Nutritional composition for preventing or improving diabetic peripheral neuropathy

Abstract

The invention provides a nutritional composition. The nutritional composition consists of vitamin D, vitamin B2, vitamin B6, vitamin B12, folic acid and acceptable auxiliary materials. The composition can be used for preparing products for preventing or improving diabetic neuropathy. In addition, the compound preparation form of the composition is beneficial to improving the taking compliance and saving the total cost.

Description

Technical Field

[0001] The present invention relates to a kind of vitamin D, vitamin B2, vitamin B6, vitamin B 12 A nutritional composition containing lecithin and folic acid for preventing or improving diabetic peripheral neuropathy. Background Art

[0002] Diabetic neuropathy is a common chronic complication of diabetes, including distal symmetric polyneuropathy (DSPN) and autonomic neuropathy, among which DSPN is the most common type, also commonly referred to as diabetic peripheral neuropathy (DPN) by some scholars.

[0003] The etiology and pathogenesis of diabetic neuropathy have not been fully elucidated. It is currently believed that it is mainly related to a series of pathophysiological changes caused by hyperglycemia, lipid metabolism disorders and abnormal insulin signaling pathways, including the polyol pathway, glycolysis pathway, hexosamine pathway, advanced glycation end product pathway, Toll-like receptor 4 signal transduction pathway, oxidized low-density lipoprotein receptor 1 signaling pathway, etc., which act alone or in combination to cause cellular Na + -K + Diabetic microcirculatory disturbances can lead to hypoxia, which in turn damages neurons and other cells. This ultimately leads to irreversible damage to neurons and glial cells, contributing to the development of diabetic neuropathy.

[0004] In recent years, as the number of people with diabetes continues to rise, the number of patients with diabetic neuropathy (DPN) has also continued to grow. DPN not only causes physical disability and unbearable pain, but can also lead to emotional and psychological problems, reducing patients' quality of life and increasing mortality. Currently, treatment options for DPN remain very limited. Summary of the Invention

[0005] In order to overcome the shortcomings of current clinical drugs for preventing and treating diabetic peripheral neuropathy, based on previous research, the present invention provides a more targeted nutritional composition.

[0006] A nutritional composition comprising:

[0007] (1) Vitamin D,

[0008] (2) Vitamin B2,

[0009] (3) Vitamin B6,

[0010] (4) Vitamin B 12 ,

[0011] (5) Folic acid substances,

[0012] (6) Acceptable excipients.

[0013] In the nutritional composition of the present invention, the vitamin D and vitamin B2, vitamin B6, vitamin B 12 , and folic acid in a total weight ratio of 1-50:600-15000.

[0014] The nutritional composition of the present invention contains, by weight, 1 to 50 parts of vitamin D, 500 to 5,000 parts of vitamin B2, 100 to 60,000 parts of vitamin B6, 1 to 100 parts of vitamin B 12 , 30 to 2000 parts of folic acid substances.

[0015] The nutritional composition of the present invention comprises 1 to 50 μg of vitamin D, 0.5 to 5 mg of vitamin B2, 0.1 to 60 mg of vitamin B6, and 0.1 to 60 mg of vitamin B6. 12 The content of vitamin B12 is 1-100μg, and the content of folic acid is 30-2000μg.

[0016] The nutritional composition of the present invention comprises 25-50 μg of vitamin D, 1-5 mg of vitamin B2, 2.5-25 mg of vitamin B6, and 1-5 mg of vitamin B6. 12 The content of vitamin B12 is 10-100 μg, and the content of folic acid is 200-1200 μg.

[0017] The nutritional composition of the present invention comprises 25 μg of vitamin D, 5 mg of vitamin B2, 25 mg of vitamin B6, and 25 mg of vitamin B6. 12 The content of vitamin B12 is 50μg and the content of folic acid is 800μg.

[0018] The nutritional composition of the present invention comprises 25 μg of vitamin D, 5 mg of vitamin B2, 25 mg of vitamin B6, and 25 mg of vitamin B6. 12 The content of vitamin B12 is 50μg and the content of folic acid is 1200μg.

[0019] In the nutritional composition of the present invention, the vitamin D is selected from ergocalciferol and cholecalciferol; the vitamin B2 is selected from riboflavin and riboflavin 5'-sodium phosphate; the vitamin B6 is selected from pyridoxine, pyridoxal and pyridoxamine; the vitamin B 12 Selected from methylcobalamin, cyanocobalamin, hydroxocobalamin, adenosylcobalamin; the folic acid substance is selected from folic acid and 5-methyltetrahydrofolate.

[0020] The nutritional composition of the present invention can be prepared into oral dosage forms such as tablets, pills, granules, oral liquids, capsules, powders and granules.

