WO2024067579A1 - Use of ginkgo terpene lactone in preparing drug for preventing or treating diabetes and diabetic complication - Google Patents
Use of ginkgo terpene lactone in preparing drug for preventing or treating diabetes and diabetic complication Download PDFInfo
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- WO2024067579A1 WO2024067579A1 PCT/CN2023/121513 CN2023121513W WO2024067579A1 WO 2024067579 A1 WO2024067579 A1 WO 2024067579A1 CN 2023121513 W CN2023121513 W CN 2023121513W WO 2024067579 A1 WO2024067579 A1 WO 2024067579A1
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- ginkgolide
- bilobalide
- diabetes
- use according
- preventing
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Links
- 208000002249 Diabetes Complications Diseases 0.000 title claims abstract description 13
- 235000008100 Ginkgo biloba Nutrition 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 229940079593 drug Drugs 0.000 title claims abstract description 12
- 235000011201 Ginkgo Nutrition 0.000 title claims abstract description 11
- 241000218628 Ginkgo Species 0.000 title claims abstract description 11
- -1 terpene lactone Chemical class 0.000 title claims abstract description 11
- 235000007586 terpenes Nutrition 0.000 title claims abstract description 11
- 206010012655 Diabetic complications Diseases 0.000 title claims abstract description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 22
- SQOJOAFXDQDRGF-WJHVHIKBSA-N ginkgolide B Natural products O=C1[C@@H](C)[C@@]2(O)[C@@H]([C@H](O)[C@]34[C@@H]5OC(=O)[C@]23O[C@H]2OC(=O)[C@H](O)[C@@]42[C@H](C(C)(C)C)C5)O1 SQOJOAFXDQDRGF-WJHVHIKBSA-N 0.000 claims description 75
- MOLPUWBMSBJXER-YDGSQGCISA-N bilobalide Chemical compound O([C@H]1OC2=O)C(=O)[C@H](O)[C@@]11[C@@](C(C)(C)C)(O)C[C@H]3[C@@]21CC(=O)O3 MOLPUWBMSBJXER-YDGSQGCISA-N 0.000 claims description 54
- FPUXKXIZEIDQKW-MFJLLLFKSA-N ginkgolide A Natural products O=C1[C@H](C)[C@@]2(O)[C@@H](O1)C[C@]13[C@@H]4OC(=O)[C@]21O[C@@H]1OC(=O)[C@H](O)[C@]31[C@@H](C(C)(C)C)C4 FPUXKXIZEIDQKW-MFJLLLFKSA-N 0.000 claims description 38
- FPUXKXIZEIDQKW-VKMVSBOZSA-N ginkgolide-a Chemical compound O[C@H]([C@]12[C@H](C(C)(C)C)C[C@H]3OC4=O)C(=O)O[C@H]2O[C@]24[C@@]13C[C@@H]1OC(=O)[C@@H](C)[C@]21O FPUXKXIZEIDQKW-VKMVSBOZSA-N 0.000 claims description 38
- SQOJOAFXDQDRGF-MMQTXUMRSA-N ginkgolide-b Chemical compound O[C@H]([C@]12[C@H](C(C)(C)C)C[C@H]3OC4=O)C(=O)O[C@H]2O[C@]24[C@@]13[C@@H](O)[C@@H]1OC(=O)[C@@H](C)[C@]21O SQOJOAFXDQDRGF-MMQTXUMRSA-N 0.000 claims description 37
- 229930184727 ginkgolide Natural products 0.000 claims description 32
- AMOGMTLMADGEOQ-FNZROXQESA-N Ginkgolide C Chemical compound O([C@H]1O2)C(=O)[C@H](O)C31[C@]14[C@@H](O)[C@@H]5OC(=O)[C@@H](C)[C@]5(O)[C@@]12C(=O)O[C@@H]4[C@@H](O)[C@H]3C(C)(C)C AMOGMTLMADGEOQ-FNZROXQESA-N 0.000 claims description 29
- AMOGMTLMADGEOQ-DPFZUGDXSA-N ginkgolide C Natural products O=C1[C@@H](C)[C@]2(O)[C@H]([C@H](O)[C@@]34[C@H]5[C@H](O)[C@@H](C(C)(C)C)[C@]63[C@H](O)C(=O)O[C@H]6O[C@@]24C(=O)O5)O1 AMOGMTLMADGEOQ-DPFZUGDXSA-N 0.000 claims description 29
- LMEHVEUFNRJAAV-HOSIAMDISA-N ginkgolide J Natural products O=C1[C@H](C)[C@@]2(O)[C@H](O1)C[C@@]13[C@H]4[C@@H](O)[C@@H](C(C)(C)C)[C@@]51[C@@H](O)C(=O)O[C@@H]5O[C@@]23C(=O)O4 LMEHVEUFNRJAAV-HOSIAMDISA-N 0.000 claims description 16
- LMEHVEUFNRJAAV-UKWFQYJJSA-N ginkgolide-j Chemical compound O([C@H]1O2)C(=O)[C@H](O)[C@@]31[C@]14C[C@@H]5OC(=O)[C@@H](C)[C@]5(O)[C@@]12C(=O)O[C@@H]4[C@H](O)[C@H]3C(C)(C)C LMEHVEUFNRJAAV-UKWFQYJJSA-N 0.000 claims description 16
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 7
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 4
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 4
- 208000004104 gestational diabetes Diseases 0.000 claims description 4
- 208000031288 Combined hyperlipidaemia Diseases 0.000 claims description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 2
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 2
- 239000000203 mixture Substances 0.000 description 29
- 241000699670 Mus sp. Species 0.000 description 21
- 210000004369 blood Anatomy 0.000 description 19
- 239000008280 blood Substances 0.000 description 19
- 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 10
- 239000008103 glucose Substances 0.000 description 10
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 10
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 8
- 239000000178 monomer Substances 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 108091005995 glycated hemoglobin Proteins 0.000 description 6
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002596 lactones Chemical class 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 244000194101 Ginkgo biloba Species 0.000 description 2
- 108010014663 Glycated Hemoglobin A Proteins 0.000 description 2
- 101001121408 Homo sapiens L-amino-acid oxidase Proteins 0.000 description 2
- 102100026388 L-amino-acid oxidase Human genes 0.000 description 2
- 101100012902 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) FIG2 gene Proteins 0.000 description 2
- 101100233916 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) KAR5 gene Proteins 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 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 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004088 microvessel Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000003820 β-cell dysfunction Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- 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
- A61P3/06—Antihyperlipidemics
-
- 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
Definitions
- the present invention relates to the field of pharmaceutical technology, and in particular to the use of ginkgo terpene lactone in preparing medicines for preventing or treating diabetes and diabetic complications.
