Application of ginkgo terpene lactone in preparation of medicine for preventing or treating diabetes and diabetic complications

Abstract

The invention provides application of ginkgo terpene lactones in preparation of drugs for preventing or treating diabetes and diabetic complications.

Description

Use of ginkgo lactones in preparing drugs for preventing or treating diabetes and diabetic complications Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to use of ginkgo terpene lactones in preparing medicines for preventing or treating diabetes and diabetic complications. Background Art

[0002] Diabetes is a disease characterized by high blood sugar levels. It is primarily categorized into type 1 and type 2 diabetes, as well as gestational diabetes and specific forms of diabetes. Type 1 diabetes is caused by autoimmune destruction of pancreatic beta cells, resulting in an absolute lack of insulin secretion. Patients must rely on insulin injections to survive. Type 2 diabetes, also known as non-insulin-dependent diabetes, is associated with beta cell dysfunction and insulin resistance, and is also influenced by genetic and environmental factors. It accounts for over 90% of all diabetes patients, and the majority are middle-aged and elderly. Treatment options include hypoglycemic medications, exercise, and a healthy diet. Patients with gestational diabetes typically have normal pancreatic function, but their blood sugar levels rise during pregnancy.

[0003] The incidence and mortality of diabetes and its complications are increasing year by year, making it a major threat to human health and survival. Chronic high blood sugar levels can damage large and small blood vessels, further endangering the heart, brain, liver, kidneys, eyes, feet, peripheral nerves, and other tissues, leading to a series of complications.

[0004] Therefore, it is necessary to develop some new drugs for preventing or treating diabetes and its complications.

[0005] Summary of the Invention

[0006] The present invention aims to provide a use of ginkgo terpene lactones in preparing a medicament for preventing or treating diabetes and diabetic complications.

[0007] The present invention solves the technical problem by adopting the following technical solutions:

[0008] In a first aspect, the present invention provides a use of ginkgo biloba lactones in the preparation of a drug for preventing or treating diabetes or a drug for preventing or treating diabetic complications.

[0009] 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.

[0010] 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:

[0011] Ginkgolide A: Ginkgolide B = (10-45): (5-40);

[0012] Ginkgolide A: Ginkgolide C = (10-45): (3-35);

[0013] Ginkgolide B: Ginkgolide C = (5-40): (3-35);

[0014] Ginkgolide A: Ginkgolide B: Ginkgolide C = (10-45): (5-40): (3-35);

[0015] Ginkgolide A: Ginkgolide B: Ginkgolide C: Ginkgolide J = (10-45): (5-40): (3-35): (1-10);

[0016] Ginkgolide A: Ginkgolide K = (3-40): (0.01-5);

[0017] Ginkgolide B: Ginkgolide K = (5-75): (0.01-5);

[0018] Ginkgolide A: Ginkgolide B: Ginkgolide K = (3-40): (5-75): (0.01-5).

[0019] In some embodiments of the present invention, the ginkgo lactones further include bilobalide.

[0020] 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:

[0021] Ginkgolide A: Ginkgolide B: Bilobalide = (10-45): (5-40): (10-70);

[0022] Ginkgolide A: Ginkgolide C: Bilobalide = (10-45): (3-35): (10-70);

[0023] Ginkgolide B: Ginkgolide C: Bilobalide = (5-40): (3-35): (10-70);

[0024] Ginkgolide A: Ginkgolide B: Ginkgolide C: Bilobalide = (10-45): (5-40): (3-35): (10-70);

[0025] Ginkgolide A: Ginkgolide B: Ginkgolide C: Ginkgolide J: Bilobalide = (10-45): (5-40): (3-35): (1-10): (10-70);

[0026] Ginkgolide A: Ginkgolide K: Bilobalide = (3-40): (0.01-5): (10-70);

[0027] Ginkgolide B: Ginkgolide K: Bilobalide = (5-75): (0.01-5): (10-70);

[0028] Ginkgolide A: Ginkgolide B: Ginkgolide K: Bilobalide = (3-40): (5-75): (0.01-5): (10-70).

[0029] In some embodiments of the present invention, the mass proportions of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, and bilobalide are selected from: 40-43 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.

[0030] In some embodiments of the present invention, the dosage of ginkgolide is 1 to 800 mg / kg / day.

[0031] In some embodiments of the present invention, the dosage of ginkgolide is 1 to 500 mg / kg / day.

[0032] In some embodiments of the present invention, the dosage of ginkgolide is 1 to 150 mg / kg / day.

[0033] 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.

[0034] In some embodiments of the present invention, the diabetes is type I diabetes, type II diabetes or gestational diabetes.

[0035] In some embodiments of the present invention, the diabetes is type II diabetes.

[0036] In some embodiments of the present invention, the diabetic complication is dyslipidemia.

