CN110227080A - 甘露葡萄糖醛酸多（寡）糖及其衍生物在制备治疗和/或预防2型糖尿病药物中的应用 - Google Patents
甘露葡萄糖醛酸多（寡）糖及其衍生物在制备治疗和/或预防2型糖尿病药物中的应用 Download PDFInfo
- Publication number
- CN110227080A CN110227080A CN201910380776.3A CN201910380776A CN110227080A CN 110227080 A CN110227080 A CN 110227080A CN 201910380776 A CN201910380776 A CN 201910380776A CN 110227080 A CN110227080 A CN 110227080A
- Authority
- CN
- China
- Prior art keywords
- aldehydic acid
- widow
- drug
- carbohydrates
- derivatives
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000002253 acid Substances 0.000 title claims abstract description 36
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 21
- 229940079593 drug Drugs 0.000 title claims abstract description 17
- 239000003814 drug Substances 0.000 title claims abstract description 17
- 150000001720 carbohydrates Chemical class 0.000 title claims abstract description 16
- 235000014633 carbohydrates Nutrition 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 230000002265 prevention Effects 0.000 title claims abstract description 8
- 230000036541 health Effects 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910003202 NH4 Inorganic materials 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000011806 microball Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims 1
- 239000004375 Dextrin Substances 0.000 claims 1
- 235000019425 dextrin Nutrition 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000012377 drug delivery Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- 235000000346 sugar Nutrition 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
- 229920001542 oligosaccharide Polymers 0.000 description 8
- 150000002482 oligosaccharides Chemical class 0.000 description 8
- 150000004676 glycans Chemical class 0.000 description 6
- 229920001282 polysaccharide Polymers 0.000 description 6
- 239000005017 polysaccharide Substances 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 210000000496 pancreas Anatomy 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- 230000003914 insulin secretion Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- DBTMGCOVALSLOR-DEVYUCJPSA-N (2s,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](CO)O[C@H](O)[C@@H]2O)O)O[C@H](CO)[C@H]1O DBTMGCOVALSLOR-DEVYUCJPSA-N 0.000 description 2
- 241000512259 Ascophyllum nodosum Species 0.000 description 2
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 229920001543 Laminarin Polymers 0.000 description 2