- Diabetes is a disease characterized by high blood sugar. Diabetes is mainly divided into type I diabetes and type II diabetes, and also includes gestational diabetes and special types of diabetes.
- the cause of type I diabetes is autoimmune destruction of pancreatic ⁇ cells, which leads to an absolute lack of insulin secretion. Patients can only maintain their lives by injecting insulin; type II diabetes is also called non-insulin-dependent diabetes. It is related to ⁇ cell dysfunction and insulin resistance, and is also affected by genetic and environmental factors.
- the number of patients accounts for more than 90% of diabetic patients, and most of them are middle-aged and elderly people. They can be treated by taking hypoglycemic drugs and a reasonable exercise diet. Patients with gestational diabetes have no problems with pancreatic islet function, but blood sugar will rise during pregnancy.
- the purpose of the present invention is to provide a use of ginkgo terpene lactones in preparing a medicine for preventing or treating diabetes and diabetic complications.
- the first aspect of the present invention provides a use of ginkgo terpene lactones in the preparation of drugs for preventing or treating diabetes, or drugs for preventing or treating diabetic complications.
- the ginkgolide comprises at least one of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J and ginkgolide K.
- the weight ratio of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, and ginkgolide K is selected from the following:
- the ginkgo terpene lactones further include bilobalide.
- the mass ratio of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide K, and bilobalide is selected from the following:
- the mass proportions of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J and bilobalide are selected from: 40 to 43 parts of bilobalide, 25 to 27 parts of ginkgolide A, 15 to 17 parts of ginkgolide B, 14 to 16 parts of ginkgolide C, and 3.5 to 5 parts of ginkgolide J.
- the dosage of ginkgolide is 1-800 mg/kg/day.
- the dosage of ginkgolide is 1-500 mg/kg/day.
- the dosage of ginkgolide is 1 to 150 mg/kg/day.
- the dosage of ginkgolide is 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 40 mg/kg/day, 50 mg/kg/day, 60 mg/kg/day, 70 mg/kg/day, 80 mg/kg/day, 90 mg/kg/day, 100 mg/kg/day, 110 mg/kg/day, 120 mg/kg/day, 130 mg/kg/day, 140 mg/kg/day or 150 mg/kg/day.
- the diabetes is type I diabetes, type II diabetes or gestational diabetes.
- the diabetes is type II diabetes.
- the diabetic complication is dyslipidemia.
- the dyslipidemia is hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia or low high-density lipoproteinemia.
- Ginkgo biloba lactones can significantly reduce the levels of fasting blood sugar, triglycerides and glycosylated hemoglobin. Ginkgo biloba lactones have a significant therapeutic effect on diabetes and can be used to prepare drugs for preventing and treating diabetes, drugs for preventing or treating diabetic complications, etc.
- FIG1 is a graph showing the changing trend of blood glucose levels in mice after administration of composition A for 0-8 weeks.
- FIG2 is a bar graph showing the glycated hemoglobin level in mice after administration of Composition A for 7 weeks.
- FIG3 is a bar graph showing TG (triglyceride) levels in mice after administration of Composition A for 7 weeks.
- prevention refers to preventing the occurrence of a disease and/or preventing the recurrence of a disease.
- the ginkgo terpene lactones of the present invention can be prepared by separation and purification through existing technologies, or can be prepared by combining corresponding ginkgo terpene lactone monomer compounds.
- the ginkgolide lactones of the present invention include two or more ginkgolide lactone monomer compounds, they can be prepared by combining the corresponding monomer compounds.
- composition containing ginkgolide A, ginkgolide B, ginkgolide C and bilobalide of the present invention can be directly purchased as commercially available ginkgolide injection, or prepared by the method of ZL200610103626.0 or ZL200610103625.6, or by combining monomer compounds.
- the ginkgo terpene lactone monomer compounds of the present invention can be obtained by purchasing commercial products, or can be prepared by separation and purification using existing methods.
