Pharmaceutical composition for treating hypertension

Abstract

The invention provides a pharmaceutical composition. The pharmaceutical composition is prepared from amlodipine, enalapril, metoprolol, folic acid substances and pharmaceutically acceptable auxiliary materials. The composition has the advantages that under the condition that the dosage of each component of the composition is lower than the lowest dosage for treating hypertension, the composition has a remarkable antihypertensive effect, so that the side effects of the medicine can be reduced. In addition, the compound form of the product can improve the taking compliance of patients.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing amlodipine, enalapril, metoprolol and folic acid substances, which is used for treating hypertension and can alleviate the symptoms of dyslipidemia. The present invention belongs to the field of pharmacy. Background Art

[0002] Hypertension is a common chronic cardiovascular disease that affects human health and has become an important risk factor for other cardiovascular diseases. Long-term hypertension can cause damage to target organs such as the heart, brain, and kidneys, resulting in various acute and chronic complications (such as cerebrovascular events, coronary heart disease or coronary events, chronic kidney disease, etc.), which seriously affect the quality of life of patients and reduce life expectancy. Therefore, it is crucial to control blood pressure to the standard (<140 / 90mmHg) through drug treatment. In addition, dyslipidemia is also one of the risk factors for cardiovascular disease. Therefore, for patients with hypertension, it is necessary to try to avoid the simultaneous combination of lipid metabolism disorders, including avoiding the side effects of increased blood lipids during antihypertensive drug treatment.

[0003] There are many antihypertensive drugs available for clinical use. Commonly used antihypertensive drugs include angiotensin II receptor antagonists (losartan, valsartan, etc.), angiotensin converting enzyme inhibitors (captopril, enalapril, perindopril, etc.), beta-blockers (metoprolol, propranolol, atenolol, etc.), calcium channel blockers (nifedipine, nitrendipine, amlodipine, etc.), diuretics (furosemide, hydrochlorothiazide, indapamide), etc. However, the blood pressure control of many hypertensive patients is still not ideal. At the same time, in the treatment of hypertension, it is not recommended to administer a single drug in large doses. Increasing the dosage of the drug is likely to lead to adverse drug reactions. For example, when a large amount of non-selective beta-blockers and diuretics are used for a long time, it is easy to have an adverse effect on blood lipids and aggravate the symptoms of dyslipidemia, which is manifested as increased blood triglycerides and cholesterol and decreased HDL cholesterol, which greatly limits the actual application value of antihypertensive drugs.

[0004] Therefore, in order to meet clinical needs, it is necessary to continuously improve existing drug treatment technologies, including using the compound enhancement or toxicity reduction effects or reducing dosage to improve the clinical benefit-risk ratio of antihypertensive drugs, improving drug efficacy through multi-target combined control, improving patient compliance through compound forms, and improving patient tolerance by reducing dosage. Summary of the invention

[0005] In order to overcome the shortcomings of antihypertensive drugs in treating hypertension, the present invention provides a safe, effective and less toxic and side-effect pharmaceutical composition.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] A pharmaceutical composition comprising:

[0008] a) amlodipine and its derivatives; b) enalapril and its derivatives; c) metoprolol and its derivatives; d) folic acid substances; e) pharmaceutically acceptable excipients.

[0009] In the present invention, derivatives include but are not limited to various salts, esters, hydrates, pharmaceutically acceptable precursors, and in vivo active metabolites of the compounds.

[0010] In the present invention, the dosage of amlodipine, enalapril or metoprolol is 20-50% of the respective minimum therapeutic dosage for hypertension.

[0011] In the present invention, the composition may further include indapamide, the dosage of which is 20-50% of the minimum hypertension treatment dosage.

[0012] In the present invention, the dosage of amlodipine, enalapril, metoprolol or indapamide is 25% of the lowest dosage for treating hypertension.

[0013] In the present invention, the dosage of amlodipine is 1 to 2.5 mg, preferably 1.25 mg.

[0014] In the present invention, the dosage of enalapril is 1 to 2.5 mg, preferably 1.25 mg.

[0015] In the present invention, the dosage of metoprolol is 20-50 mg, preferably 25 mg.

[0016] In the present invention, the dosage of indapamide is 0.25-0.625 mg, preferably 0.31 mg.

[0017] In the present invention, the folic acid substance is selected from one of 5-methyltetrahydrofolate, formyltetrahydrofolate, active metabolites of folic acid or folate and substances that can release / generate folic acid in vivo, and the dosage is 0.1-5 mg, preferably 0.4-1.6 mg.