- 239000005717 Laminarin Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 150000002016 disaccharides Chemical class 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229940097043 glucuronic acid Drugs 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 150000003538 tetroses Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229920002271 DEAE-Sepharose Polymers 0.000 description 1
- 108010015776 Glucose oxidase Proteins 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011805 ball Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- 235000019420 glucose oxidase Nutrition 0.000 description 1
- 108091005995 glycated hemoglobin Proteins 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000000990 heteronuclear single quantum coherence spectrum Methods 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
-
- 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
- A61K31/7016—Disaccharides, e.g. lactose, lactulose
-
- 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
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- 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
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- 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
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/736—Glucomannans or galactomannans, e.g. locust bean gum, guar gum
-
- 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
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Mycology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Nutrition Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicinal Preparation (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
本发明提供了甘露葡萄糖醛酸多(寡)糖及其衍生物在制备治疗和/或预防2型糖尿病药物或保健品中的应用，所述甘露葡萄糖醛酸多(寡)糖及其衍生物的结构式如式(I)或(II)所示，其毒副作用小，安全有效；
Description
(一)技术领域
本发明属于生物医药领域，涉及甘露葡萄糖醛酸多(寡)糖及其衍生物在制备治疗和/或预防2型糖尿病药物或保健品中的应用。
(二)背景技术
糖尿病是当今严重影响人类生命健康的疾病之一。世卫组织报告指出，2014年全球成人糖尿病患者约4.22亿，患病率达到8.5％；并且现在患病率呈逐年递增的趋势。尽管目前已经具有多种用于降糖的药物，但糖尿病的控制现状依然十分严峻。63％的2型糖尿病患者仍然得不到有效的治疗，体内糖化血红蛋白水平(HBA1c)大于美国糖尿病协会所提出7％的标准水平。因此，需要进一步揭示糖尿病的发病机制，研发一系列各具特点的降糖药物，满足不同糖尿病患者的需求。因此，阐明糖尿病发病机制，开发新糖尿病治疗药物，为未来糖尿病患者个体化治疗提供更多的选择，具有重要现实的意义。
糖尿病是一种由于胰岛素分泌缺陷或胰岛素作用障碍所致的以高血糖为特征的代谢性疾病。持续高血糖与长期代谢紊乱等可导致全身组织器官(例如：肝、眼、肾、心血管及神经系统)的损害及其功能障碍和衰竭。在发病早期，胰岛素抵抗较轻，胰岛β细胞可通过提高单细胞工作负荷和/或代偿性增生增加细胞的数量增加胰岛素分泌，以满足机体相对较高的胰岛素需求，维持血糖浓度的相对稳定。随着2型糖尿病的进展，胰岛素抵抗愈发严重，机体慢性炎症也不断加重，血脂血糖水平不断升高，对胰岛β细胞产生不可逆转的损伤，最终发展成为2型糖尿病。
近年来，糖类药物从其药效和安全性方面考虑，其发展趋势逐渐从对多糖的研究转到对低聚糖和寡糖的研究。寡糖在医疗保健领域具有巨大的需求空间。寡糖类药物结构均一，质量可控，作用机制明确，已经成为糖类药物的主攻方向之一。
甘露葡萄糖醛酸多(寡)糖及其衍生物是一类酸性多(寡)糖，研究发现甘露葡萄糖醛酸多(寡)糖及其衍生物对2型糖尿病具有显著疗效，可以应用于2型糖尿病的预防和治疗。
(三)发明内容
本发明的目的是提供甘露葡萄糖醛酸多(寡)糖及其衍生物在制备治疗和/或预防2型糖尿病药物或保健品中的应用。
本发明的技术方案如下：
甘露葡萄糖醛酸多(寡)糖及其衍生物在制备治疗和/或预防2型糖尿病药物或保健品中的应用，所述甘露葡萄糖醛酸多(寡)糖具有如下特征：