- the ginkgolide monomer of the present invention can specifically be ginkgolide A, B, C, M, J, K, L, N, P, Q or bilobalide and other ginkgolide monomer compounds.
- SPF 6-week-old db/db male spontaneous type II diabetic mice (strain name: BKS-Leprem2Cd479/Gpt, strain number: T002407) were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd. After one week of adaptive feeding, diabetic mice with fasting blood glucose (FBG) of 7mmol/L ⁇ FBG ⁇ 16.8mmol/L were selected for inclusion in the group.
- FBG fasting blood glucose
- Composition A comprises the following components in parts by weight: 41.5 parts of bilobalide, 26 parts of ginkgolide A, 16 parts of ginkgolide B, 15 parts of ginkgolide C, and 4.3 parts of ginkgolide J.
- Ginkgolide, Ginkgolide A, Ginkgolide B, Ginkgolide C, and Ginkgolide J are all from Chengdu Baiyu Pharmaceutical Co., Ltd.
- mice Body weight and blood sugar were monitored weekly. Before testing, mice were fasted for 12-14 hours, blood was collected from the tail vein, and the blood sugar level of mice was measured using a Roche blood glucose meter.
- TG Triglyceride
- HbA1c% glycated hemoglobin content
- FIG1 is a graph showing the changing trend of blood glucose levels in mice after administration of composition A for 0 to 8 weeks, wherein Vehicle is a blank control group.
- Table 1 and Figure 1 show that the blood glucose levels of the model group, the low-dose group of Composition A, and the high-dose group of Composition A were significantly higher than those of the blank control mice on the day of dosing (D0); after 8 weeks of administration, the fasting blood glucose levels of the low-dose group of Composition A and the high-dose group of Composition A were significantly lower than those of the model group, and Composition A significantly lowered fasting blood glucose in a dose-dependent manner.
- composition A The effect of composition A on glycosylated hemoglobin in mice is shown in Table 2.
- FIG2 is a bar graph showing the glycated hemoglobin level in mice after administration of Composition A for 7 weeks, wherein Vehicle is a blank control group.
- mice The TG (triglyceride) levels of mice after administration of Composition A for 7 weeks are shown in Table 3.
- FIG3 is a bar graph showing TG (triglyceride) levels in mice after administration of Composition A for 7 weeks, wherein Vehicle is a blank control.
- composition A of the present invention has a significant therapeutic effect on diabetes and can be used to prepare drugs for preventing and treating diabetes, drugs for preventing or treating diabetic complications, etc.
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Abstract
The present invention provides use of a ginkgo terpene lactone in preparing a drug for preventing or treating diabetes and a diabetic complication.
Description
本发明涉及药物技术领域,具体涉及银杏萜内酯在制备预防或治疗糖尿病及糖尿病并发症药物上的用途。The present invention relates to the field of pharmaceutical technology, and in particular to the use of ginkgo terpene lactone in preparing medicines for preventing or treating diabetes and diabetic complications.
糖尿病是高血糖为主要特征的疾病。糖尿病主要分为I型糖尿病和II型糖尿病两种,还包括妊娠糖尿病和特殊类型糖尿病。I型糖尿病的发病原因是自身免疫破坏胰岛β细胞,从而导致胰岛素分泌的绝对缺乏,患者只有通过注射胰岛素才能维持生命;II型糖尿病也称非胰岛素依赖性糖尿病,它与β细胞功能障碍和胰岛素抵抗有关,同时也受到遗传因素和环境因素的影响,患者人数占糖尿病患者90%以上,且大多数是中老年人,可以通过服用降糖类药物和合理的运动饮食进行治疗。妊娠糖尿病的患者胰岛功能没有问题,但孕期血糖会升高。Diabetes is a disease characterized by high blood sugar. Diabetes is mainly divided into type I diabetes and type II diabetes, and also includes gestational diabetes and special types of diabetes. The cause of type I diabetes is autoimmune destruction of pancreatic β cells, which leads to an absolute lack of insulin secretion. Patients can only maintain their lives by injecting insulin; type II diabetes is also called non-insulin-dependent diabetes. It is related to β cell dysfunction and insulin resistance, and is also affected by genetic and environmental factors. The number of patients accounts for more than 90% of diabetic patients, and most of them are middle-aged and elderly people. They can be treated by taking hypoglycemic drugs and a reasonable exercise diet. Patients with gestational diabetes have no problems with pancreatic islet function, but blood sugar will rise during pregnancy.
现如今,糖尿病及其并发症的发生率及致死率呈现逐年升高的趋势,己成为威胁人类健康和生存的主要疾病。同时患者长期高血糖水平会导致体内大血管、微血管受损,从而进一步危及心、脑、肝、肾、眼睛、足、周围神经等组织,导致一系列并发症。Nowadays, the incidence and mortality of diabetes and its complications are increasing year by year, and have become a major disease threatening human health and survival. At the same time, long-term high blood sugar levels in patients can cause damage to large blood vessels and microvessels in the body, further endangering the heart, brain, liver, kidneys, eyes, feet, peripheral nerves and other tissues, leading to a series of complications.
因此,开发一些新的用于预防或治疗糖尿病及其并发症的药物十分必要。Therefore, it is necessary to develop some new drugs for preventing or treating diabetes and its complications.
发明内容Summary of the invention
本发明的目的在于提供一种银杏萜内酯在制备预防或治疗糖尿病及糖尿病并发症药物上的用途。The purpose of the present invention is to provide a use of ginkgo terpene lactones in preparing a medicine for preventing or treating diabetes and diabetic complications.
