A composition for preventing hypertension

Abstract

This invention provides a composition containing vitamins and minerals, comprising vitamin D, folic acid, vitamin B12, potassium, and excipients in specific proportions. The invention may also include vitamin B1 and vitamin B2. The components of this composition have a synergistic effect in preventing hypertension, particularly in preventing hypertension accompanied by elevated homocysteine ​​levels. Furthermore, this composition can also be used for targeted nutritional supplementation in specific populations.

Description

Technical Field

[0001] This invention relates to a product for preventing hypertension. This invention belongs to the field of vitamin and mineral technology. Background Technology

[0002] Hypertension is the most common cardiovascular disease and the most prevalent chronic non-communicable disease in China. It is also the leading risk factor for cardiovascular disease-related deaths among urban and rural residents in my country, and once diagnosed, lifelong medication is often required. Therefore, preventing hypertension undoubtedly has significant clinical and health economic implications.

[0003] Hypertension can be divided into primary hypertension and secondary hypertension. Primary hypertension is more common, accounting for the majority of clinical cases. Its exact cause is not fully understood, but it may be related to genetic factors and environmental factors (such as long-term mental stress or pressure, excessive sodium intake). Secondary hypertension refers to elevated blood pressure caused by other diseases (such as chronic kidney disease, endocrine abnormalities, etc.), and often requires etiological treatment. This invention focuses only on primary hypertension.

[0004] According to the "Guidelines for the Prevention and Treatment of Hypertension in China (2024 Revised Edition)," excessive sodium intake and / or insufficient potassium intake, as well as a low potassium-sodium ratio, are important risk factors for hypertension in my country. Therefore, moderately reducing sodium intake and increasing dietary potassium intake can help lower blood pressure. A low-salt diet is recommended for the general population, and for hypertensive patients, a "limited intake and promoted excretion" approach to dietary salt is advised.

[0005] Undoubtedly, a healthy diet can reduce the risk of developing hypertension. The DASH (Dietary Approaches to Stop Hypertension) diet is a dietary pattern specifically designed by international health research institutions to control hypertension, based on the principles of "rich in fruits, vegetables, and protein; low in fat, sugar, and salt." This diet requires a high intake of fresh vegetables, fruits, low-fat dairy products, poultry, fish, soybeans, and nuts; low in sugary drinks and red meat; low in saturated fat and cholesterol; and rich in trace elements such as potassium, magnesium, and calcium, as well as high-quality protein and fiber. Reports indicate that the DASH diet can lower blood pressure in as little as 14 days.

[0006] However, implementing the DASH diet model in vast rural areas of my country presents significant challenges. In fact, precision nutrition research suggests that the nutrients and minerals that play a decisive role in preventing hypertension do not need to be all-encompassing; the key lies in the synergistic effect of key components, such as how increased potassium intake can promote sodium excretion. Therefore, through precision nutrition formulation and experimental exploration, existing technologies can be improved to enhance the feasibility and effectiveness of dietary prevention for hypertension. Summary of the Invention

[0007] To address the shortcomings of current hypertension prevention products, we conducted exploratory experiments with vitamins and minerals. The results showed that the combined use of certain proportions of vitamin D, folic acid, vitamin B12, potassium-containing active ingredients, vitamin B1, and vitamin B2 can prevent elevated blood pressure, especially in cases of elevated homocysteine ​​levels or sodium overload, exhibiting a significant preventative effect. Based on this, the present invention, through optimization, provides a multi-component composition for the prevention of hypertension.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] A composition containing vitamins and minerals, comprising:

[0010] (1) Vitamin D,

[0011] (2) Folic acid-like substances,

[0012] (3) Vitamin B12,

[0013] (3) Contains potassium-containing active ingredients.

[0014] (4) Acceptable excipients.

[0015] In the composition described in this invention, the mass ratio of vitamin D, folic acid, vitamin B12, and potassium-containing active ingredient is 0.2–15000:10–2000:0.2–50:10000–2400000; preferably, the mass ratio of vitamin D, folic acid, vitamin B12, and potassium-containing active ingredient is 0.8–20:20–500:0.3–10:100000–2400000; more preferably, the preferred mass ratio of vitamin D, folic acid, vitamin B12, and potassium-containing active ingredient is 0.8–4.5:20–158:0.3–3:170000–190000.