(1)组成糖：甘露糖和葡糖糖醛酸或其盐；
(2)2-连接的甘露糖和4-连接的葡萄糖醛酸或其盐交替连接；
所述甘露葡萄糖醛酸多(寡)糖及其衍生物的结构式如式(I)或(II)所示：
式(I)中，R为H、Na、K或NH4 +，n为0～40之间的整数；
式(II)中，R为H、Na、K或NH4 +，n为0～40之间的整数。
进一步，所述药物为含有甘露葡萄糖醛酸多(寡)糖及其衍生物和药学可接受的载体和/或赋形剂的药物组合物；
所述载体例如：海藻酸钠微球、脂质体等；
所述赋形剂例如：甘露醇、硬脂酸镁、淀粉、环糊精等；
所述药物的剂型为注射剂、口服制剂或局部给药制剂。
本发明具有如下优点：
甘露葡萄糖醛酸多(寡)糖及其衍生物对2型糖尿病具有预防和治疗作用，毒副作用小，安全有效，可以用于制备治疗和预防2型糖尿病的药物和保健品。
(四)附图说明
图1寡糖的制备过程中酒精洗脱液的凝胶色谱图。
图2甘露葡萄糖醛酸寡糖G1-G4的ESI-MS和HPLC图；a为GM2；b为GM4；c为GM6；d为GM8。
图3 GMn的氢谱。
图4 GMn的碳谱。
图5 GMn的二维HMBC谱图。
图6 GMn的二维HSQC谱图。
图7 GMn的二维HHCOSY谱图。
图8 GMn的GPC-HPLC谱图。
图9甘露葡萄糖醛酸多(寡)糖促进葡萄糖消耗。
图10甘露葡萄糖醛酸多(寡)糖促进胰岛素分泌。
(五)具体实施方式
下面通过具体实施例对本发明作进一步的描述，但本发明的保护范围并不仅限于此。
实施例1甘露葡萄糖醛酸寡糖的制备
将干海带采用30倍质量的蒸馏水100℃下提取3小时，提取液经过过滤，浓缩后，加乙醇至终浓度为75％沉淀，静置12小时后收集沉淀，沉淀经真空干燥得到海带多糖。将海带多糖样品溶于质量浓度为4％的硫酸溶液中(料液比为60mg/mL)加热回流5小时，用氢氧化钡中和至pH＝6-7，离心，上清液浓缩至原始体积的五分之一，浓缩液上活性炭柱层析，首先用蒸馏水平衡，然后用体积分数50％乙醇(500mL)和90％乙醇(500mL)的水溶液梯度洗脱，合并洗脱液，浓缩至原始体积的五分之一，蒸去乙醇，直接上Bio-gel P4柱层析，分离得到五个组分(图1所示)，对上面收集得到的样品进行ESI-MS和HPLC分析(图2所示)。结果进一步确认寡糖的结构。结果显示，G1-G4分别为甘露葡萄糖醛酸八糖(GM8)，六糖(GM6)，四糖(GM4)和二糖(GM2)。其结构均符合下图所示的结构式：
其中G1为甘露葡萄糖醛酸八糖(GM8)，式中n1＝3，R1为H或者NH4 +；
G2为甘露葡萄糖醛酸六糖(GM6)，式中n1＝2，R1为H或者NH4 +；
G3为甘露葡萄糖醛酸四糖(GM4)，式中n1＝1，R1为H或者NH4 +；
G4为甘露葡萄糖醛酸二糖(GM2)，式中n1＝0，R1为H或者NH4 +。
实施例2甘露葡萄糖醛酸多糖的制备
将实施例1中的得到海带多糖溶于质量浓度为4％的硫酸溶液中(料液比为60mg/mL)加热回流4小时，用氢氧化钡中和至pH＝6-7，离心，上清液浓缩至原始体积的五分之一，浓缩液上DEAESepharose Fast Flow分离，分别采用水洗(5L)，0.2M氯化钠(5L)和2M氯化钠(5L)洗脱，2M洗脱液通过500Da透析袋透析制备得到甘露葡萄糖醛酸多糖GMn(7.0kDa)，对样品进行1H-NMR，13C-NMR，二维NMR和GPC-HPLC等(图3-图8所示)。结果进一步确认甘露葡萄糖醛酸多糖的结构。其结构均符合下图所示的结构式：
其中GMn为甘露葡萄糖醛酸多糖，式中n1≈20，R1为H，K或者Na。
实施例3：甘露葡萄糖醛酸多(寡)糖能促进HepG2细胞的葡萄糖消耗
HepG2是人源肝癌细胞系，生长迅速，性状稳定，是研究肝脏保护作用的常用细胞系。促进外周组织的葡萄糖代谢，提高肝细胞对胰岛素的敏感性。用二甲双胍和实施例1和2的甘露葡萄糖醛酸多(寡)糖进行药物处理24h，采用葡萄糖氧化酶法测定培养液中葡萄糖的变化。在葡萄糖消耗实验24h孵育结束后，每孔加入MTT，进行细胞活力的测定。结果显示甘露葡萄糖醛酸多(寡)糖组的葡萄糖消耗呈聚合度和剂量增加(图9)。此外，甘露葡萄糖醛酸多(寡)糖组对HepG2细胞没有抑制，二甲双胍组抑制率达到4.76％±3.46。
实施例4：甘露葡萄糖醛酸多(寡)糖能增强胰岛β细胞的胰岛素分泌
实验采用正常小鼠的胰岛，用棕榈酸处理得到胰岛细胞损伤模型。用GSIS进行胰岛素分泌功能的测定。实施例1和2中的甘露葡萄糖醛酸多(寡)糖能明显增强胰岛的胰岛素分泌功能(图10)。同时，甘露葡萄糖醛酸多(寡)糖对胰岛没有抑制作用，胰岛的形态，结构完整。
以上描述了本发明的具体实施例，然并非用以限定本发明，本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (5)
1.甘露葡萄糖醛酸多(寡)糖及其衍生物在制备治疗和/或预防2型糖尿病药物或保健品中的应用，所述甘露葡萄糖醛酸多(寡)糖及其衍生物的结构式如式(I)或(II)所示：
式(I)中，R为H、Na、K或NH4 +，n为0～40之间的整数；
式(II)中，R为H、Na、K或NH4 +，n为0～40之间的整数。
2.如权利要求1所述的应用，其特征在于，所述药物为含有甘露葡萄糖醛酸多(寡)糖及其衍生物和药学可接受的载体和/或赋形剂的药物组合物。
3.如权利要求2所述的应用，其特征在于，所述载体为：海藻酸钠微球或脂质体。
4.如权利要求2所述的应用，其特征在于，所述赋形剂为：甘露醇、硬脂酸镁、淀粉或环糊精。
5.如权利要求2所述的应用，其特征在于，所述药物的剂型为注射剂、口服制剂或局部给药制剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910380776.3A CN110227080B (zh) | 2019-05-08 | 2019-05-08 | 甘露葡萄糖醛酸多(寡)糖及其衍生物在制备治疗和/或预防2型糖尿病药物中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910380776.3A CN110227080B (zh) | 2019-05-08 | 2019-05-08 | 甘露葡萄糖醛酸多(寡)糖及其衍生物在制备治疗和/或预防2型糖尿病药物中的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110227080A true CN110227080A (zh) | 2019-09-13 |
