材としては、例えば、茶ポリフェノール(例えば、非特許文献3を参照)などが知られている。また、琥珀に含まれる成分として知られているコハク酸が、糖尿病モデルラットにおいて血糖値上昇抑制効果を示した報告があるが(例えば、特許文献10を参照)、そのメカニズムは不明である。しかし、これまでに琥珀抽出物におけるα−グルコシダーゼ活性抑制作用及びグルコース吸収抑制作用などをメカニズムとした血糖値上昇抑制効果は報告がされていない。
<1>琥珀抽出物を含有することを特徴とするα−グルコシダーゼ活性抑制剤。
<2>琥珀抽出物を含有することを特徴とするグルコース吸収抑制剤。
<3>前記琥珀抽出物を製造するための抽出溶媒が含水アルコール(含水率:1質量%~60質量%)である<1>又は<2>に記載の剤。
<4><1>~<3>のいずれかに記載の剤の1種又は2種以上を配合して成る経口投与組成物。
<5>態様が医薬品、医薬部外品、飲食品又は食品添加物である<4>に記載の経口投与組成物。
図2はCaco−2細胞における、琥珀抽出物によるスクラーゼ‐イソマルターゼ複合体のタンパク質発現抑制を示す図(a)及びグラフ(b)(n=3、*p<0.05、**p<0.01、50%エタノール抽出物とは製造例1の琥珀抽出物を指す)
本発明のα−グルコシダーゼ活性抑制剤及び/又はグルコース吸収抑制剤は、有効成分として琥珀抽出物を含有することを特徴とする。ここで、本発明で言う琥珀抽出物とは、琥珀そのもの、琥珀を粉砕、細切等加工した加工物、琥珀又はその加工物に溶媒を加え抽出した抽出物、抽出物から溶媒を除去した抽出物の溶媒除去物、それらの精製物等が例示でき、これらの内では抽出物又はその溶媒除去物が特に好ましい。
抽出物の溶媒としては、例えば、水、メタノールやエタノール、1,3−ブタンジオール、プロピレングリコール、グリセリン等のアルコール類、酢酸エチルや蟻酸メチル等のエステル類、アセトニトリル等のニトリル類、ジエチルエーテルやテトラヒドロフラン等のエーテル類、クロロホルムや塩化メチレン等のハロゲン化炭化水素類、アセトンやメチルエチルケトン等のケトン類等が例示でき、これらの1種又は2種以上を単独あるいは混合して用いればよい。これらの内好ましいものは水又はアルコール類、より好ましいものは含水アルコールである。さらにアルコールとしてはエタノールが好ましい。含水率は1質量%~60質量%が好ましく、10質量%~50質量%がさらに好ましい。これより高くても低くても、抽出効率が悪くなる場合が存する。
抽出の方法は、例えば琥珀の粉砕物に2~20倍量の溶媒を加え、室温であれば数日間、沸点付近の温度であれば数時間浸漬すればよい。その後濾過等によって不溶物を除去し、減圧濃縮等すればよい。又、これをシリカゲル、オクタデシルシリル化シリカゲル、イオン交換樹脂等を充填したカラムでカラムクロマトグラフィーによって精製してもよい。
製造例1
琥珀の粉末100gを50%エタノールで抽出し、それを減圧濃縮、凍結乾燥し、50%エタノール抽出物10gを得た。
得られた抽出物を用いてα−グルコシダーゼ活性抑制作用を調べる方法としては、例えば、ヒト結腸癌由来細胞(以下、Caco−2細胞とする)に抽出物を添加し培養した後、細胞を回収し、その粗酵素液に基質としてスクロース、マルトースを反応させ、生じたグルコース量を、グルコースオキシダーゼを用いた酵素法により定量する方法を用いることができる。グルコース取込み阻害作用を調べる方法としては、腸管上皮様に分化させたCaco−2細胞にグルコースと抽出物を同時添加し、細胞に取込まれた、あるいは細胞を透過したグルコース量を、グルコースオキシダーゼを用いた酵素法により定量する方法を用いることができる。
本発明の抽出物を含む飲料の例としては、茶飲料、コーヒー飲料、清涼飲料、酒、乳飲料、炭酸飲料、健康飲料、栄養ドリンク、スポーツドリンク等とこれら飲料の濃縮原液及び調製粉末等であり、食品の例としては、ガム、キャンディー、ゼリー、錠菓、健康食品、栄養補給食品、サプリメント等である。
本発明の抽出物を糖尿病予防薬等の医薬として用いる場合には、散剤、顆粒剤、錠剤、カプセル剤、液剤、注射剤等の形態で提供される。本発明の抽出物をそのまま、あるいは水等で希釈して、経口的に投与できる。もしくはこれを公知の医薬用担体と共に製剤化することにより調製される。例えば、本発明の抽出物をシロップ剤などの経口液状製剤として、又はエキス、粉末などに加工して、薬学的に許容される担体と配合し、錠剤、カプセル剤、顆粒剤、散剤などの経口固形製剤として投与できる。薬学的に許容できる担体としては、製剤素材として慣用の各種有機あるいは無機担体物質が用いられ、固形製剤における賦形剤、滑沢剤、結合剤、崩壊剤、液状製剤における溶剤、賦形剤、懸濁化剤、結合剤などとして配合される。また、必要に応じて、防腐剤、抗酸化剤、着色料、甘味剤などの製剤添加物を用いることもできる。