本发明解决技术问题是采用以下技术方案来实现的:The present invention solves the technical problem by adopting the following technical solutions:
本发明第一方面,提供一种银杏萜内酯在制备预防或治疗糖尿病药物、预防或治疗糖尿病并发症药物上的用途。The first aspect of the present invention provides a use of ginkgo terpene lactones in the preparation of drugs for preventing or treating diabetes, or drugs for preventing or treating diabetic complications.
在本发明的一些实施例中,所述银杏萜内酯包括银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯J、银杏内酯K中的至少一种。In some embodiments of the present invention, the ginkgolide comprises at least one of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J and ginkgolide K.
在本发明的一些实施例中,所述银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯J、银杏内酯K的重量比选自如下之一:In some embodiments of the present invention, the weight ratio of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, and ginkgolide K is selected from the following:
银杏内酯A:银杏内酯B=(10~45):(5~40);Ginkgolide A: Ginkgolide B = (10-45): (5-40);
银杏内酯A:银杏内酯C=(10~45):(3~35);Ginkgolide A: Ginkgolide C = (10-45): (3-35);
银杏内酯B:银杏内酯C=(5~40):(3~35);
Ginkgolide B: Ginkgolide C = (5-40): (3-35);
银杏内酯A:银杏内酯B:银杏内酯C=(10~45):(5~40):(3~35);Ginkgolide A: Ginkgolide B: Ginkgolide C = (10-45): (5-40): (3-35);
银杏内酯A:银杏内酯B:银杏内酯C:银杏内酯J=(10~45):(5~40):(3~35):(1~10);Ginkgolide A: Ginkgolide B: Ginkgolide C: Ginkgolide J = (10-45): (5-40): (3-35): (1-10);
银杏内酯A:银杏内酯K=(3~40):(0.01~5);Ginkgolide A: Ginkgolide K = (3-40): (0.01-5);
银杏内酯B:银杏内酯K=(5~75):(0.01~5);Ginkgolide B: Ginkgolide K = (5-75): (0.01-5);
银杏内酯A:银杏内酯B:银杏内酯K=(3~40):(5~75):(0.01~5)。Ginkgolide A: Ginkgolide B: Ginkgolide K = (3-40): (5-75): (0.01-5).
在本发明的一些实施例中,所述银杏萜内酯还包括白果内酯。In some embodiments of the present invention, the ginkgo terpene lactones further include bilobalide.
在本发明的一些实施例中,所述银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯J、银杏内酯K、白果内酯的质量比选自如下之一:In some embodiments of the present invention, the mass ratio of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide K, and bilobalide is selected from the following:
银杏内酯A:银杏内酯B:白果内酯=(10~45):(5~40):(10~70);Ginkgolide A: Ginkgolide B: Bilobalide = (10-45): (5-40): (10-70);
银杏内酯A:银杏内酯C:白果内酯=(10~45):(3~35):(10~70);Ginkgolide A: Ginkgolide C: Bilobalide = (10-45): (3-35): (10-70);
银杏内酯B:银杏内酯C:白果内酯=(5~40):(3~35):(10~70);Ginkgolide B: Ginkgolide C: Bilobalide = (5-40): (3-35): (10-70);
银杏内酯A:银杏内酯B:银杏内酯C:白果内酯=(10~45):(5~40):(3~35):(10~70);Ginkgolide A: Ginkgolide B: Ginkgolide C: Bilobalide = (10-45): (5-40): (3-35): (10-70);
银杏内酯A:银杏内酯B:银杏内酯C:银杏内酯J:白果内酯=(10~45):(5~40):(3~35):(1~10):(10~70);Ginkgolide A: Ginkgolide B: Ginkgolide C: Ginkgolide J: Bilobalide = (10-45): (5-40): (3-35): (1-10): (10-70);
银杏内酯A:银杏内酯K:白果内酯=(3~40):(0.01~5):(10~70);Ginkgolide A: Ginkgolide K: Bilobalide = (3-40): (0.01-5): (10-70);
银杏内酯B:银杏内酯K:白果内酯=(5~75):(0.01~5):(10~70);Ginkgolide B: Ginkgolide K: Bilobalide = (5-75): (0.01-5): (10-70);
银杏内酯A:银杏内酯B:银杏内酯K:白果内酯=(3~40):(5~75):(0.01~5):(10~70)。Ginkgolide A: Ginkgolide B: Ginkgolide K: Bilobalide = (3-40): (5-75): (0.01-5): (10-70).
在本发明的一些实施例中,所述银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯J、白果内酯的质量份数选自:40~43份的白果内酯,25~27份的银杏内酯A,15~17份的银杏内酯B,14~16份的银杏内酯C,3.5~5份的银杏内酯J。In some embodiments of the present invention, the mass proportions of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J and bilobalide are selected from: 40 to 43 parts of bilobalide, 25 to 27 parts of ginkgolide A, 15 to 17 parts of ginkgolide B, 14 to 16 parts of ginkgolide C, and 3.5 to 5 parts of ginkgolide J.
在本发明的一些实施例中,所述银杏内酯的剂量1~800mg/kg/日。In some embodiments of the present invention, the dosage of ginkgolide is 1-800 mg/kg/day.