| CN110227080B CN110227080B (zh) | 2021-04-06 |
Family
ID=67861199
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910380776.3A Active CN110227080B (zh) | 2019-05-08 | 2019-05-08 | 甘露葡萄糖醛酸多(寡)糖及其衍生物在制备治疗和/或预防2型糖尿病药物中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110227080B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113940939A (zh) * | 2021-11-19 | 2022-01-18 | 浙江大学 | 甘露葡萄糖醛酸寡糖和多糖及衍生物在制备治疗和/或预防衰老药物中的应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103800348A (zh) * | 2014-03-13 | 2014-05-21 | 中国科学院海洋研究所 | 甘露葡萄糖醛酸寡糖在制备治疗或预防帕金森病和/或老年痴呆药物和/或保健品中的应用 |
-
2019
- 2019-05-08 CN CN201910380776.3A patent/CN110227080B/zh active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103800348A (zh) * | 2014-03-13 | 2014-05-21 | 中国科学院海洋研究所 | 甘露葡萄糖醛酸寡糖在制备治疗或预防帕金森病和/或老年痴呆药物和/或保健品中的应用 |
Non-Patent Citations (1)
| Title |
|---|
| 丛瑶 等: "褐藻多糖硫酸酯降解及其产物活性研究进展", 《水产科学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113940939A (zh) * | 2021-11-19 | 2022-01-18 | 浙江大学 | 甘露葡萄糖醛酸寡糖和多糖及衍生物在制备治疗和/或预防衰老药物中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110227080B (zh) | 2021-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1267456C (zh) | 一种降糖的沙蒿多糖制备方法及其应用 | |
| CN107441078B (zh) | 一种治疗糖尿病的药物组合物及其制备方法和用途 | |
| CN103520199B (zh) | 枸杞多糖在制备用于治疗糖尿病药物中的应用 | |
| CN113004432A (zh) | 一种铁皮石斛寡糖、铁皮石斛寡糖衍生物及其制备方法和应用 | |
| CN104922176A (zh) | 一种野菊花提取物的应用 | |
| CN101862346B (zh) | 人参酸性多糖在制备降血糖药物中的应用 | |
| CN104107187B (zh) | 一种罗布麻酸性多糖在治疗糖尿病药物中的应用 | |
| CN110227080A (zh) | 甘露葡萄糖醛酸多（寡）糖及其衍生物在制备治疗和/或预防2型糖尿病药物中的应用 | |
| CN101744844B (zh) | 具有降血糖作用的黄腐酸或黄腐酸钠物质 | |
| CN101953867B (zh) | 天山雪莲石油醚提取物及其应用制备方法和应用 | |
| CN109820887B (zh) | 具有治疗脚气作用的组合物及其应用 | |
| CN110218262A (zh) | 褐藻来源的富含葡萄糖醛酸的低硫酸化杂聚糖在制备治疗2型糖尿病药物中的应用 | |
| CN102078397A (zh) | 一种中药复方及其制备方法 | |
| CN101884723B (zh) | 一种用于治疗糖尿病的知母黄连组合物制剂及其制备方法 | |
| CN101716165A (zh) | 氧化白藜芦醇的用途 | |
| CN108165499A (zh) | 一种猴头菌的培养基、山药生物转化菌丝体、山药生物转化菌丝体的提取物及其用途 | |
| CN110143989B (zh) | 一种鞣花单宁类α-葡萄糖苷酶抑制剂及其制备方法 | |
| CN101837061B (zh) | 山楂叶及其提取物的制药用途 | |
| CN112979839A (zh) | 一种西番莲叶酸性多糖的制备方法 | |
| CN1434042A (zh) | 蒲黄提取物及其制备方法和用途 | |
| CN101433534B (zh) | 白藜芦醇二聚体用于制备降血糖药物的用途 | |
| CN104906145A (zh) | 蝙蝠蛾拟青霉诱变菌株ph40在治疗糖尿病中的医用用途 | |
| CN104162163A (zh) | 脂酰辅酶a氧化酶作为糖尿病的治疗靶点的应用 | |
| CN1480462A (zh) | 胡芦巴提取物及其生产方法 | |
| CN101628022A (zh) | 一种红花滴丸及其制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |