Medicament for treating diabetes mellitus at early stage of pregnancy and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, and particularly discloses a medicament for treating diabetes mellitus at the early stage of pregnancy and a preparation method thereof. The invention discloses a medicament for treating diabetes mellitus in early pregnancy. The medicament is prepared from the following raw materials in parts by weight: 1 to 2 parts of metformin, 0.5 to 1 part of vitamin D, 0.4 to 0.8 part of insulin aspart, 0.3 to 0.4 part of Chinese yam polysaccharide, 0.2 to 0.4 part of mulberry twig extract and 0.1 to 0.2 part of resveratrol. The preparation method comprises the following steps: mixing the metformin, the vitamin D, the insulin aspart, the Chinese yam polysaccharide, the mulberry twig extract and the resveratrol, grinding, and pressing into tablets. The medicament disclosed by the invention is used for preventing and treating early-stage diabetes mellitus in pregnancy, is beneficial to intervention of the early-stage diabetes mellitus, and reduces adverse pregnancy outcomes.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and more specifically, to a medicament for treating early gestational diabetes and a preparation method thereof. Background Art

[0002] Gestational diabetes mellitus (GDM) refers to a metabolic disease in which glucose tolerance is normal or potentially impaired before pregnancy, and abnormal glucose tolerance appears for the first time during pregnancy. It increases the risk of infection and miscarriage during pregnancy, and the risks of preeclampsia, cesarean section, birth trauma, neonatal hypoglycemia, neonatal hyperbilirubinemia, etc. GDM is one of the most common complications during pregnancy, and about 3%-8% of pregnant women develop GDM during pregnancy. It is particularly noteworthy that with the increase in obesity rates among women of childbearing age, the incidence of GDM continues to rise.

[0003] At present, the clinic mainly provides disease-related knowledge education, diet guidance, and exercise guidance for pregnant women with GDM to control blood sugar and improve delivery outcomes. However, in actual diagnosis and treatment, conventional diet and exercise interventions often fail to achieve the expected results, and most patients still need drug treatment. In drug treatment, insulin or hypoglycemic drugs are generally used to achieve the purpose of lowering blood sugar. However, this treatment plan has strict requirements on drug dosage, and as the patient's pregnancy cycle increases, the body's insulin-resistant substances will gradually increase, which will cause the treatment effect of the disease to decrease, thereby causing a variety of complications and neonatal diseases. Therefore, early diagnosis, early intervention, and timely and reasonable treatment are the key to preventing GDM and reducing maternal and infant complications, and are major scientific issues that need to be solved urgently.

[0004] In view of the above-mentioned related technologies, the inventors found that it is urgent to develop a drug that can effectively control early gestational diabetes, which can help with early intervention and reduce adverse pregnancy outcomes. Summary of the invention

[0005] In order to reduce the occurrence of early gestational diabetes, the present application provides a medicament for early gestational diabetes and a preparation method thereof.

[0006] In a first aspect, the present application provides a medicament for treating early gestational diabetes, using the following technical solution: A medicament for treating early gestational diabetes comprises the following raw materials in parts by weight: 1-2 parts of metformin, 0.5-1 parts of vitamin D, 0.4-0.8 parts of aspart insulin, 0.3-0.4 parts of yam polysaccharide, 0.2-0.4 parts of mulberry branch extract, and 0.1-0.2 parts of resveratrol.