在本发明的一些实施例中,所述银杏内酯的剂量为1~500mg/kg/日。In some embodiments of the present invention, the dosage of ginkgolide is 1-500 mg/kg/day.
在本发明的一些实施例中,所述银杏内酯的剂量为1~150mg/kg/日。In some embodiments of the present invention, the dosage of ginkgolide is 1 to 150 mg/kg/day.
在本发明的一些实施例中,所述银杏内酯的剂量为10mg/kg/日、20mg/kg/日、30mg/kg/日、40mg/kg/日、50mg/kg/日、60mg/kg/日、70mg/kg/日、80mg/kg/日、90mg/kg/日、100mg/kg/日、110mg/kg/日、120mg/kg/日、130mg/kg/日、140mg/kg/日或150mg/kg/日。In some embodiments of the present invention, the dosage of ginkgolide is 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, 40 mg/kg/day, 50 mg/kg/day, 60 mg/kg/day, 70 mg/kg/day, 80 mg/kg/day, 90 mg/kg/day, 100 mg/kg/day, 110 mg/kg/day, 120 mg/kg/day, 130 mg/kg/day, 140 mg/kg/day or 150 mg/kg/day.
在本发明的一些实施例中,所述糖尿病为I型糖尿病、II型糖尿病或妊娠糖尿病。
In some embodiments of the present invention, the diabetes is type I diabetes, type II diabetes or gestational diabetes.
在本发明的一些实施例中,所述糖尿病为II型糖尿病。In some embodiments of the present invention, the diabetes is type II diabetes.
在本发明的一些实施例中,所述糖尿病并发症为血脂异常。In some embodiments of the present invention, the diabetic complication is dyslipidemia.
在本发明的一些实施例中,所述血脂异常为高胆固醇血症、高甘油三酯血症、混合型高血脂症或低高密度脂蛋白血症。In some embodiments of the present invention, the dyslipidemia is hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia or low high-density lipoproteinemia.
本发明包括以下有益效果:银杏萜内酯可以显著降低空腹血糖、甘油三酯和糖化血红蛋白的水平。银杏萜内酯对糖尿病具有显著的治疗作用,可用于制备预防和治疗糖尿病的药物、预防或治疗糖尿病并发症的药物等。The invention has the following beneficial effects: Ginkgo biloba lactones can significantly reduce the levels of fasting blood sugar, triglycerides and glycosylated hemoglobin. Ginkgo biloba lactones have a significant therapeutic effect on diabetes and can be used to prepare drugs for preventing and treating diabetes, drugs for preventing or treating diabetic complications, etc.
图1为组合物A给药0-8周小鼠血糖水平变化趋势图。FIG1 is a graph showing the changing trend of blood glucose levels in mice after administration of composition A for 0-8 weeks.
图2为组合物A给药7周后小鼠糖化血红蛋白水平柱状图。FIG2 is a bar graph showing the glycated hemoglobin level in mice after administration of Composition A for 7 weeks.
图3为组合物A给药7周后小鼠TG(甘油三酯)水平柱状图。FIG3 is a bar graph showing TG (triglyceride) levels in mice after administration of Composition A for 7 weeks.
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。Unless stated otherwise, the terms used in the specification and claims have the following meanings.
如本发明所述,术语“预防”指预防疾病发生和/或预防疾病复发。As used herein, the term "prevention" refers to preventing the occurrence of a disease and/or preventing the recurrence of a disease.
本发明所述银杏萜内酯可以通过现有技术分离纯化制得,也可以由相应银杏萜内酯单体化合物组合而成。The ginkgo terpene lactones of the present invention can be prepared by separation and purification through existing technologies, or can be prepared by combining corresponding ginkgo terpene lactone monomer compounds.
当本发明所述的银杏萜内酯包含两种或两种以上的银杏萜内酯单体化合物时,可以通过将相应单体化合物组合而成。When the ginkgolide lactones of the present invention include two or more ginkgolide lactone monomer compounds, they can be prepared by combining the corresponding monomer compounds.
本发明所述的含有银杏内酯A、银杏内酯B、银杏内酯C和白果内酯的组合物,可以直接购买市售的银杏内酯注射液,或者通过ZL200610103626.0或ZL200610103625.6的方法制得,还可通过将单体化合物组合而成。The composition containing ginkgolide A, ginkgolide B, ginkgolide C and bilobalide of the present invention can be directly purchased as commercially available ginkgolide injection, or prepared by the method of ZL200610103626.0 or ZL200610103625.6, or by combining monomer compounds.
本发明所述的银杏萜内酯单体化合物,均可以通过购买市售产品得到,或通过现有方法分离纯化制备。The ginkgo terpene lactone monomer compounds of the present invention can be obtained by purchasing commercial products, or can be prepared by separation and purification using existing methods.
本发明所述银杏萜内酯单体,具体地,可以是银杏内酯A、B、C、M、J、K、L、N、P、Q或白果内酯等银杏萜内酯单体化合物。The ginkgolide monomer of the present invention can specifically be ginkgolide A, B, C, M, J, K, L, N, P, Q or bilobalide and other ginkgolide monomer compounds.