[0018] In the present invention, the amount of folic acid is calculated based on folic acid. For example, 0.416 mg of 5-methyltetrahydrofolate and 0.4 mg of folic acid are equimolar in mass. In this case, the amount of 5-methyltetrahydrofolate (calculated based on equimolar folic acid mass) is 0.4 mg.

[0019] As a preferred embodiment, the pharmaceutical composition provided by the present invention contains 25% of the minimum hypertension treatment dosage of amlodipine, enalapril and metoprolol and 0.4-1.6 mg of folic acid.

[0020] Preferably, the pharmaceutical composition provided by the present invention contains 0.4 mg folic acid, 1.25 mg amlodipine, 1.25 mg enalapril and 25 mg metoprolol.

[0021] As a preferred embodiment, the pharmaceutical composition provided by the present invention contains 20% of the minimum hypertension treatment amount of amlodipine, enalapril, metoprolol and indapamide and 0.4-1.6 mg of folic acid.

[0022] As a preferred embodiment, the pharmaceutical composition provided by the present invention contains 0.8 mg 5-methyltetrahydrofolate, 1 mg amlodipine, 1 mg enalapril, 20 mg metoprolol and 0.25 mg indapamide.

[0023] As a preferred embodiment, the pharmaceutical composition provided by the present invention contains 25% of the minimum hypertension treatment dosage of amlodipine, enalapril, metoprolol and indapamide and 0.4-1.6 mg of folic acid.

[0024] As a preferred embodiment, the pharmaceutical composition provided by the present invention contains 1.6 mg 5-methyltetrahydrofolate, 1.25 mg amlodipine, 1.25 mg enalapril, 25 mg metoprolol and 0.31 mg indapamide.

[0025] In the present invention, the pharmaceutically effective amount of the active ingredient of the composition refers to the dosage range of the active ingredient in the composition after the active ingredient is combined with other active ingredients to make the composition exert its pharmacological effect. The preferred effective amount is the preferred pharmaceutically effective amount of the active ingredient of the composition, and the pharmacological effect of the preferred effective amount is better than that of the pharmaceutically effective amount. Generally, the pharmaceutically effective amount of the active ingredient of the composition includes the optimal effective amount or the optimal effective amount range that makes the composition produce the maximum pharmacological effect, and this optimal effective amount or the optimal effective amount range will benefit the patient more.

[0026] In the present invention, "treat" or "improve" or "alleviate" are used interchangeably. These terms refer to methods for obtaining beneficial or desired results, which include, but are not limited to, therapeutic benefit and / or preventive benefit. "Therapeutic benefit" means eradication or alleviation of the underlying condition being treated. In addition, a therapeutic benefit is achieved when one or more physiological symptoms associated with the underlying condition are eradicated or alleviated, such that an improvement is observed in the patient, although the patient may still be suffering from the underlying condition. For preventive benefit, the composition can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even though the disease may not have been diagnosed.

[0027] In the present invention, the pharmaceutical composition is used in preparing a product for treating hypertension.

[0028] In the present invention, the pharmaceutical composition is used in preparing a product for treating dyslipidemia combined with hypertension.

[0029] In the present invention, the pharmaceutically acceptable excipients include one or more of pharmaceutical or food sugars or functional sweeteners, fillers, wetting agents, binders and lubricants.

[0030] The inventors have found in experiments that the use of a specific antihypertensive drug with a different antihypertensive mechanism and a dosage lower than that of conventional treatment in combination with folic acid substances can not only effectively reduce blood pressure, but also improve abnormal lipid metabolism, and is particularly suitable for patients with dyslipidemia and hypertension. Accordingly, the present invention provides a synergistic pharmaceutical composition containing amlodipine, enalapril, metoprolol, indapamide and folic acid substances through optimization. When the dosage of each component is lower than the minimum dosage of the component for treating hypertension, the composition still has a significant antihypertensive effect and produces a beneficial effect of improving abnormal lipid metabolism, providing a new solution for the treatment of hypertension combined with dyslipidemia. DETAILED DESCRIPTION

[0031] The present invention is further described below in conjunction with specific implementation modes, which is not intended to limit the present invention. Any equivalent replacements in the art made according to the contents of the present invention shall fall within the protection scope of the present invention.

[0032] In order to verify the scientific nature of the pharmaceutical composition provided by the present invention, and to illustrate that the four / five components of the pharmaceutical composition are reasonably formulated and can play a synergistic role in combination, rather than simply superimposing pharmacological effects, the Jin Zhengjun Q value method is introduced for analysis. The Jin Zhengjun Q value method is also known as the probability addition method. According to the pharmacological effects of the combination of two drugs and the pharmacological effects of the two drugs alone in the dose-effect curve area, the following calculation formula is used to calculate: 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 pharmacological effects of components and combinations, 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 be antagonistic; when it is less than 1.15 and greater than 0.85, it is considered to be additive; when it is greater than 1.15, it is considered to be synergistic.