[0007] By adopting the above technical scheme, metformin is a commonly used drug for diabetes. It mainly improves the utilization rate of blood glucose by improving insulin sensitivity, and finally improves blood lipids and blood sugar. It can help patients with gestational diabetes achieve more significant blood sugar control effects, but its therapeutic effect is single, so it is used in combination with components such as vitamin D. Vitamin D is a nutrient essential to the human body. Since its receptors are expressed in most body tissues, it will have a great impact on the occurrence and progression of the disease. In addition, vitamin D can stimulate the secretion of insulin, thereby effectively regulating glucose tolerance, regulating inflammation and immune response, and effectively protecting kidney function and reducing the degree of kidney damage. Aspart insulin is a fast-acting insulin analog that can simulate the insulin naturally produced in the human body, thereby playing a role in lowering blood sugar levels. Aspart insulin, as a short-acting insulin, can combine with insulin receptors on muscle and fat cells through aspart insulin molecules to increase tissue absorption of blood glucose, and at the same time have a certain inhibitory effect on the release of liver glycogen, ultimately achieving the purpose of lowering blood sugar. Metformin is a common hypoglycemic drug. After oral administration, it is mainly absorbed by the small intestine. It can reduce blood sugar by improving insulin sensitivity, inhibiting liver glycogen output, and increasing glucose utilization. Metformin may also regulate liver function by activating adenylate-activated protein kinase (AMPK), improve cell capacity balance and metabolism, and play a positive role in promoting the recovery of the body's internal environment homeostasis. Therefore, adding metformin to aspart insulin treatment can further improve insulin sensitivity and improve blood sugar control effects. With the improvement of blood sugar fluctuations, serum PLGF and IGF-1 levels will recover accordingly, which will help the body's metabolism and endocrine recovery; vitamin D can effectively improve clinical hyperthyroidism by reducing the activity of the promoter in the renin gene and increasing blood calcium levels, and reduce the body's proteinuria by inhibiting the signal transduction of nuclear factor-κB and reducing the synthesis of angiotensin II. In addition, the drug can also reduce the damage to the body's cells, block the excessive proliferation of mesangial cells, and effectively inhibit the secretion of inflammatory factors to protect the glomeruli from excessive damage. In addition, the drug can further inhibit the maturation of fat in the body and regulate the flow of calcium ions in fat cells, thereby blocking the effects of related factors such as visfatin and RPB4. Therefore, the combination of vitamin D and metformin can effectively prevent renal damage in patients with gestational diabetes, regulate serum biochemical indicators, and stabilize blood lipid status.

[0008] Insulin is an important cause of resistance to the onset of gestational diabetes. Yam polysaccharides have the effect of lowering blood sugar and improving pregnancy outcomes. They can lower fasting blood sugar and serum insulin indicators, and to a certain extent improve insulin resistance, improve lipid metabolism disorders in gestational diabetes, reduce the birth of macrosomia, and reduce placental weight. They can also achieve the purpose of lowering blood sugar by improving insulin sensitivity, regulating the activity of enzymes related to glucose and lipid metabolism, and synergistic antioxidant effects. Yam polysaccharides can improve the glucose consumption ability of HepG2 cells and enhance the sensitivity of cells to insulin, and have an in vitro hypoglycemic effect. Yam polysaccharides have a significant ability to scavenge hydroxyl free radicals and superoxide anions, and also have a certain degree of reducing ability and total antioxidant activity. Yam polysaccharides have a strong inhibitory effect on α-glucosidase activity and α-amylase activity, which shows that yam polysaccharides have significant antioxidant activity and hypoglycemic activity.

[0009] Mulberry branch extract can improve the glucose and lipid metabolism of parents with gestational diabetes, slow down the progression of diabetes, and reduce organ damage in the parents. Its mechanism of action may be related to the PI3K / AKT signaling pathway and the PPARγ signaling pathway. At the same time, it plays a certain protective role on offspring and reduces the risk of diabetes recurrence in offspring.

[0010] Resveratrol can improve glucose metabolism, fat metabolism, insulin resistance and pregnancy outcomes during pregnancy; AMPK (adenosine monophosphate-activated protein kinase) is a type of cellular energy metabolism receptor that plays a key role in many human metabolisms. AMPK activation can inhibit the synthesis of gluconeogenesis in fatty liver and increase the rate of fat decomposition. Therefore, AMPK can be used as an effective target for the treatment of gestational diabetes. Resveratrol can relieve the symptoms of gestational diabetes by enhancing the activation of AMPK.

[0011] Optionally, the medicament further contains calcitriol, and the mass ratio of calcitriol to yam polysaccharide is 4:1.5×10 -5 .