[0037] In some embodiments of the present invention, the dyslipidemia is hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia or low high-density lipoproteinemia.

[0038] The present invention has the following beneficial effects: Ginkgo biloba lactones can significantly reduce fasting blood sugar, triglyceride, and glycosylated hemoglobin levels. Ginkgo biloba lactones have significant therapeutic effects on diabetes and can be used to prepare drugs for preventing and treating diabetes, and drugs for preventing or treating diabetic complications. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIG1 is a graph showing the changing trend of blood glucose levels in mice after administration of composition A for 0 to 8 weeks.

[0040] FIG2 is a bar graph showing the glycated hemoglobin levels in mice after administration of Composition A for 7 weeks.

[0041] FIG3 is a bar graph showing TG (triglyceride) levels in mice after administration of Composition A for 7 weeks.

[0042] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0043] As used herein, the term "prevention" refers to preventing the occurrence of a disease and / or preventing the recurrence of a disease.

[0044] The ginkgo terpene lactones of the present invention can be prepared by separation and purification using existing technologies, or can be prepared by combining corresponding ginkgo terpene lactone monomer compounds.

[0045] When the ginkgolide lactones of the present invention comprise two or more ginkgolide lactone monomer compounds, they can be prepared by combining the corresponding monomer compounds.

[0046] 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 prepared by combining monomer compounds.

[0047] The ginkgo terpene lactone monomer compounds of the present invention can be obtained by purchasing commercial products or prepared by separation and purification using existing methods.

[0048] The ginkgo lactone monomer of the present invention can specifically be ginkgo lactone A, B, C, M, J, K, L, N, P, Q or bilobalide and other ginkgo lactone monomer compounds. DETAILED DESCRIPTION

[0049] While the present invention specification describes specific embodiments in detail, those skilled in the art should recognize that the following embodiments are illustrative and are not to be construed as limiting the present invention. Those skilled in the art will appreciate that improvements and modifications to the present invention, without departing from the principles of the present invention, will be made, and that the resulting technical solutions will fall within the scope of the claims. The following examples illustrate the beneficial effects of the present invention.

[0050] Drug efficacy testing in the db / db mouse diabetic model

[0051] 1. Experimental steps

[0052] 1.1 Experimental animals and reagents

[0053] Six-week-old SPF db / db male spontaneously developing type 2 diabetes (strain name: BKS-Leprem2Cd479 / Gpt, strain number: T002407) were purchased from Jiangsu Jicui Pharmaceutical Kang Biotechnology Co., Ltd. After one week of adaptive feeding, diabetic mice with fasting blood glucose (FBG) values ​​of 7 mmol / L ≤ FBG ≤ 16.8 mmol / L were selected for enrollment.

[0054] Composition A includes 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.

[0055] Ginkgolide, Ginkgolide A, Ginkgolide B, Ginkgolide C, and Ginkgolide J were all obtained from Chengdu Baiyu Pharmaceutical Co., Ltd.

[0056] 1.2 Dosage method:

[0057] The mice were randomly divided into 4 groups, each with 11 mice (n=11), including: db / m control mice (blank control group, Vehicle), db / db model group (model group), high-dose Composition A group (200 mg / kg, BID), low-dose Composition A group (50 mg / kg, BID), Composition A dose I group (10 mg / kg, BID), Composition A dose II group (50 mg / kg, BID), Composition A dose III group (100 mg / kg, BID), and Composition A dose IV group (150 mg / kg, BID). The blank control group and the model group were gavaged with vehicle (DMSO:0.5% MC (V:V=5:95)) for 8 weeks.

[0058] 2. Detection indicators

[0059] 2.1 Determination of fasting blood glucose

[0060] Body weight and blood glucose were monitored weekly. Before testing, mice were fasted for 12-14 hours, blood was collected from the tail vein, and blood glucose levels were measured using a Roche blood glucose meter.

[0061] 2.2 Biochemical index detection

[0062] Blood was collected from the eyeballs and centrifuged at 4000 r / min for 5 minutes to separate the serum. Triglyceride (TG) was measured using an automatic biochemical analyzer, and the glycated hemoglobin content (HbA1c%) was measured using a kit.

[0063] 2.3 Statistical methods

[0064] 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 between groups. The differences were considered statistically significant when P < 0.05.

[0065] 3. Experimental results

[0066] 3.1 Effect of Composition A on Blood Glucose Levels in Type II Diabetic Mice

[0067] The changing trends of blood glucose levels in mice after administration of composition A for 0 to 8 weeks are shown in Table 1.

[0068] Table 1

[0069] Note: *P<0.05, **<0.01, ***<0.001, VS model group

[0070] #P<0.05, ##<0.01, ###<0.001, VS blank control group

[0071] 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 the vehicle group is a blank control group.