[0016] In the composition described in this invention, the mass ratio of vitamin D, folic acid, vitamin B12, and potassium-containing active ingredient is 0.8:200:0.3:190000; or the mass ratio of vitamin D, folic acid, vitamin B12, and potassium-containing active ingredient is 4:100:1.5:190000; or the mass ratio of vitamin D, folic acid, vitamin B12, and potassium-containing active ingredient is 4.5:158:3:170000.

[0017] In the composition described in this invention, the amount of vitamin D is 0.2–15000 μg, the amount of folic acid is 10–2000 μg, the amount of vitamin B12 is 0.2–50 μg, and the amount of potassium-containing active ingredient is 10000–2400000 μg; preferably, the amount of vitamin D is 0.8–20 μg, and the amount of folic acid is 20–500 μg. The amount of vitamin B12 is 0.3–10 μg, and the amount of potassium-containing active ingredient is 100,000–2,400,000 μg; more preferably, the amount of vitamin D is 0.8–4.5 μg, the amount of folic acid is 20–158 μg, the amount of vitamin B12 is 0.3–3 μg, and the amount of potassium-containing active ingredient is 170,000–190,000 μg.

[0018] The composition of the present invention may further include vitamin B1 and vitamin B2. In the composition of the present invention, the mass ratio of vitamin D, folic acid, vitamin B12, potassium-containing active ingredient, vitamin B1, and vitamin B2 is 0.8–20: 20–500: 0.3–10: 100,000–2,400,000: 200–20,000: 200–20,000; preferably, the mass ratio of vitamin D, folic acid, vitamin B12, potassium-containing active ingredient, vitamin B1, and vitamin B2 is 0.8–4.5: 20–158: 0.3–3: 170,000–190,000: 200–2,000: 100–2,000.

[0019] In the composition described in this invention, the mass ratio of vitamin D, folic acid, vitamin B12, potassium-containing active ingredient, vitamin B1, and vitamin B2 is 0.8:200:0.3:190000:200:100; or the mass ratio of vitamin D, folic acid, vitamin B12, potassium-containing active ingredient, vitamin B1, and vitamin B2 is 4:100:1.5:190000:2000:1000.

[0020] In the composition described in this invention, the amount of vitamin D is 0.2–15000 μg, the amount of folic acid is 10–2000 μg, the amount of vitamin B12 is 0.2–50 μg, the amount of potassium-containing active ingredient is 10000–2400000 μg, the amount of vitamin B1 is 200–20000 μg, and the amount of vitamin B2 is 200–20000 μg; preferably, the amount of vitamin D is 0.8–20 μg, and the amount of folic acid is 2…

[0021] The dosage is 0-500 μg, the dosage of vitamin B12 is 0.3-10 μg, the dosage of potassium-containing active ingredient is 100,000-2,400,000 μg, the dosage of vitamin B1 is 200-2,000 μg, and the dosage of vitamin B2 is 100-2,000 μg.

[0022] In the composition described in this invention, the vitamin D is selected from one or more of vitamin D2, vitamin D3, alfacalcidol, calcitriol, ducalcidol, and paricalcitol; the folic acid is selected from one or more of 5-methyltetrahydrofolate, 6S-5-methyltetrahydrofolate calcium, formyltetrahydrofolate, active metabolites of folic acid or folate, and substances that can release / generate folic acid in vivo; the vitamin B12 is selected from one or more of cobalamin, methylcobalamin, 5'-deoxyadenosylcobalamin, hydroxycobalamin, cyanocobalamin, and other cobalamin derivatives, and substances that can release / generate cobalamin in vivo; the potassium-containing active ingredient is selected from one or more of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium chloride, potassium citrate, potassium carbonate, potassium bicarbonate, potassium gluconate, potassium caseinate, and potassium alginate; the vitamin B1 is selected from one or two of thiamine hydrochloride and thiamine nitrate; and the vitamin B2 is selected from one or two of riboflavin and riboflavin 5'-phosphate sodium.

[0023] In this invention, acceptable excipients include one or more of sugars or functional sweeteners, fillers, wetting agents, binders, and lubricants.

[0024] In this invention, the dosage forms of the composition include, but are not limited to, lyophilized powder, oral liquid, ordinary tablet, bilayer tablet, multilayer tablet, granules, capsules, pills, compressed candy, solid beverage, syrup, liquid preparation, powder, etc.

[0025] Use of the composition described in this invention in the preparation of products for the prevention of hypertension.

[0026] The use of the composition described in this invention in the preparation of products for the prevention of hypertension or salt-sensitive hypertension with elevated homocysteine ​​levels.