[0012] By adopting the above technical scheme, the cooperation of calcitriol and yam polysaccharide can reduce the blood sugar level and HOMA-IR index (insulin resistance index assessed by homeostasis model) of gestational diabetes, inhibit the production of ROS (reactive oxygen) and improve liver damage. The combination of the two can also upregulate the expression level of VDR (vitamin D receptor), activate the insulin signaling pathway and PI3K / AKT signaling pathway, inhibit FOXO1 (forkhead box transcription factor O1) protein expression, inhibit liver gluconeogenesis, and improve IR (insulin resistance) of gestational diabetes. The combination of calcitriol and yam polysaccharide can also improve the blood lipid level of gestational diabetes, inhibit the expression of SREBP1c (sterol regulatory element binding protein-1c) protein, upregulate the expression of PPAR-γ (peroxisome proliferator-activated receptor-γ) protein, improve abnormal lipid metabolism, and thus improve insulin resistance.

[0013] Optionally, the extraction method of the mulberry branch extract is as follows: The mulberry branches are dried and crushed to obtain mulberry branch powder, which is evenly mixed with ethanol, subjected to ultrasonic-assisted extraction at 60-70° C. for 50-60 min, centrifuged, concentrated, and dried.

[0014] By adopting the above technical scheme, ultrasound is used to assist ethanol in extracting mulberry branches. Microwave radiation can make the molecules in plant cells move rapidly and generate heat, thereby promoting the extraction of effective ingredients. Microwave extraction can effectively destroy plant cell walls, making it easier for the effective ingredients in the cells to be released into the extract, thereby improving the extraction efficiency. Ethanol can dissolve a variety of active ingredients in mulberry branches, such as flavonoids, alkaloids, etc., thereby ensuring the comprehensiveness and activity of the extract. The combination of microwave-assisted and ethanol extraction can give full play to the advantages of both and further improve the extraction efficiency and the quality of the extract. During the microwave extraction process, the energy consumption is low, and ethanol, as an environmentally friendly solvent, can reduce pollution to the environment. The microwave-assisted ethanol extraction process is relatively simple, easy to control and operate, and suitable for industrial production.

[0015] Optionally, the ethanol concentration is 70-80%, and the solid-liquid ratio is 20-25:1.

[0016] By adopting the above technical solution, too high ethanol concentration will affect the quality of the extract, and too low ethanol concentration will have low solubility for the active ingredients, resulting in poor extraction effect; too high or too low solid-liquid ratio will affect the extraction efficiency.

[0017] Optionally, the extraction method of yam polysaccharide is as follows: The yam is peeled, dried and crushed to obtain yam powder; The yam powder and ethanol are mixed, extracted at 49-55°C with an ultrasonic power of 800-850W for 50-60 minutes, centrifuged, the supernatant is concentrated, ethanol is added to a final concentration of 285% for alcohol precipitation, centrifuged, and the precipitate is washed with anhydrous ethanol, acetone, and petroleum ether in sequence, and dried to obtain yam polysaccharide.

[0018] By adopting the above technical solution, ultrasound can produce strong vibration and cavitation effects, which can destroy the plant cell walls and make it easier for active ingredients such as polysaccharides in the cells to be released into the extract, while ethanol can promote the extraction of polysaccharides and other ingredients. In addition, the combination of ultrasound and ethanol can reduce energy consumption, shorten extraction time, and improve extraction efficiency.

[0019] Optionally, the ethanol concentration is 60-65wt%.

[0020] By adopting the above technical solution, the appropriate ethanol concentration can increase the rupture rate of the yam cell wall, destroy the stability of starch, and gradually dissolve the yam polysaccharide. However, if the ethanol concentration is too high, it may cause changes or destruction in the molecular structure of the polysaccharide, thereby affecting the extraction efficiency.

[0021] Optionally, the mass ratio of the yam powder to ethanol is 1:8-10.

[0022] By adopting the above technical scheme, at this solid-liquid ratio, it is beneficial to the dissolution and mass transfer of yam polysaccharides, thereby improving the extraction efficiency. When the solid-liquid ratio is too small and the amount of solvent is insufficient, the yam polysaccharides cannot be completely dissolved in the solvent, resulting in incomplete extraction. However, when the solid-liquid ratio is too large, although the extraction rate of yam polysaccharides is not greatly affected, it will affect the drying time, and too much solvent will dilute the polysaccharides and reduce the polysaccharide concentration.