本发明说明书对具体实施方案进行了详细描述,本领域技术人员应认识到,下述实施方案是示例性的,不能理解为对本发明的限制,对于本领域技术人员来说,在不脱离本发明原
理的前提下,通过对本发明进行若干改进和修饰,这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。以下通过实施例具体说明本发明的有益效果。The present invention describes the specific embodiments in detail. Those skilled in the art should recognize that the following embodiments are exemplary and cannot be construed as limiting the present invention. On the premise of the principle, by making some improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the protection scope of the claims of the present invention. The beneficial effects of the present invention are specifically described by examples below.
db/db小鼠糖尿病模型中的药效试验Drug efficacy test in db/db mouse diabetes model
1、实验步骤1. Experimental steps
1.1试验动物与试剂1.1 Experimental animals and reagents
SPF级6周龄db/db雄性自发性II型糖尿病小鼠(品系名称:BKS-Leprem2Cd479/Gpt,品系编号:T002407),购自江苏集萃药康生物科技股份有限公司。适应性饲养一周后,筛选空腹血糖值(FBG)在7mmol/L≤FBG≤16.8mmol/L的糖尿病小鼠入组。SPF 6-week-old db/db male spontaneous type II diabetic mice (strain name: BKS-Leprem2Cd479/Gpt, strain number: T002407) were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd. After one week of adaptive feeding, diabetic mice with fasting blood glucose (FBG) of 7mmol/L≤FBG≤16.8mmol/L were selected for inclusion in the group.
组合物A包括如下重量份的组分:41.5份的白果内酯,26份的银杏内酯A,16份的银杏内酯B,15份的银杏内酯C,4.3份的银杏内酯J。Composition A comprises the following components in parts by weight: 41.5 parts of bilobalide, 26 parts of ginkgolide A, 16 parts of ginkgolide B, 15 parts of ginkgolide C, and 4.3 parts of ginkgolide J.
白果内酯、银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯J均来自成都百裕制药股份有限公司。Ginkgolide, Ginkgolide A, Ginkgolide B, Ginkgolide C, and Ginkgolide J are all from Chengdu Baiyu Pharmaceutical Co., Ltd.
1.2给药方法:1.2 Administration method:
采用随机分组的方式分成4组,每组11只(n=11),组别包括:db/m对照小鼠组(空白对照组,Vehicle)、db/db模型组(模型组)、组合物A高剂量组(200mg/kg,BID)、组合物A低剂量组(50mg/kg,BID)、组合物A剂量I组(10mg/kg,BID)、组合物A剂量II组(50mg/kg,BID)、组合物A剂量III组(100mg/kg,BID)、组合物A剂量IV组(150mg/kg,BID)。空白对照组和模型组灌胃溶媒(DMSO:0.5%MC(V:V=5:95)),灌胃给药8周。The mice were randomly divided into 4 groups, each with 11 mice (n=11), including db/m control mice group (blank control group, Vehicle), db/db model group (model group), high-dose group of composition A (200 mg/kg, BID), low-dose group of composition A (50 mg/kg, BID), dose group I of composition A (10 mg/kg, BID), dose group II of composition A (50 mg/kg, BID), dose group III of composition A (100 mg/kg, BID), and dose group IV of composition A (150 mg/kg, BID). The blank control group and the model group were intragastrically administered with vehicle (DMSO: 0.5% MC (V:V=5:95)) for 8 weeks.
2、检测指标2. Detection indicators
2.1空腹血糖的测定2.1 Determination of fasting blood glucose
每周监测体重,血糖。检测前将小鼠禁食12~14h,经尾静脉采血,用罗氏血糖仪测定小鼠的血糖值。Body weight and blood sugar were monitored weekly. Before testing, mice were fasted for 12-14 hours, blood was collected from the tail vein, and the blood sugar level of mice was measured using a Roche blood glucose meter.
2.2生化指标检测2.2 Biochemical index detection
摘眼球取血,于4000r/min离心5分钟,分离血清,采用全自动生化分析仪检测甘油三脂(TG),采用试剂盒检测糖化血红蛋白含量(HbA1c%)。Blood was collected by removing the eyeballs and centrifuged at 4000 r/min for 5 minutes to separate serum. Triglyceride (TG) was detected by an automatic biochemical analyzer, and the glycated hemoglobin content (HbA1c%) was detected by a kit.
2.3统计学方法2.3 Statistical methods
采用Graphpad Prism8.0统计学软件进行处理分析,结果以Mean±SEM表示,组间比较用One-wayANOVA单因素方差分析,P<0.05差异具有统计学意义。Graphpad Prism 8.0 statistical software was used for processing and analysis. The results were expressed as Mean ± SEM. One-way ANOVA was used for comparison among the groups. The differences were considered statistically significant when P < 0.05.
3、实验结果3. Experimental results
3.1组合物A对II型糖尿病小鼠血糖水平的影响
3.1 Effect of Composition A on Blood Glucose Levels in Type II Diabetic Mice
组合物A给药0~8周小鼠血糖水平变化趋势如表1所示。The changing trend of blood glucose levels in mice after administration of composition A for 0 to 8 weeks is shown in Table 1.
表1
Table 1
Table 1
注:*P<0.05,**<0.01,***<0.001,VS模型组Note: *P<0.05, **<0.01, ***<0.001, VS model group
#P<0.05,##<0.01,###<0.001,VS空白对照组#P<0.05, ##<0.01, ###<0.001, VS blank control group
图1为组合物A给药0~8周小鼠血糖水平变化趋势图,其中Vehicle为空白对照组。FIG1 is a graph showing the changing trend of blood glucose levels in mice after administration of composition A for 0 to 8 weeks, wherein Vehicle is a blank control group.