[0033] Example 1. Synergistic hypotensive effect of the composition of the present invention on spontaneously hypertensive rats

[0034] 1. Methods

[0035] Spontaneously hypertensive rats (SHR) were purchased from Beijing Weitong Lihua. The blood pressure of rats increased after 8 weeks of age and increased significantly after 10 weeks of age. The blood pressure of rats was measured for 1 week (1st and 6th day), and rats with stable blood pressure were used for the experiment. The grouping and dosage of hypertensive rats are shown in Table 1. WKY rats were also selected to set up a normal control group (n=7). The animals were gavaged once a day for 2 consecutive weeks. The blood pressure of the rats was measured before and after the last administration.

[0036] Among them, "Amin" in the group represents "amlodipine", "Yi" represents enalapril, and "Me" represents metoprolol. The dosage of amlodipine, enalapril, and metoprolol in the Amin-Yime group and the folic acid + Amin-Yime group was about 25% of the lowest dosage of each single drug for the treatment of hypertension. The dosage of amlodipine in the Amin group was about the lowest dosage for the treatment of hypertension.

[0037] Statistical methods: The experimental data are The t test was used for comparison between the groups. P<0.05 indicated a significant statistical difference, and P<0.01 indicated a very significant statistical difference. The synergistic effect was analyzed by Q value.

[0038] 2. Results

[0039] As shown in Table 1, compared with the SHR group, folic acid alone had no significant antihypertensive effect on SHR rats, while the other experimental groups all produced significant antihypertensive effects (P < 0.01), and the antihypertensive effect of the Amitriptyline group was stronger than that of the ammonia group.

[0040] Compared with amiloride, after combined use of 0.04 mg / kg folic acid, the blood pressure reduction amplitude of rats in the folic acid + amiloride group was significantly enhanced (P < 0.01), and the Q value was 1.20, which was greater than 1.15, indicating that the combination of amlodipine, enalapril, metoprolol and folic acid has a significant synergistic antihypertensive effect on SHR rats, which can reduce the dosage of amlodipine, enalapril and metoprolol to one-fourth of the original routine minimum dosage, thereby reducing their side effects.

[0041] Table 1 Antihypertensive effect of the composition of the present invention on spontaneously hypertensive rats ( n=7)

[0042]

[0043] Note: Compared with SHR group, ** P<0.01.

[0044] Example 2: Therapeutic effect of the composition of the present invention on rats with dyslipidemia and hypertension

[0045] 1. Methods

[0046] Experimental animals and grouping: Sprague-Dawley rats (SHR) of specific pathogen-free (SPF) grade, with an equal number of males and females, weighing 180 ± 20 g, were purchased from Vital River Laboratories in Beijing. They were housed in an environment with a room temperature of 18 - 28°C and a relative humidity of 40% - 70%, with free access to food and water. After 1 week of adaptive feeding with regular feed, they were randomly divided into the groups shown in Table 2 below, with 7 rats in each group.

[0047] In the group names, "Ye" represents "5-methyltetrahydrofolate", "An" represents "amlodipine", "Yi" represents enalapril, "Mei" represents metoprolol, and "Yin" represents indapamide. In the experimental groups, the dosage of each single drug of amlodipine, enalapril, metoprolol, and indapamide in Group 1 was approximately 20% of the minimum dosage for treating hypertension with each single drug alone, and in Group 2 it was 50% of the minimum dosage for treating hypertension with each single drug alone.

[0048] Modeling: The rats in the SHR group continued to be fed with regular feed, while the other groups were fed with a high-fat diet (calorie ratio: 35% carbohydrate, 51% fat, 14% protein) for a total of 8 weeks. After 8 weeks, they were intragastrically administered drugs at the doses shown in Table 2 below. The SHR group and the SHR high-fat group were intragastrically administered normal saline once a day for 12 weeks.