本発明の抽出物を含む飲食品又は医薬組成物には、本発明の抽出物を任意の濃度で含ませることができる。好ましくは、本発明の抽出物を1~100μg/mlの濃度で含み、より好ましくは5~50μg/mlの濃度で含む。
また、有効な用量は、患者の年齢及び体重、疾病の種類及び重篤度並びに投与の経路により適宜決定することができる。
実施例1:スクラーゼ、マルターゼ活性抑制試験
本試験はOGAWAらの方法(N.Ogawaら,The Journal Of Nutrition,130:507−513,2000)を参考にした。
ダルベッコ変性イーグル培地(DMEM)(Thermo Fisher Scientific社製)に10%ウシ血清(FETAL BOVINE SERUM、以下FBSとする)(Thermo Fisher Scientific社製)と1%抗菌剤(Penicillin−Streptomycin−L−Glutamine)(wako社製)と1%非必須アミノ酸混合液(MEM Non−Essential Amino Acids)(Thermo Fisher Scientific社製)を添加した培養液(以下、DMEM培地とする)に、Caco−2細胞を懸濁し、1.0×104cells/cm2となるように24ウェルプレート(TPP社製)に播種した。95%空気−5%炭酸ガスの下、37℃で培養し、2~3日おきに培地交換を行いコンフルエントになるまで8から10日間培養した。培養上清を吸引除去後、製造例1の琥珀抽出物(50%エタノール抽出物)を終濃度100、200μg/mLになるようにジメチルスルホキシド(以下、DMSOとする)に溶解させ、DMEM培地に混ぜたもの(DMSO終濃度:0.25%)を500μLずつ添加した。また、DMEM培地にDMSO終濃度0.25%になるようDMSOを添加した培養液を処理したものをcontrolとし、アカルボース(以下、ACAとする)を終濃度100μg/mLになるようにDMSOに溶解させ、DMEM培地に混ぜた培養液(DMSO終濃度:0.25%)を処理したものを陽性対照とした。さらに、琥珀抽出物に含有される相当量のコハク酸についてもスクラーゼ、マルターゼ活性抑制試験を実施した。具体的には、製造例1の琥珀抽出物のコハク酸含有量を分析/分取高速液体クロマトグラフィー装置及びフーリエ変換赤外分光光度計を用いて算出し、コハク酸含有率が2%以下であることを確認した。そこでコハク酸を終濃度2、5、25μg/mLになるようにDMSOに溶解させ、DMEM培地に混ぜたもの(DMSO終濃度:0.25%)を処理した。これらのプレートを95%空気−5%炭酸ガスの下、37℃で7日間培養した。
溶解バッファー(0.1Mリン酸バッファー(pH6.8)、0.5%TritonX−100)で細胞を回収し氷上で20分間静置した後、4℃下で30分間遠心分離(10,000xg)を行い、上清を採取した。上清と等量のスクロース液(スクロースを56mMの濃度でPBS(+)に溶解したもの)又はマルトース液(マルトースを56mMの濃度でPBS(+)に溶解したもの)を混合し、37℃下で1時間反応させた後、生成したグルコースの量を、グルコースCIIテストワコー(wako社製)を用いて酵素法により定量した。グルコース生成量を基にスクラーゼ活性又はマルターゼ活性をそれぞれ算出した。そして、controlサンプルの酵素活性を100としたときの試料添加サンプルにおける相対的な変化を算出した。
表1にスクラーゼ、マルターゼ活性測定の結果を示す。本発明の琥珀抽出物はCaco−2細胞におけるスクラーゼ活性およびマルターゼ活性に対し強い抑制作用を示した。一方で、琥珀抽出物に含有される相当量のコハク酸で処理したCaco−2細胞においては、スクラーゼ活性、マルターゼ活性ともに抑制効果が確認されなかった。つまり、本発明の琥珀抽出物にはCaco−2細胞のスクラーゼ活性、マルターゼ活性を抑制する成分が含まれるが、その成分はコハク酸以外の化合物もしくは混合物であることが分かった。