[0023] In a second aspect, the present application provides a method for preparing a medicament for treating early gestational diabetes, using the following technical solution: A method for preparing a medicine for treating early gestational diabetes comprises the following steps: mixing metformin, vitamin D, insulin aspart, yam polysaccharide, mulberry branch extract and resveratrol, grinding the mixture and then pressing the mixture into tablets.

[0024] By adopting the above technical solution, the raw materials are blended and then ground to obtain powder with smaller fineness, which is then compressed to obtain tablets for easy administration.

[0025] In summary, this application has the following beneficial effects: 1. Since the present application adopts metformin in combination with vitamin D and Tianmen insulin, and incorporates a certain amount of yam polysaccharides, mulberry branch extract and resveratrol, it improves insulin sensitivity, stimulates insulin secretion, increases the utilization rate of blood glucose, improves blood sugar control, reduces kidney damage, reduces the birth of macrosomia, reduces placental quality, and improves pregnancy outcomes.

[0026] 2. In the present application, it is preferred to add a certain amount of calcitriol to the medicament. Calcitriol can cooperate with yam polysaccharides to enhance the control of blood sugar level and HOMA-IR index of gestational diabetes, inhibit the production of reactive oxygen species, reduce liver damage, improve insulin resistance, and reduce blood lipid levels. DETAILED DESCRIPTION

[0027] The following examples further illustrate the present application in detail.

[0028] Example Example 1: A medicament for treating early gestational diabetes, comprising the following raw materials by weight: 2 g of metformin, 1 g of vitamin D, 0.8 g of aspart insulin, 0.4 g of yam polysaccharide, 0.4 g of mulberry branch extract and 0.2 g of resveratrol. The mulberry branch extract is extracted by drying, crushing and sieving the mulberry branch (≤ 0.425 mm) to obtain mulberry branch powder, mixing 5 g of the mulberry branch powder with 70% ethanol, and performing ultrasonic assisted extraction at 60°C for 60 min with a power of 600 W. , centrifugation, concentration, drying, the solid-liquid ratio of yam polysaccharide, mulberry branch powder and ethanol is 20:1, and the preparation method of yam polysaccharide is as follows: peel the yam, dry and crush it to obtain 250μm yam powder; mix the yam powder with 65wt% ethanol, the mass ratio of yam powder to ethanol is 1:10, extract for 60min at 49°C with an ultrasonic power of 850W, centrifuge, concentrate the supernatant, wash with anhydrous ethanol, acetone and petroleum ether in turn, and dry to obtain yam polysaccharide.

[0029] The preparation method of the above-mentioned medicament for treating early-stage diabetes comprises the following steps: Metformin, vitamin D, insulin aspart, yam polysaccharide, mulberry branch extract and resveratrol are mixed and ground, and then compressed into tablets of 0.5 g / tablet.

[0030] Example 2: A medicament for treating early gestational diabetes, comprising the following raw materials by weight: 1.5 g of metformin, 0.8 g of vitamin D, 0.6 g of insulin aspart, 0.35 g of yam polysaccharide, 0.3 g of mulberry branch extract and 0.15 g of resveratrol. The mulberry branch extract is extracted by drying, crushing and sieving the mulberry branch (≤ 0.425 mm) to obtain mulberry branch powder. 5 g of the mulberry branch powder is uniformly mixed with 75% ethanol, and subjected to ultrasonic assisted extraction at 65°C for 5 min. 5min, centrifuge, concentrate and dry, the solid-liquid ratio of yam polysaccharide, mulberry branch powder and ethanol is 23:1, and the preparation method of yam polysaccharide is as follows: peel, dry and crush the yam to obtain 250μm yam powder; mix the yam powder with 60wt% ethanol, the mass ratio of yam powder to ethanol is 1:9, extract for 55min at 50℃ with an ultrasonic power of 830W, centrifuge, concentrate the supernatant, wash with anhydrous ethanol, acetone and petroleum ether in turn, and dry to obtain yam polysaccharide.

[0031] The preparation method of the above-mentioned medicament for treating early-stage diabetes comprises the following steps: Metformin, vitamin D, insulin aspart, yam polysaccharide, mulberry branch extract and resveratrol are mixed and ground, and then compressed into tablets of 0.5 g / tablet.