[0021] In the present invention, the nutritional composition may be in the form of a pharmaceutical, nutritional formulation, tube feeding formulation, dietary supplement, functional food, health food, beverage product, or the like.

[0022] Use of the nutritional composition of the present invention in preparing a product for preventing or improving diabetic peripheral neuropathy.

[0023] The nutritional composition provided by the present invention and its use in preparing a product for preventing or improving diabetic peripheral neuropathy have the advantages of focusing on exploring the nutritional factors of diabetic peripheral neuropathy through experimental research, thereby providing a variety of targeted nutritional components, including vitamin D, vitamin B2, vitamin B6, vitamin B 12 Experiments have shown that the nutritional composition provided by the present invention can assist in preventing diabetic peripheral neuropathy, relieve pain caused by neuropathy, and nourish nerves at the same time, with a synergistic effect. Specific embodiments

[0024] Example 1: Effect of the nutritional composition of the present invention on peripheral neuropathy in diabetic rats

[0025] Six-week-old male Sprague-Dawley rats, with an average body weight of (160 ± 20) g, were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd. They were fed a standard diet with free access to food and water. The room temperature was (22 ± 2)°C, the humidity was 55% ± 10%, and the light and dark cycles were alternating every 12 h.

[0026] After one week of adaptive feeding, all rats were randomly divided into a control group and a model group. The model group was fed a high-sugar and high-fat diet for 6 weeks to induce insulin resistance; the control group was fed a normal diet. Subsequently, the model group was intraperitoneally injected with 35 mg / g of STZ buffer (pH 4.1) according to body weight to induce pancreatic-specific damage; the control group was intraperitoneally injected with an equal amount of buffer. The fasting blood glucose of the rats was measured 48 hours later. If it was greater than 11.1 mmol / L, the diabetes model was considered to be successfully established, as shown in Table 1. The model rats with successful modeling continued to be fed a high-sugar and high-fat diet until the end of the experiment, and the control rats continued to be fed a normal diet until the end of the experiment. The diabetic model rats with successful modeling were randomly divided into 10 groups, 10 rats in each group, and were given the corresponding doses of the test substances according to Table 2 below for 8 consecutive weeks, once a day. The model group was given an equal amount of normal saline, and the gavage volume was calculated according to 10 ml / kg body weight.

[0027] At the end of the administration, the following indicators of rats in each group were measured:

[0028] 1. Thermal pain threshold and sciatic nerve conduction velocity (NCV).

[0029] Thermal pain valve test method:

[0030] Rats were placed in an RCY-2 hot plate analgesia apparatus at 52°C. Their paws were placed in contact with the hot plate, prompting them to lick their paws. The latency from the moment both hind paws contacted the hot plate to the moment they licked their paws (i.e., the licking latency) was used as the pain response indicator, also known as the pain threshold. Each rat was tested three times, with a 5-minute interval between each measurement, and the average value was calculated. The room temperature was maintained at 20 ± 0.5°C throughout the test.

[0031] NCV test method:

[0032] NCV reflects the condition of large peripheral nerve fibers. The slowing of large fiber NCV is the gold standard for diagnosing diabetic neuropathy and is also used to evaluate treatment efficacy.

[0033] In this embodiment, the sciatic nerve is selected as the target site to detect the sciatic nerve conduction velocity (NCV), which represents the conduction velocity of the peripheral nerve.

[0034] Rats were anesthetized with an intraperitoneal injection of 3% sodium pentobarbital and immobilized in the prone position. The surgical field was depilated. The skin was incised along the course of the sciatic nerve, and the musculature of the femoris muscles was separated to the sciatic notch to expose the sciatic nerve. The sciatic nerves were carefully dissected bilaterally using a glass needle. Liquid paraffin was used to protect the sciatic nerves throughout the process. Gentle and delicate dissection was performed to avoid nerve damage. The sciatic nerves were fully exposed from the sciatic notch to the ankle. Measurements were taken immediately after dissection. A 7-row hook electrode with a 2 mm inter-electrode spacing was connected to the BL-420E+ biofunctional experimental system. The hook electrode was gently hooked around the sciatic nerve. From proximal to distal, the following sequence was used: a pair of stimulating electrodes (connected to the stimulation output channel), the first pair of reference electrodes + recording electrodes (connected to channel 1), and the second pair of reference electrodes + recording electrodes (connected to channel 2).