[0027] In the compositions described in this invention, the proportion or amount of vitamin D is calculated based on calcitriol; the proportion or amount of folic acid is calculated based on folic acid; the proportion or amount of vitamin B12 is calculated based on cobalamin; the proportion or amount of potassium-containing active ingredients is calculated based on potassium; the proportion or amount of vitamin B1 is calculated based on thiamine; and the proportion or amount of vitamin B2 is calculated based on riboflavin.

[0028] The beneficial effects of this invention are as follows: This invention provides a composition for preventing hypertension. The combination of vitamin D, folic acid, vitamin B12, and potassium-containing active ingredients produces an unexpected synergistic effect in preventing elevated blood pressure. This composition effectively regulates the body's sodium levels while preventing vascular endothelial dysfunction caused by elevated homocysteine ​​levels. + / K + The composition, through further combination with vitamins B1 and B2, achieves a synergistic effect in preventing high blood pressure while lowering homocysteine ​​levels. This invention's composition can effectively prevent the risk of hypertension and cardiovascular disease caused by long-term low folic acid and / or high-salt diets. Detailed Implementation

[0029] The present invention will be further described below with reference to specific embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in the art in accordance with the content of the present invention shall fall within the protection scope of the present invention.

[0030] Examples 1-6: Methods for preparing tablets of the compositions of the present invention

[0031] Formulation: based on 1000 pharmaceutical units

[0032] Components Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Vitamin D 0.0008g 0.004g 0.0045g 0.02g 0.2g 15g folic acid 0.02g 0.1g 0.158g 0.5g 0.5g 2g Vitamin B12 0.0003g 0.0015g 0.003g 0.01g 0.01g 0.05g Potassium 190g 190g 170g 190g 190g 190g Vitamin B1 0.2g 2g 2g 2g 2g Vitamin B2 0.1g 1g 1g 2g 2g

[0033] (1) Take vitamin D, folic acid, vitamin B12, potassium, vitamin B1, and vitamin B2 according to the dosage in the table above. (2) Take appropriate amounts of fructooligosaccharides, microcrystalline cellulose, isomaltooligosaccharides, and isomaltitol and dry them until the water activity is ≤0.2. (3) Mix vitamin D, folic acid, vitamin B12, potassium, vitamin B1, and vitamin B2 with fructooligosaccharides, microcrystalline cellulose, isomaltooligosaccharides, isomaltitol, flavoring, and magnesium stearate evenly, and compress them into double-layer or single-layer tablets according to a certain tablet weight using a tablet press to obtain the tablet product.

[0034] Examples 7-12: Preparation methods of the powdered composition of the present invention

[0035] Formulation: based on 1000 pharmaceutical units

[0036]

[0037]

[0038] (1) Take vitamin D, folic acid, vitamin B12, potassium, vitamin B1, and vitamin B2 according to the dosage in the table above. (2) Take an appropriate amount of fructooligosaccharide, maltodextrin, and isomaltooligosaccharide and dry them until the water activity is ≤0.2. (3) Mix vitamin D, folic acid, vitamin B12, potassium, vitamin B1, and vitamin B2 with fructooligosaccharide, maltodextrin, and isomaltooligosaccharide evenly, and then package them into composite film bags according to a certain amount to obtain the powder product.

[0039] Example 13: Effects of the composition of the present invention on rats with elevated homocysteine ​​levels.

[0040] Eight-week-old male SPF-grade Wistar rats were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. They were housed at room temperature (18–28°C) and relative humidity (40%–70%) with free access to food and water. After a one-week acclimatization period with standard feed, they were included in the experiment.

[0041] Wistar rats were randomly divided into 15 groups according to Tables 1 and 2 below. Except for the control group, which was fed a normal diet, the other groups were fed a high-salt, low-folate diet (containing 8% NaCl) for 16 weeks. During the feeding period, the corresponding doses of the test substance were administered by gavage according to Tables 1 and 2 (all doses in the vitamin D group were calculated as calcitriol; all doses in the folic acid group were calculated as folic acid; all doses in the vitamin B12 group were calculated as cobalamin; all doses in the potassium active ingredient group were calculated as potassium; all doses in the vitamin B1 group were calculated as thiamine hydrochloride; all doses in the vitamin B2 group were calculated as riboflavin). The gavage volume was calculated at 10 ml / kg body weight. The administration lasted for 16 weeks.

[0042] Blood samples were collected from the orbital venous plexus of all rats before drug administration and at 8 and 16 weeks post-administration to measure serum HCY levels. Systolic blood pressure was measured using the tail pressure method.

[0043] The effect analysis of the pharmacological efficacy between two module components was performed using the Jin Zhengjun Q-value method.