[0032] Example 3: A medicament for treating early gestational diabetes, comprising the following raw materials by weight: 1 g of metformin, 0.5 g of vitamin D, 0.4 g of insulin aspart, 0.3 g of yam polysaccharide, 0.2 g of mulberry branch extract and 0.1 g of resveratrol. The mulberry branch extract is extracted by drying, crushing and sieving the mulberry branch (≤ 0.425 mm) to obtain mulberry branch powder. 5 g of the mulberry branch powder is uniformly mixed with 80% ethanol, and 50 m3 of the mulberry branch powder is extracted by ultrasonic assisted extraction at 70°C with a power of 650 W. in, centrifuged, concentrated, and dried, the solid-liquid ratio of yam polysaccharide, mulberry branch powder, and ethanol is 25:1. The preparation method of yam polysaccharide is as follows: peel the yam, dry, and crush it to obtain 250μm yam powder; mix the yam powder with 63wt% ethanol, the mass ratio of yam powder to ethanol is 1:8, extract for 50min at 55°C with an ultrasonic power of 800W, centrifuge, concentrate the supernatant, wash with anhydrous ethanol, acetone, and petroleum ether in turn, and dry to obtain yam polysaccharide.

[0033] The preparation method of the above-mentioned medicament for treating early-stage diabetes comprises the following steps: Metformin, vitamin D, insulin aspart, yam polysaccharide, mulberry branch extract and resveratrol are mixed and ground, and then compressed into tablets of 0.5 g / tablet.

[0034] Example 4: A drug for treating early gestational diabetes, which is different from Example 1 in that calcitriol is also added, and the mass ratio of solidified triol to tri-drug polysaccharide is 0.4:1.5×10 -6 , that is, the dosage of calcitriol is 1.5μg.

[0035] Comparative Example Comparative Example 1: A medicament for treating early gestational diabetes, which differs from Example 1 in that yam polysaccharide is not added.

[0036] Comparative Example 2: A medicament for treating early gestational diabetes, which differs from Example 1 in that no mulberry branch extract is added.

[0037] Comparative Example 3: A medicament for treating early gestational diabetes, which differs from Example 1 in that resveratrol is not added.

[0038] Comparative Example 4: A medicament for treating early gestational diabetes, which differs from Example 1 in that insulin aspart is not added.

[0039] Comparative Example 5: A medicament for treating early gestational diabetes, which differs from Example 1 in that insulin aspart and vitamin D are not added.

[0040] Performance testing Establishment of gestational diabetes model: 5-week-old SPF SD rats were selected, with a female to male ratio of 2:1, female rats weighing 190-200g and male rats weighing 300-330g. They were housed together to allow for pregnancy. They were adaptively fed for 3 weeks before being housed together. Conception was successful if a vaginal plug was seen on the second day, which was day 0 of pregnancy. Modeling was performed on the first day after conception in female rats fed a high-fat and high-sugar diet. Intraperitoneal injection of 35ml / kg of streptozotocin was used. Random blood glucose was measured to be higher than 16.9mmol / l, indicating that the GDM model was successful. Pregnant rats whose blood glucose did not meet the standard were discarded, and the normal control group fed with ordinary feed was intraperitoneally injected with normal saline as a control.

[0041] The pregnant mice that were successfully conceived and met the requirements were divided into 11 groups, including Example 1-4 group, Comparative Example 1-5 group, normal control group and model control group. The rats in Example 1-4, Comparative Example 1-5 and model control group were fed with high-fat and high-sugar feed (60% ordinary feed, 12% lard, 10% egg yolk powder, 6% sucrose, 5% milk powder, 5% peanuts, 1% sesame oil and 1% salt). The normal control group was fed with ordinary feed. The rats were gavaged from the 10th day after conception. The dosing solvent for the rats was 10 ml / kg. The rats in Example 1-4 and Comparative Example 1-5 groups were gavaged with 300 mg of the medicament prepared in Example 1-4 and Comparative Example 1-5, respectively. / kg·d. The normal control group and the high-fat and high-sugar diet group were gavaged with distilled water. All research subjects were gavaged continuously for 4 weeks (lasting until about 16 days after delivery). The offspring were weaned 25 days after delivery. The female mice were fasted for 12 hours and then blood was collected from the tail. Blood glucose and blood lipids were recorded. The female mice were killed, and the important organs were removed, wiped dry and weighed. The wet weight of the tissue / the rat's own body weight was used as the organ coefficient ratio. The test results are recorded in Table 1. Ten offspring were kept in each group, 5 males and 5 females. They were fed with ordinary diet for 8 weeks after weaning and then killed. Before killing, various indicators of random blood glucose and blood lipids were tested, and important organs were removed, wiped dry and weighed to obtain the organ coefficient. The test results are recorded in Table 2.