DMEM培地に、Caco−2細胞を懸濁し、1.0×104cells/cm2となるように直径4cmのディッシュ(TPP社製)に播種した。95%空気−5%炭酸ガスの下、37℃で培養し、2から3日おきに培地交換を行いコンフルエントになるまで10日間培養した。培養上清を吸引除去後、製造例1の琥珀抽出物を終濃度100、200μg/mLになるようにDMSOに溶解させ、DMEM培地に混ぜたもの(DMSO終濃度:0.25%)を1mLずつ添加した。また、DMEM培地にDMSO終濃度0.25%になるようDMSOを添加した培養液を処理したものをcontrolとした。これらのディッシュを95%空気−5%炭酸ガスの下、37℃で7日間培養した。
RNA精製キットNucleoSpin RNA(マッハライ・ナーゲル社製)を用いて処理した細胞から総RNAを抽出した(産物を以下、total RNAとする)。total RNA量はナノスケール分光光度計(Nano 200)を用いて260nmにおける吸光度により求めた。次いでこのtotal RNAを元に、PrimeScriptTM RT reagent Kit(タカラバイオ社製)を用い、添付文書に従ってRT反応を行った。更にSYBR(商標)Premix Ex TaqTM II(タカラバイオ社製)を用い、添付文書に従って反応液を調製した。この反応液をquantitative RT−PCR法によりスクラーゼ−イソマルターゼ複合体(以下、SIとする)及び内部標準であるGAPDHの各プライマー(Thermo Fisher Scientific社製)と反応させた。そして、controlサンプルのSI mRNA発現量を100としたときの試料添加サンプルにおける相対的な変化を算出した。その際、内部標準であるGAPDHの値で補正した。
SI mRNA発現の結果を図1に示す。本発明の琥珀抽出物はSI mRNA発現を抑制することが確認された。
実施例3:SIタンパク発現抑制試験
DMEM培地に、Caco−2細胞を懸濁し、1.0×104cells/cm2となるように直径4cmのディッシュ(TPP社製)に播種した。95%空気−5%炭酸ガスの下、37℃で培養し、2~3日おきに培地交換を行いコンフルエントになるまで10日間培養した。培養上清を吸引除去後、製造例1の琥珀抽出物を終濃度100、200μg/mLになるようにDMSOに溶解させ、DMEM培地に混ぜたもの(DMSO終濃度:0.25%)を1mLずつ添加した。また、DMEM培地にDMSO終濃度0.25%になるようDMSOを添加した培養液を処理したものをcontrolとした。これらのディッシュを95%空気−5%炭酸ガスの下、37℃で8日間培養した。
RIPA Buffer(PCC社製)で細胞を回収した後、4℃下で15分間遠心分離(10,000xg)を行い、上清を採取した。総タンパク量はBradford試薬(Bio−rad社製)を用いて595nmにおける吸光度により求めた。次いで、常法に従いポリアクリルアミド電気泳動を行い、ポリビニリデンジフルオリドメンブレン(Bio−rad社製)にタンパク質を転写した。SIタンパクの検出には、一次抗体としてマウス抗ヒトSI(A−12)抗体(santa cruz社製)、二次抗体としてヤギホースラディッシュペルオキシダーゼ標識抗マウス抗体(santa cruz社製)を用いた。内部標準であるβ−actinタンパクの検出には、一次抗体としてウサギ抗ヒトβ−actin抗体(abcam社製)、二次抗体としてロバホースラディッシュペルオキシダーゼ標識抗ラビット抗体(Jackson社製)を用いた。バンドの検出は、ECL(bio−rad社製)と二次抗体を反応させ、化学発光検出専用撮影装置を用いてシグナルを検出した。解析にはImage Jソフトウェアを用い、controlサンプルのSIタンパク発現量を100としたときの試料添加サンプルにおける相対的な変化を算出した。その際、内部標準であるβ−actinの値で補正した。
SIタンパク発現の結果を図2に示す。図2(a)はウエスタンブロットのバンドの代表例である。バンドのシグナル強度積算値(Volume)の平均値を算出したものを図2(b)に示す。本発明の琥珀抽出物はSIタンパク発現を抑制することが確認された。
実施例4:腸管上皮様細胞によるグルコース取込みの抑制試験
本試験はKonishiらの方法(Konishiら,Biosci.Biotechnol.Biochem.,67(4),856−862,2003)に従った。DMEM培地に、Caco−2細胞を懸濁し、1.0×105cells/cm2となるようにTranswell−COL 12mm Diameter 0.4μm Pore Size(corning社製)(以下、トランズウェルとする)に播種した。95%空気−5%炭酸ガス、37℃の下、2~3日おきに培地交換を行い3週間培養した。