[0035] Experimental parameter settings: Mode: Fine Voltage, Mode: Single Stimulation Delay 5.0, Wave Width 0.05 ms, Intensity 1.0 V, Wave Interval 99. After electrical stimulation, the latency (Δt) of the action potential generated from the proximal to distal end of the sciatic nerve was recorded. The distance between the two recording electrodes (Δs) was fixed, and NCV = distance between recording electrodes / difference in action potential latency. The electrical stimulation was repeated three times and the average value was calculated.

[0036] 2. CAMP and CGMP levels in the sciatic nerve.

[0037] Determination of CAMP and CGMP Content in Sciatic Nerve: Take the isolated sciatic nerve and homogenize it in an ice bath with 2 mL of cold 50 mg acetate buffer (pH 4.75) per 50 mg of nerve tissue. Blow dry the homogenate in a 60°C water bath and store at -20°C. CAMP and CGMP content were determined using a radioimmunoassay analyzer.

[0038] Statistical analysis

[0039] SPSS 11.0 software was used for statistical analysis, and the normally distributed measurement data were analyzed. t-test was used for comparison between groups.

[0040] In order to verify the scientific nature of the composition provided by the present invention and to demonstrate that the components of the composition are reasonably formulated and can be combined to produce a synergistic effect rather than simply a superposition of pharmacological effects, the Jin Zhengjun Q value method is introduced for analysis. The Jin Zhengjun Q value method, also known as the probability addition method, calculates the pharmacological effects of the two drugs in combination and the pharmacological effects of the two drugs alone within the dose-effect curve using the following formula: Q = E A+B / (E A +E B -E A *E B ), where the numerator represents the "measured combined effect" and the denominator represents the "expected combined effect". (In order to analyze the relationship between the pharmacological effects of components and compositions, their pharmacological effects are converted into effects that can intuitively reflect the strength of the pharmacological effects. The calculation formula is: E i =1-P i / P 模型组 , P i is the pharmacological index of each component, P 模型组 is the pharmacological index of the model group), Q is the ratio of the two: when Q is less than 0.85, the combination of the two drugs is considered to have an antagonistic effect; when it is less than 1.15 and greater than 0.85, it is considered to have an additive effect; when it is ≥1.15, it is considered to have a synergistic effect.

[0041] Experimental results:

[0042] Table 1: Fasting blood glucose levels of rats in each group before grouping ( )

[0043]

[0044] Note: Compared with the control group, ## P < 0.01;

[0045] From the results in Table 1, it can be seen that after the above experimental modeling, the blood glucose level of the rats in the model group was significantly increased compared with the control group (P<0.01), and the fasting blood glucose was >11.1mmol / L, proving that the diabetes model standard has been established.

[0046] Table 2: Effects of the composition of the present invention on thermal pain threshold and sciatic nerve conduction velocity (NCV) in rats ( n=9~10)

[0047]

[0048]

[0049] Note: Compared with the control group, # P<0.05, ## P<0.01; compared with the model group, * P<0.05, ** P<0.01.

[0050] Table 2 shows that the thermal pain threshold and sciatic nerve NCV of the model group rats were significantly reduced, proving that peripheral nerve damage occurred in the model rats.

[0051] After 8 weeks of administration, there was no significant difference in the increase of thermal pain threshold and sciatic nerve conduction velocity (NCV) levels between the single riboflavin group and the model group. However, in the quadruple combination group, there were significant differences in the increase of thermal pain threshold and sciatic nerve conduction velocity (NCV) levels between the medium-dose group of cholecalciferol + pyridoxal 5-phosphate + methylcobalamin + 5-methyltetrahydrofolate (0.0025+2.5+0.005+0.12) mg / kg and the high-dose group of cholecalciferol + pyridoxamine hydrochloride + hydroxocobalamin + 5-methyltetrahydrofolate (0.01+10+0.02+0.4) mg / kg compared with the model group (P<0.05).

[0052] On the basis of the quadruple vitamin combination, vitamin B2 (riboflavin) was further added, and its thermal pain threshold and sciatic nerve conduction velocity (NCV) were further increased (P<0.01), and no matter in the low-dose group (0.0025+0.25+0.001+0.02+0.1) mg / kg, the medium-dose group (0.0025+2.5+0.005+0.12+0.5) mg / kg, or the high-dose group (0.01+10+0.02+0.4+2) mg / kg, there was a synergistic effect (Q>1.15). It was proved that the composition provided by the present invention can effectively improve the peripheral nervous system damage caused by diabetes.

[0053] Table 3: Effects of the composition of the present invention on the contents of CAMP and CGMP in rat sciatic nerve ( n=9~10)

[0054]

[0055] Note: Compared with the control group, #P<0.05, ##P<0.01; compared with the model group, *P<0.05, **P<0.01.

