WO2024067579A1

WO2024067579A1 - Use of ginkgo terpene lactone in preparing drug for preventing or treating diabetes and diabetic complication

Info

Publication number: WO2024067579A1
Application number: PCT/CN2023/121513
Authority: WO
Inventors: 叶飞; 楚洪柱; 苏桂转; 魏用刚; 高志文; 孙毅
Original assignee: 成都百裕制药股份有限公司
Priority date: 2022-09-29
Filing date: 2023-09-26
Publication date: 2024-04-04

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

Use of ginkgo terpene lactones in the preparation of drugs for preventing or treating diabetes and diabetic complications

Technical Field

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.

Background technique

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.

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.

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

Summary of the invention

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 present invention solves the technical problem by adopting the following technical solutions:

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.

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.

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:

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).

In some embodiments of the present invention, the ginkgo terpene lactones further include bilobalide.

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:

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).

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.

In some embodiments of the present invention, the dosage of ginkgolide is 1-800 mg/kg/day.

In some embodiments of the present invention, the dosage of ginkgolide is 1-500 mg/kg/day.

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

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.

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

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

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

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

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.

BRIEF DESCRIPTION OF THE DRAWINGS

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.

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

As used herein, the term "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.

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.

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.

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.

Detailed ways

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.

Drug efficacy test in db/db mouse diabetes model

1. Experimental steps

1.1 Experimental animals and reagents

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.

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.

1.2 Administration method:

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. Detection indicators

2.1 Determination of fasting blood glucose

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 Biochemical index detection

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 Statistical methods

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. Experimental results

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

The changing trend of blood glucose levels in mice after administration of composition A for 0 to 8 weeks is shown in Table 1.

Table 1

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

#P＜0.05, ##＜0.01, ###＜0.001, VS blank control group

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.

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 Effect of Composition A on Glycated Hemoglobin Levels in Type II Diabetic Mice

The effect of composition A on glycosylated hemoglobin in mice is shown in Table 2.

Table 2

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

#P＜0.05, ##＜0.01, ###＜0.001, VS blank control group

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.

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 Effect of Composition A on Blood Lipid Levels in Type II Diabetic Mice

The TG (triglyceride) levels of mice after administration of Composition A for 7 weeks are shown in Table 3.

table 3

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

#P＜0.05, ##＜0.01, ###＜0.001, VS blank control group

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.

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.

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.

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

Use of ginkgo terpene lactones in preparing drugs for preventing or treating diabetes and drugs for preventing or treating diabetic complications.
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.
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:

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).
The use according to claim 2 is characterized in that the ginkgo terpene lactones also include bilobalide.
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).
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 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.
The use according to claim 1, characterized in that the dosage of ginkgolide is 1 to 800 mg/kg/day.
The use according to claim 1, characterized in that the dosage of ginkgolide is 1 to 500 mg/kg/day.
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.
The use according to any one of claims 1 to 8, characterized in that the diabetic complication is dyslipidemia.
The use according to claim 10, characterized in that the dyslipidemia is hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia or low high-density lipoproteinemia.