ミリセル(Millicell)ERS−2抵抗値測定システム(メルクミリポア社製)を用いて細胞間電気抵抗値(TER値)が350Ω・cm2以上であることを確認した後、apical側に製造例1の琥珀抽出物を終濃度0.2、1、2mg/mLになるようにDMSOに溶解させ、PBS(+)に0.5%の濃度でD(+)−グルコースを溶かしたもの(以下、0.5%グルコース溶液とする)に混ぜた溶液(DMSO終濃度:1%)を500μLずつ添加した。また、0.5%グルコース溶液にDMSO終濃度1%になるようDMSOを添加した溶液を処理したものをcontrolとし、フロリジンn水和物,リンゴ由来(以下、フロリジンとする)を終濃度1mg/mLになるようにDMSOに溶解させ、0.5%グルコース溶液に混ぜた溶液(DMSO終濃度:1%)を処理したものを陽性対照とした。さらに、琥珀抽出物に含有される相当量のコハク酸についてもグルコース透過抑制試験を実施した。具体的には、製造例1の琥珀抽出物のコハク酸含有量を分析/分取高速液体クロマトグラフィー装置及びフーリエ変換赤外分光光度計を用いて算出し、コハク酸含有率が2%以下であることが確認できた。そこでコハク酸を終濃度0.02、0.05、0.1mg/mLになるようにDMSOに溶解させ、PBS(+)に混ぜた溶液(DMSO終濃度:1%)を処理した。また、それぞれのbasolateral側にはPBS(+)を500μLずつ添加した。これらのトランズウェルを95%空気−5%炭酸ガスの下、37℃で2時間培養した後、basolateral側に透過したグルコースの量を、グルコースCIIテストワコーを用いて定量した。そして、controlサンプルのグルコース透過量を100としたときの試料添加サンプルにおける相対的な変化を算出した。また、試験後にはTER値が350Ω・cm2以上であることを確認した。
グルコース透過率の結果を表2に示す。本発明の抽出物は腸管上皮様細胞によるグルコースの取込みを抑制することが確認された。一方で、琥珀抽出物に含有される相当量のコハク酸で処理したCaco−2細胞においては、グルコース透過抑制効果が確認されなかった。つまり、本発明の琥珀抽出物にはCaco−2細胞におけるグルコース透過を抑制する成分が含まれるが、その成分はコハク酸以外の化合物もしくは混合物であることが分かった。
Claims (5)
- 琥珀抽出物を含有することを特徴とするα−グルコシダーゼ活性抑制剤。
- 琥珀抽出物を含有することを特徴とするグルコース吸収抑制剤。
- 前記琥珀抽出物を製造するための抽出溶媒が含水アルコール(含水率:1質量%~60質量%)である請求項1又は2に記載の剤。
- 請求項1~3のいずれか1項に記載の剤の1種又は2種以上を配合して成る経口投与組成物。
- 態様が医薬品、医薬部外品、飲食品又は食品添加物である請求項4に記載の経口投与組成物。
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WO2020031638A1 (ja) * | 2018-08-10 | 2020-02-13 | 琥珀バイオテクノロジー株式会社 | アンジオテンシンi変換酵素活性阻害剤 |
WO2021112263A1 (ja) * | 2019-12-05 | 2021-06-10 | 琥珀バイオテクノロジー株式会社 | アディポネクチン産生促進剤 |
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US20200147160A1 (en) | 2020-05-14 |
EP3626246A1 (en) | 2020-03-25 |
US11007237B2 (en) | 2021-05-18 |
JP6601860B2 (ja) | 2019-11-06 |
JPWO2018212362A1 (ja) | 2019-06-27 |
JP2019163343A (ja) | 2019-09-26 |
JP6599592B2 (ja) | 2019-10-30 |
EP3626246A4 (en) | 2021-03-10 |
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