[0056] The CAMP and CGMP test results in Table 3 show that there was no significant difference in CAMP and CGMP levels between the riboflavin alone group and the model group. However, in the quadruple combination, significant increases were observed in the medium-dose group (0.0025+2.5+0.005+0.12) mg / kg of cholecalciferol + pyridoxal 5-phosphate + methylcobalamin + 5-methyltetrahydrofolate) and the high-dose group (0.01+10+0.02+0.4) mg / kg of cholecalciferol + pyridoxamine hydrochloride + hydroxocobalamin + 5-methyltetrahydrofolate (P<0.05).

[0057] On the basis of the quadruple combination, vitamin B2 (riboflavin) was further added to form a five-combination compound. Whether it was the low-dose group (0.0025+0.25+0.001+0.02+0.1) mg / kg, the medium-dose group (0.0025+2.5+0.005+0.12+0.5) mg / kg, or the high-dose group (0.01+10+0.02+0.4+2) mg / kg, the CAMP and CGMP levels in the sciatic nerve had further increases (P<0.01), and all had a synergistic effect (Q>1.15). It was proved that the composition provided by the present invention can effectively improve the peripheral nervous system damage caused by diabetes, has an improvement effect on the CAMP and CGMP levels caused by diabetes-induced peripheral neuropathy, and can significantly increase the nerve signal conduction rate of the sciatic nerve.

[0058] In the above experiments, it was observed that in the high-dose five-compound combination, in the high-dose group (0.01+10+0.02+0.4+2) mg / kg of cholecalciferol + pyridoxamine hydrochloride + hydroxycobalamin + 5-methyltetrahydrofolate + riboflavin, some rats showed decreased appetite, dull hair, bloodstains at the corners of the mouth, and coffee-colored urine. After autopsy, diffuse pulmonary hemorrhage and intestinal obstruction were found. Such toxic and side effects were not observed in the low-dose and medium-dose groups. This may be a side effect caused by excessive combination doses. Therefore, the dosage ratio range of the five-vitamin composition provided by the present invention has the advantages of significant efficacy and few toxic and side effects.

Claims

1. A nutritional composition comprising: (1) Vitamin D, (2) Vitamin B2, (3) Vitamin B6, (4) Vitamin B 12 , (5) Folic acid substances, (6) Acceptable excipients.

2. The nutritional composition according to claim 1, characterized in that The vitamin D and vitamin B2, vitamin B6, vitamin B 12 , and the total weight ratio of folic acid substances is 1-50:600-15000.

3. The nutritional composition according to claim 1, characterized in that By weight, it contains 1 to 50 parts of vitamin D, 500 to 5000 parts of vitamin B2, 100 to 60000 parts of vitamin B6, 1 to 100 parts of vitamin B 12 , 30 to 2000 parts of folic acid substances.

4. The nutritional composition according to claim 1, characterized in that The vitamin D is 1-50 μg, the vitamin B2 is 0.5-5 mg, the vitamin B6 is 0.1-60 mg, and the vitamin B 12 The content of vitamin B12 is 1-100μg, and the content of folic acid is 30-2000μg.

5. The nutritional composition according to claim 4, characterized in that The vitamin D is 25-50 μg, vitamin B2 is 1-5 mg, vitamin B6 is 2.5-25 mg, vitamin B 12 The content of vitamin B12 is 10-100 μg, and the content of folic acid is 200-1200 μg.

6. The nutritional composition according to claim 5, characterized in that The vitamin D is 25 μg, vitamin B2 is 5 mg, vitamin B6 is 25 mg, vitamin B 12 The content of vitamin B12 is 50μg and the content of folic acid is 800μg.

7. The nutritional composition according to claim 5, characterized in that The vitamin D is 25 μg, vitamin B2 is 5 mg, vitamin B6 is 25 mg, vitamin B 12 The content of vitamin B12 is 50μg and the content of folic acid is 1200μg.

8. The nutritional composition according to any one of claims 1 to 7, characterized in that The vitamin D is selected from ergocalciferol and cholecalciferol; the vitamin B2 is selected from riboflavin and riboflavin 5'-sodium phosphate; the vitamin B6 is selected from pyridoxine, pyridoxal and pyridoxamine; the vitamin B 12 Selected from methylcobalamin, cyanocobalamin, hydroxocobalamin, adenosylcobalamin; the folic acid substance is selected from folic acid and 5-methyltetrahydrofolate.

9. The nutritional composition according to any one of claims 1 to 7, characterized in that The nutritional composition can be prepared into oral dosage forms such as tablets, pills, granules, oral liquids, capsules, powders and granules.

10. Use of the nutritional composition according to any one of claims 1 to 7 in preparing a product for preventing or improving diabetic peripheral neuropathy.

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