表1和图1结果表明:模型组、组合物A低剂量组、组合物A高剂量组的血糖在给药分组当天(D0)时已经明显高于空白对照小鼠;给药8周后,组合物A低剂量组、组合物A高剂量组相较于模型组均显著性地降低空腹血糖,组合物A显著性的以剂量依赖的方式降低空腹血糖。The results in Table 1 and Figure 1 show that the blood glucose levels of the model group, the low-dose group of Composition A, and the high-dose group of Composition A were significantly higher than those of the blank control mice on the day of dosing (D0); after 8 weeks of administration, the fasting blood glucose levels of the low-dose group of Composition A and the high-dose group of Composition A were significantly lower than those of the model group, and Composition A significantly lowered fasting blood glucose in a dose-dependent manner.
3.2组合物A对II型糖尿病小鼠糖化血红蛋白水平的影响3.2 Effect of Composition A on Glycated Hemoglobin Levels in Type II Diabetic Mice
组合物A对小鼠糖化血红蛋白的影响如表2所示。The effect of composition A on glycosylated hemoglobin in mice is shown in Table 2.
表2
Table 2
Table 2
注:*P<0.05,**<0.01,***<0.001,VS模型组Note: *P<0.05, **<0.01, ***<0.001, VS model group
#P<0.05,##<0.01,###<0.001,VS空白对照组#P<0.05, ##<0.01, ###<0.001, VS blank control group
图2为组合物A给药7周后小鼠糖化血红蛋白水平柱状图,其中Vehicle为空白对照组。FIG2 is a bar graph showing the glycated hemoglobin level in mice after administration of Composition A for 7 weeks, wherein Vehicle is a blank control group.
表2和图2结果表明:给药7周后,组合物A低剂量组、组合物A高剂量组相较于模型组均显著性地降低糖化血红蛋白水平,组合物A显著性的以剂量依赖的方式降低糖化血红蛋白。The results in Table 2 and Figure 2 show that after 7 weeks of administration, both the low-dose group and the high-dose group of Composition A significantly reduced the level of glycated hemoglobin compared with the model group, and Composition A significantly reduced glycated hemoglobin in a dose-dependent manner.
3.3组合物A对II型糖尿病小鼠血脂水平的影响3.3 Effect of Composition A on Blood Lipid Levels in Type II Diabetic Mice
组合物A给药7周后小鼠TG(甘油三酯)水平如表3所示。The TG (triglyceride) levels of mice after administration of Composition A for 7 weeks are shown in Table 3.
表3
table 3
table 3
注:*P<0.05,**<0.01,***<0.001,VS模型组Note: *P<0.05, **<0.01, ***<0.001, VS model group
#P<0.05,##<0.01,###<0.001,VS空白对照组#P<0.05, ##<0.01, ###<0.001, VS blank control group
图3为组合物A给药7周后小鼠TG(甘油三酯)水平柱状图,其中Vehicle为空白对照。FIG3 is a bar graph showing TG (triglyceride) levels in mice after administration of Composition A for 7 weeks, wherein Vehicle is a blank control.
表3和图3结果表明:与空白对照组(Vehicle)相比,模型组小鼠血清中TG水平显著升高(P<0.01)。给药治疗7周后,与模型组相比,组合物A高剂量组、组合物A低剂量组的TG水平都不同程度显著下降。The results in Table 3 and Figure 3 show that compared with the blank control group (Vehicle), the TG level in the serum of the model group mice was significantly increased (P < 0.01). After 7 weeks of treatment, compared with the model group, the TG levels of the high-dose group and the low-dose group of Composition A were significantly decreased to varying degrees.
综上说明:本发明的组合物A对糖尿病具有显著的治疗作用,可用于制备预防和治疗糖尿病的药物、预防或治疗糖尿病并发症的药物等。In summary, the composition A of the present invention has a significant therapeutic effect on diabetes and can be used to prepare drugs for preventing and treating diabetes, drugs for preventing or treating diabetic complications, etc.
本发明说明书对具体实施方案进行了详细描述,本领域技术人员应认识到,上述实施方案是示例性的,不能理解为对本发明的限制,对于本领域技术人员来说,在不脱离本发明原理的前提下,通过对本发明进行若干改进和修饰,这些改进和修饰获得的技术方案也落在本发明的权利要求书的保护范围内。
The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principle of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (11)
- 银杏萜内酯在制备预防或治疗糖尿病药物、预防或治疗糖尿病并发症药物上的用途。Use of ginkgo terpene lactones in preparing drugs for preventing or treating diabetes and drugs for preventing or treating diabetic complications.
- 根据权利要求1所述的用途,其特征在于:所述银杏萜内酯包括银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯J、银杏内酯K中的至少一种。The use according to claim 1, characterized in that the ginkgolide comprises at least one of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J and ginkgolide K.