[0072] The results in Table 1 and Figure 1 show that the blood glucose levels of the model group, the low-dose composition A group, and the high-dose composition A group were significantly higher than those of the blank control mice on the day of administration (D0); after 8 weeks of administration, the fasting blood glucose levels of the low-dose composition A group and the high-dose composition A group were significantly lower than those of the model group, and composition A significantly reduced fasting blood glucose in a dose-dependent manner.

[0073] 3.2 Effect of Composition A on Glycated Hemoglobin Levels in Type II Diabetic Mice

[0074] The effects of composition A on glycated hemoglobin in mice are shown in Table 2.

[0075] Table 2

[0076] Note: *P<0.05, **<0.01, ***<0.001, VS model group

[0077] #P<0.05, ##<0.01, ###<0.001, VS blank control group

[0078] FIG2 is a bar graph showing the glycated hemoglobin levels in mice after administration of Composition A for 7 weeks, wherein Vehicle is a blank control group.

[0079] 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 glycated hemoglobin level compared with the model group, and Composition A significantly reduced glycated hemoglobin in a dose-dependent manner.

[0080] 3.3 Effect of Composition A on Blood Lipid Levels in Type II Diabetic Mice

[0081] Table 3 shows the TG (triglyceride) levels in mice after 7 weeks of administration of Composition A.

[0082] Table 3

[0083] Note: *P<0.05, **<0.01, ***<0.001, VS model group

[0084] #P<0.05, ##<0.01, ###<0.001, VS blank control group

[0085] 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.

[0086] The results in Table 3 and Figure 3 show that compared with the blank control group (Vehicle), the serum TG level of the model group mice was significantly increased (P < 0.01). After 7 weeks of treatment, the TG levels of the high-dose and low-dose Composition A groups were significantly decreased compared with the model group.

[0087] 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.

[0088] 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 principles 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

1. Use of ginkgo biloba lactones in the preparation of drugs for preventing or treating diabetes, or drugs for preventing or treating diabetic complications.

2. The use according to claim 1, characterized in that: The ginkgolide lactones include at least one of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, and ginkgolide K.

3. 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 the following: Ginkgolide A: Ginkgolide B = (10-45): (5-40); Ginkgolide A: Ginkgolide C = (10-45): (3-35); Ginkgolide B: Ginkgolide C = (5-40): (3-35); Ginkgolide A: Ginkgolide B: Ginkgolide C = (10-45): (5-40): (3-35); Ginkgolide A: Ginkgolide B: Ginkgolide C: Ginkgolide J = (10-45): (5-40): (3-35): (1-10); Ginkgolide A: Ginkgolide K = (3-40): (0.01-5); Ginkgolide B: Ginkgolide K = (5-75): (0.01-5); Ginkgolide A: Ginkgolide B: Ginkgolide K = (3-40): (5-75): (0.01-5).

4. The use according to claim 2, characterized in that: The ginkgo terpene lactones also include bilobalide.

5. 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: Ginkgolide A: Ginkgolide B: Bilobalide = (10-45): (5-40): (10-70); Ginkgolide A: Ginkgolide C: Bilobalide = (10-45): (3-35): (10-70); Ginkgolide B: Ginkgolide C: Bilobalide = (5-40): (3-35): (10-70); Ginkgolide A: Ginkgolide B: Ginkgolide C: Bilobalide = (10-45): (5-40): (3-35): (10-70); Ginkgolide A: Ginkgolide B: Ginkgolide C: Ginkgolide J: Bilobalide = (10-45): (5-40): (3-35): (1-10): (10-70); Ginkgolide A: Ginkgolide K: Bilobalide = (3-40): (0.01-5): (10-70); Ginkgolide B: Ginkgolide K: Bilobalide = (5-75): (0.01-5): (10-70); Ginkgolide A: Ginkgolide B: Ginkgolide K: Bilobalide = (3-40): (5-75): (0.01-5): (10-70).

6. The use according to claim 5, characterized in that: The mass fractions of Ginkgolide A, Ginkgolide B, Ginkgolide C, Ginkgolide J and Bilobalide are selected from: 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.

7. The use according to claim 1, characterized in that: The dosage of the ginkgolide is 1 to 800 mg / kg / day.

8. The use according to claim 1, characterized in that: The dosage of the ginkgolide is 1 to 500 mg / kg / day.

9. The use according to any one of claims 1 to 8, characterized in that: The diabetes mellitus is type I diabetes, type II diabetes or gestational diabetes.

10. The use according to any one of claims 1 to 8, characterized in that The diabetic complication is dyslipidemia.

11. The use according to claim 10, characterized in that The dyslipidemia is hypercholesterolemia, hypertriglyceridemia, mixed hyperlipidemia or low high-density lipoproteinemia.

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