[0042] Table 1 Detection of parental rats Examples 1-3 use different amounts of metformin, vitamin D and other raw materials to prepare the medicaments. It can be seen from the gavage of feed that the medicaments prepared in Examples 1-3 can still achieve a good blood sugar and blood lipid control effect when female mice are gavaged with high-fat and high-sugar feed, and can effectively reduce fasting blood sugar.

[0043] Compared with Example 1, Example 4 also uses calcitriol and yam polysaccharide in combination. It can be seen that the blood sugar of the parent female mice is significantly lower than that of the high-fat and high-sugar model control group, and the organ coefficient is reduced, which has a more optimized hypoglycemic effect.

[0044] In Comparative Example 1, no yam polysaccharide was added, and in Comparative Example 2, no mulberry branch extract was added. It can be seen that the control effect of blood sugar and blood lipids of the parent female mice was weakened compared with that in Example 1.

[0045] Comparative Example 3 did not add resveratrol, Comparative Example 4 did not add aspart insulin, and Comparative Example 5 did not add aspart insulin and vitamin D. Table 1 shows that the control effects of the agents prepared in Comparative Examples 3-5 on blood sugar, blood lipids and organ coefficients were not as good as those in Example 1.

[0046] Table 2 Detection of offspring mice Table 2 shows that the drugs prepared in Examples 1-4 were gavaged into the offspring, which were fed for 8 weeks after weaning and then killed. Before killing, their blood sugar and blood lipid levels were better than those of other groups, which shows that the drugs prepared in the present application are safer for offspring.

[0047] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed, but such modifications are protected by patent law as long as they are within the scope of the claims of the present application.

Claims

1. A medicament for treating early gestational diabetes, characterized in that: The invention comprises the following raw materials in parts by weight: 1-2 parts of metformin, 0.5-1 parts of vitamin D, 0.4-0.8 parts of aspart insulin, 0.3-0.4 parts of yam polysaccharide, 0.2-0.4 parts of mulberry branch extract and 0.1-0.2 parts of resveratrol.

2. The medicament for treating early gestational diabetes according to claim 1, characterized in that: The medicament also contains calcitriol, and the mass ratio of yam polysaccharide to calcitriol is 4:1.5×10 -6 .

3. The medicament for treating early gestational diabetes according to claim 1, characterized in that: The extraction method of the mulberry branch extract is as follows: The mulberry branches are dried and crushed to obtain mulberry branch powder, which is evenly mixed with ethanol, subjected to ultrasonic-assisted extraction at 60-70° C. for 50-60 min, centrifuged, concentrated, and dried.

4. The medicament for treating early gestational diabetes according to claim 3, characterized in that: The ethanol concentration is 70-80%, and the solid-liquid ratio is 20-25:

1.

5. The medicament for treating early gestational diabetes according to claim 1, characterized in that: The extraction method of the yam polysaccharide is as follows: The yam is peeled, dried and crushed to obtain yam powder; The yam powder and ethanol are mixed, extracted at 49-55°C with an ultrasonic power of 800-850W for 50-60 minutes, centrifuged, the supernatant is concentrated, washed with anhydrous ethanol, acetone, petroleum ether in sequence, and dried to obtain yam polysaccharide.

6. The medicament for treating early gestational diabetes according to claim 5, characterized in that: The ethanol concentration is 60-65wt%.

7. The medicament for treating early gestational diabetes according to claim 5, characterized in that: The mass ratio of the yam powder to ethanol is 1:8-10.

8. The method for preparing the medicament for treating early gestational diabetes according to any one of claims 1 to 7, characterized in that: The following steps are involved: Metformin, vitamin D, insulin aspart, yam polysaccharide, mulberry branch extract and resveratrol are mixed, ground and then compressed into tablets.

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