[0044] Jin Zhengjun's Q-value method [Jin Zhengjun, Zhang Xiaowen, A new method for estimating the combined drug effect using equal probability sum curves and Q5e-, Journal of Shanghai Second Medical College, 1981], also known as the probability addition method, calculates Q = E based on the pharmacological effects of two drugs used in combination and the pharmacological effects of two drugs used alone within the dose-response curve region using the following formula. A+B / (E A 10E B -E A *E B), where the numerator represents the "measured combined effect" and the denominator represents the "expected combined effect". (To satisfy the analysis of the pharmacological action relationship between components and the composition, their pharmacological actions are transformed into effects that can intuitively reflect the strength of the pharmacological action. The calculation formula: E i = 1 - P i / P 模型组 , where Pi is the pharmacological index of each component, and P 模型组 is the pharmacological index of the model group), and Q is the ratio of the two. When Q < 0.85, the combination of the two drugs is considered an antagonistic effect; when 0.85 < Q < 1.15, it is considered an additive effect; when Q > 1.15, it is considered a synergistic effect.

[0045] The results were statistically processed using GraphPad Prism 5 statistical analysis software; the data results were all expressed as mean ±

[0046] standard deviation, and a t-test was performed between groups. P < 0.05 indicates a significant statistical difference, and P > 0.05 indicates no significant statistical difference.

[0047] Table 1: Effects of the composition of the present invention on the HCY level of rats fed a high-salt and low-folate diet (x ± s, n = 9 - 10)

[0048]

[0049]

[0050] Note: Compared with the control group: ## P < 0.01, compared with the model group, * P < 0.05, ** P < 0.01.

[0051] Table 2: Effects of the composition of the present invention on the systolic blood pressure of rats fed a high-salt and low-folate diet (x ± s, n = 9 - 10)

[0052]

[0053]

[0054] Note: Compared with the control group: ## P < 0.01, compared with the model group, * P < 0.05, ** P < 0.01.

[0055] The above experimental results show that after 16 weeks of feeding with a high-salt, low-folate diet, the HCY level in the model group rats was significantly higher than that in the control group, and the difference was statistically significant (P < 0.01). Furthermore, the systolic blood pressure (SBP) of the model group rats measured after 16 weeks of feeding was > 140 mmHg, demonstrating that a long-term high-salt, low-folate diet led to the formation of a hyperhomocysteinemia and hypertension model in rats.

[0056] In all drug administration groups, compared with the model group, the three groups given a single dose of potassium-containing components showed no effect in reducing HCY levels, but a slight effect in preventing hypertension. However, the systolic blood pressure of the rats in all three groups was not significantly different from that in the model group. In the three groups given different doses of vitamin D + folic acid + vitamin B12 combinations, the HCY levels of the rats in all three groups decreased, and a dose-response relationship was observed. In the alfacalcidol + 6S-5-methyltetrahydrofolate calcium + methylcobalamin group (0.0004+0.01+0.00015) mg / kg and the calcitriol + folic acid + methylcobalamin group (0.00045+0.0158+0.0003) mg / kg, the HCY levels were significantly different from those in the model group (P<0.05), but the systolic blood pressure of the rats in the three combined dose groups was not significantly different from that in the model group.

[0057] In six groups where different doses of potassium-containing components were added to the three-drug combination dosage group for 16 weeks, compared with the model group, rats showed further decreases in HCY levels and systolic blood pressure, with significant differences (P<0.05 or P<0.01), and all showed a synergistic effect (Q>1.15). Furthermore, compared to the shorter 8-week administration period, the six groups of the quadruple combination showed better prevention of HCY and systolic blood pressure elevation after a longer 16-week administration period, demonstrating that the composition of the present invention has better long-term efficacy.

[0058] Compared to the combination of vitamin D, folic acid, vitamin B12, and potassium mentioned above, the addition of vitamin B1 and vitamin B2 further reduces both HCY levels and systolic blood pressure, resulting in better efficacy.

Claims

1. A composition comprising: (1) Vitamin D, (2) Folic acid-like substances, (3) Vitamin B12, (4) Contains potassium-containing active ingredients. (5) Acceptable excipients.

2. The composition of claim 1, wherein, The mass ratio of vitamin D, folic acid, vitamin B12, and potassium-containing active ingredients is 0.2–15000:10–2000:0.2–50:10000– 2400000; Preferably, the mass ratio of vitamin D, folic acid, vitamin B12, and potassium-containing active ingredient is 0.8-20:20-500:0.3-10:100000-2400000; More preferably, the preferred mass ratio of vitamin D, folic acid, vitamin B12, and potassium-containing active ingredient is 0.8-4.5:20-158:0.3-3:170000-190000.