[0049] After the last drug administration, the following indicators were measured: (1) Systolic blood pressure of the caudal artery: Using a non-invasive blood pressure measurement and analysis system, the systolic blood pressure of the caudal artery of rats in each group was measured 3 times continuously, and the average value was taken as the mean blood pressure value; (2) Contents of serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C): The rats in each group were anesthetized with 10% chloral hydrate, blood was taken from the abdominal aorta, allowed to stand for 1 - 2 h, centrifuged at 3000 r / min for 20 min, and then the serum was separated and stored at -80°C. The contents of TG, TC, HDL-C, and LDL-C in the rat serum were detected using an automatic biochemical analyzer; (3) Content of serum adiponectin (APN): The content of APN in the rat serum was detected by ELISA. APN is a plasma protein derived from adipose tissue and is related to the regulation of insulin resistance and blood glucose balance. Dyslipidemia can cause abnormal initiation of APN polymerization, a decrease in APN levels, and thus a reduction in the binding to APN receptors on target cells.

[0050] Statistical method: The experimental data are expressed as . Inter-group comparisons were made using a t-test. A significant statistical difference was considered when P < 0.05, and a very significant statistical difference was considered when P < 0.01.

[0051] II. Results

[0052] As shown in Tables 2 and 3, compared with the SHR group, the tail artery systolic pressure, TG, TC, and LDL-C of rats in the SHR high-fat group were significantly increased (P < 0.01), and the serum APN and HDL-C levels were significantly decreased (P < 0.01), indicating that the model was successfully established.

[0053] Compared with the SHR high-fat group, the systolic blood pressure of rats in the aimifolia group (quadruple) and aimifolia + indapamide group (pentapamide) were significantly reduced (P < 0.05 or P < 0.01), and the antihypertensive effect was more obvious after the quadruple drug combination with indapamide, even slightly lower than that of the SHR group. The Q values ​​were all greater than 1.15, producing a synergistic antihypertensive effect.

[0054] Compared with the SHR high-fat group, there were no significant differences in the tail artery systolic pressure, serum TG, TC, LDL-C, APN, and HDL-C levels of the rats in the indapamide group (P>0.05). There were significant differences in some blood lipid indicators in the amiloride group (quadruple) (P<0.05), and the quintuple drug group had a significant effect of reducing TG, TC, and LDL-C and increasing APN and HDL-C levels, and the Q values ​​were all greater than 1.15, indicating that the combination of 20% or 50% of the minimum dose of amlodipine, enalapril, metoprolol, indapamide and 5-methyltetrahydrofolate for the treatment of hypertension played a synergistic role in improving lipid metabolism and reducing the increase of serum triglycerides, thereby avoiding or reducing the occurrence of abnormal lipid metabolism.

[0055] Table 2 Comparison of tail artery systolic pressure and serum APN content in rats of each group ( n=6~7)

[0056]

[0057]

[0058] Note: Compared with SHR group, aa P<0.01; compared with the SHR high-fat group, b P<0.05, bb P<0.01.

[0059] Table 3 Comparison of serum TG, TC, HDL-C and LDL-C levels in rats of each group ( n=6~7)

[0060]

[0061] Note: Compared with SHR group, aa P<0.01; compared with the SHR high-fat group, b P<0.05, bb P<0.01.

Claims

1. A pharmaceutical composition, include: a) Amlodipine; b) Enalapril; c) Metoprolol; d) Folic acid substances; e) pharmaceutically acceptable excipients, wherein the dosage of amlodipine, enalapril or metoprolol is 20-50% of the respective minimum dosage for treating hypertension.

2. The pharmaceutical composition according to claim 1, It is characterized in that The composition also includes indapamide.

3. The pharmaceutical composition according to claim 2, It is characterized in that The dosage of indapamide is 20-50% of the minimum dosage for treating hypertension.

4. The pharmaceutical composition according to claim 3, It is characterized in that The dosage of amlodipine is 1-2.5 mg, the dosage of enalapril is 1-2.5 mg, the dosage of metoprolol is 20-50 mg, and the dosage of indapamide is 0.25-0.625 mg.

5. The pharmaceutical composition according to claim 3, It is characterized in that The dosage of amlodipine, enalapril, metoprolol or indapamide is 25% of the minimum dosage for treating hypertension.

6. The pharmaceutical composition according to claim 5, It is characterized in that The dosage of amlodipine is 1.25 mg, the dosage of enalapril is 1.25 mg, the dosage of metoprolol is 25 mg, and the dosage of indapamide is 0.31 mg.

7. The pharmaceutical composition according to claim 1, It is characterized in that The folic acid substance is selected from one of 5-methyltetrahydrofolate, formyltetrahydrofolate, active metabolites of folic acid or folate, and substances that can release / generate folic acid in vivo, and the dosage is 0.1-5 mg.

8. The pharmaceutical composition according to claim 7, It is characterized in that The dosage of the folic acid substance is 0.4-1.6 mg.

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

10. Use of the pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a product for treating hypertension combined with dyslipidemia.

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