- 根据权利要求2所述的用途,其特征在于:所述银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯J、银杏内酯K的重量比选自如下之一:The use according to claim 2, characterized in that the weight ratio of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J and ginkgolide K is selected from one of the following:银杏内酯A:银杏内酯B=(10~45):(5~40);Ginkgolide A: Ginkgolide B = (10-45): (5-40);银杏内酯A:银杏内酯C=(10~45):(3~35);Ginkgolide A: Ginkgolide C = (10-45): (3-35);银杏内酯B:银杏内酯C=(5~40):(3~35);Ginkgolide B: Ginkgolide C = (5-40): (3-35);银杏内酯A:银杏内酯B:银杏内酯C=(10~45):(5~40):(3~35);Ginkgolide A: Ginkgolide B: Ginkgolide C = (10-45): (5-40): (3-35);银杏内酯A:银杏内酯B:银杏内酯C:银杏内酯J=(10~45):(5~40):(3~35):(1~10);Ginkgolide A: Ginkgolide B: Ginkgolide C: Ginkgolide J = (10-45): (5-40): (3-35): (1-10);银杏内酯A:银杏内酯K=(3~40):(0.01~5);Ginkgolide A: Ginkgolide K = (3-40): (0.01-5);银杏内酯B:银杏内酯K=(5~75):(0.01~5);Ginkgolide B: Ginkgolide K = (5-75): (0.01-5);银杏内酯A:银杏内酯B:银杏内酯K=(3~40):(5~75):(0.01~5)。Ginkgolide A: Ginkgolide B: Ginkgolide K = (3-40): (5-75): (0.01-5).
- 根据权利要求2所述的用途,其特征在于:所述银杏萜内酯还包括白果内酯。The use according to claim 2 is characterized in that the ginkgo terpene lactones also include bilobalide.
- 根据权利要求4所述的用途,其特征在于:所述银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯J、银杏内酯K、白果内酯的质量比选自如下之一:The use according to claim 4, characterized in that the mass ratio of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide K and bilobalide is selected from the following:银杏内酯A:银杏内酯B:白果内酯=(10~45):(5~40):(10~70);Ginkgolide A: Ginkgolide B: Bilobalide = (10-45): (5-40): (10-70);银杏内酯A:银杏内酯C:白果内酯=(10~45):(3~35):(10~70);Ginkgolide A: Ginkgolide C: Bilobalide = (10-45): (3-35): (10-70);银杏内酯B:银杏内酯C:白果内酯=(5~40):(3~35):(10~70);Ginkgolide B: Ginkgolide C: Bilobalide = (5-40): (3-35): (10-70);银杏内酯A:银杏内酯B:银杏内酯C:白果内酯=(10~45):(5~40):(3~35):(10~70);Ginkgolide A: Ginkgolide B: Ginkgolide C: Bilobalide = (10-45): (5-40): (3-35): (10-70);银杏内酯A:银杏内酯B:银杏内酯C:银杏内酯J:白果内酯=(10~45):(5~40):(3~35):(1~10):(10~70);Ginkgolide A: Ginkgolide B: Ginkgolide C: Ginkgolide J: Bilobalide = (10-45): (5-40): (3-35): (1-10): (10-70);银杏内酯A:银杏内酯K:白果内酯=(3~40):(0.01~5):(10~70);Ginkgolide A: Ginkgolide K: Bilobalide = (3-40): (0.01-5): (10-70);银杏内酯B:银杏内酯K:白果内酯=(5~75):(0.01~5):(10~70);Ginkgolide B: Ginkgolide K: Bilobalide = (5-75): (0.01-5): (10-70);银杏内酯A:银杏内酯B:银杏内酯K:白果内酯=(3~40):(5~75):(0.01~5):(10~70)。Ginkgolide A: Ginkgolide B: Ginkgolide K: Bilobalide = (3-40): (5-75): (0.01-5): (10-70).
- 根据权利要求5所述的用途,其特征在于:所述银杏内酯A、银杏内酯B、银杏内酯C、 银杏内酯J、白果内酯的质量份数选自:The use according to claim 5, characterized in that: the ginkgolide A, ginkgolide B, ginkgolide C, The mass fractions of Ginkgolide J and Bilobalide are selected from:40~43份的白果内酯,25~27份的银杏内酯A,15~17份的银杏内酯B,14~16份的银杏内酯C,3.5~5份的银杏内酯J。40-43 parts of bilobalide, 25-27 parts of ginkgolide A, 15-17 parts of ginkgolide B, 14-16 parts of ginkgolide C, and 3.5-5 parts of ginkgolide J.
- 根据权利要求1所述的用途,其特征在于:所述银杏内酯的剂量1~800mg/kg/日。The use according to claim 1, characterized in that the dosage of ginkgolide is 1 to 800 mg/kg/day.
- 根据权利要求1所述的用途,其特征在于:所述银杏内酯的剂量为1~500mg/kg/日。The use according to claim 1, characterized in that the dosage of ginkgolide is 1 to 500 mg/kg/day.
- 根据权利要求1~8任一项所述的用途,其特征在于:所述糖尿病为I型糖尿病、II型糖尿病或妊娠糖尿病。The use according to any one of claims 1 to 8, characterized in that the diabetes is type I diabetes, type II diabetes or gestational diabetes.
- 根据权利要求1~8任一项所述的用途,其特征在于,所述糖尿病并发症为血脂异常。The use according to any one of claims 1 to 8, characterized in that the diabetic complication is dyslipidemia.
- 根据权利要求10所述的用途,其特征在于,所述血脂异常为高胆固醇血症、高甘油三酯血症、混合型高血脂症或低高密度脂蛋白血症。 The use according to claim 10, characterized in that the dyslipidemia is hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia or low high-density lipoproteinemia.
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