3. The composition of claim 2, wherein, The mass ratio of vitamin D, folic acid, vitamin B12, and potassium-containing active ingredient is 0.8:200:0.3:190000; or the mass ratio of vitamin D, folic acid, vitamin B12, and potassium-containing active ingredient is 4:100:1.5:190000; or the mass ratio of vitamin D, folic acid, vitamin B12, and potassium-containing active ingredient is 4.5:158:3:170000.

4. The composition of claim 2, wherein, The dosage of vitamin D is 0.2–15000 μg, the dosage of folic acid is 10–2000 μg, the dosage of vitamin B12 is 0.2–50 μg, and the dosage of potassium-containing active ingredient is 10000–2400000 μg; preferably, the dosage of vitamin D is 0.8–20 μg, the dosage of folic acid is 20–500 μg, the dosage of vitamin B12 is 0.3–10 μg, and the dosage of potassium-containing active ingredient is 100000–2400000 μg; more preferably, the dosage of vitamin D is 0.8–4.5 μg, the dosage of folic acid is 20–158 μg, the dosage of vitamin B12 is 0.3–3 μg, and the dosage of potassium-containing active ingredient is 170000–190000 μg.

5. The composition of claim 1, wherein The composition comprises vitamin B1 and vitamin B2, wherein the mass ratio of vitamin D, folic acid, vitamin B12, potassium-containing active ingredient, vitamin B1, and vitamin B2 is 0.8–20: 20–500: 0.3–10: 100,000–2,400,000: 200– 20000:200~20000; preferably, the mass ratio of vitamin D, folic acid, vitamin B12, potassium-containing active ingredient, vitamin B1, and vitamin B2 is 0.8~4.5:20~158:0.3~3: 170000～190000∶200～2000∶100～2000。 6. The composition according to claim 5, characterized in that, The mass ratio of vitamin D, folic acid, vitamin B12, potassium-containing active ingredient, vitamin B1, and vitamin B2 is 0.8:200:0.3: 190000∶200∶100; or the mass ratio of the vitamin D, folic acid, vitamin B12, potassium-containing active ingredient, vitamin B1, and vitamin B2 is 4∶100∶1.5∶190000∶2000∶1000.

7. The composition according to claim 5, characterized in that, The dosage of vitamin D is 0.2–15000 μg, the dosage of folic acid is 10–2000 μg, the dosage of vitamin B12 is 0.2–50 μg, the dosage of potassium-containing active ingredient is 10000–2400000 μg, the dosage of vitamin B1 is 200–20000 μg, and the dosage of vitamin B2 is 200–20000 μg; preferably, the dosage of vitamin D is 0.8–20 μg, the dosage of folic acid is 20–500 μg, the dosage of vitamin B12 is 0.3–10 μg, the dosage of potassium-containing active ingredient is 100000–2400000 μg, the dosage of vitamin B1 is 200–2000 μg, and the dosage of vitamin B2 is 100–2000 μg.

8. The composition according to claim 1, characterized in that, The vitamin D is selected from one or more of vitamin D2, vitamin D3, alfacalcidol, calcitriol, dulcitol, and paricalcitol; the folic acid is selected from one or more of 5-methyltetrahydrofolate, 6S-5-methyltetrahydrofolate calcium, formyltetrahydrofolate, active metabolites of folic acid or folic acid salts, and substances that can release / generate folic acid in the body; the vitamin B12 is selected from one or more of cobalamin, methylcobalamin, 5'-deoxyadenosylcobalamin, hydroxycobalamin, cyanocobalamin, and other cobalamin derivatives, and substances that can release / generate cobalamin in the body; the potassium-containing active ingredient is selected from one or more of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium chloride, potassium citrate, potassium carbonate, potassium bicarbonate, potassium gluconate, potassium caseinate, and potassium alginate; the vitamin B1 is selected from one or two of thiamine hydrochloride and thiamine nitrate; the vitamin B2 is selected from riboflavin, riboflavin 5'- One or two of sodium phosphates.

9. Use of the composition according to any one of claims 1 to 8 in the preparation of a product for the prevention of hypertension.

10. Use of the composition according to any one of claims 1 to 8 in the preparation of a product for the prevention of hypertension or salt-sensitive hypertension with elevated homocysteine ​​levels.

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