Pharmaceutical composition for treating hypertension complicated with heart failure

Abstract

The invention provides a pharmaceutical composition. The pharmaceutical composition is prepared from amlodipine with the minimum hypertension treatment dosage of 20%-50%, valsartan with the minimum hypertension treatment dosage of 20%-50%, metoprolol with the minimum hypertension treatment dosage of 20%-50%, hydrochlorothiazide with the minimum hypertension treatment dosage of 20%-50%, homocysteine reducing medicine and pharmaceutically acceptable auxiliary materials. The pharmaceutical composition is used for treating hypertension, is especially suitable for hypertension with heart failure, and can reduce the death risk of patients.

Description

Technical Field

[0001] The invention relates to a pharmaceutical composition for treating hypertension, which contains amlodipine, valsartan, metoprolol, hydrochlorothiazide and a homocysteine-lowering drug. The invention belongs to the field of pharmacy. Background Art

[0002] Hypertension is a common cardiovascular disease that endangers human health and is also an important risk factor for other cardiovascular diseases. Target organ damage caused by hypertension refers to pathological damage to the heart, brain, kidneys, blood vessels and other organs caused by hypertension, including subclinical target organ damage and clinical complications, among which chronic heart failure is one of the more common clinical complications.

[0003] The Framingham Heart Study showed that hypertension has the highest attributable risk for heart failure (HF), surpassing myocardial infarction, coronary heart disease and diabetes, and is the most common cause of HF. Another study showed that 75% of patients had hypertension before developing chronic HF. Butler J et al.'s study showed that the risk of HF increases with increasing blood pressure levels, and hypertension increases the incidence of HF by 2 to 3 times.

[0004] At present, the commonly used drugs for the treatment of hypertension include angiotensin converting enzyme inhibitors, calcium channel blockers, angiotensin II receptor blockers, diuretics and beta-blockers. These drugs can be used alone, in combination or in the form of single-tablet fixed-dose compound preparations for clinical use, but the principle of their combination is to enhance the antihypertensive effect, with the goal of controlling blood pressure within a certain normal range (systolic / diastolic blood pressure control below 140 / 90 mmHg). Various antihypertensive drugs have different pharmacological mechanisms of action, and their suitable populations for hypertensive patients are different, and their main side effects or adverse reactions are also different. Therefore, for complex diseases such as hypertension combined with heart failure or accompanied by elevated homocysteine, how to achieve both effective treatment and minimize drug side effects or adverse reactions is a difficult problem in clinical practice, and existing compound products cannot meet clinical needs. Summary of the invention

[0005] In response to the clinical needs of existing hypertension therapeutic drugs, especially for patients with hypertension complicated by heart failure, the present invention provides a novel pharmaceutical composition.

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

[0007] A pharmaceutical composition comprising:

[0008] (1) 20% to 50% of the minimum hypertension treatment dose of amlodipine;

[0009] (2) 20% to 50% of the minimum hypertension treatment dose of valsartan;

[0010] (3) 20% to 50% of the minimum hypertension treatment dose of metoprolol;

[0011] (4) 20% to 50% of the minimum hypertension treatment dose of hydrochlorothiazide;

[0012] (5) Homocysteine-lowering drugs;

[0013] (6) Pharmaceutically acceptable excipients.

[0014] In the pharmaceutical composition of the present invention, the dosage of 20% to 50% of the minimum hypertension treatment dosage of amlodipine is 0.5 to 1.25 mg.

[0015] In the pharmaceutical composition of the present invention, the dosage of 20% to 50% of the minimum hypertension treatment dosage of valsartan is 16 to 40 mg.

[0016] In the pharmaceutical composition of the present invention, the dosage of metoprolol which is 20% to 50% of the minimum hypertension treatment dosage is 10 to 25 mg.

[0017] In the pharmaceutical composition of the present invention, the dosage of 20% to 50% of the minimum hypertension treatment dosage of hydrochlorothiazide is 2.5 to 6.25 mg.

[0018] In the pharmaceutical composition of the present invention, the homocysteine ​​lowering drug is selected from folic acid or 5-methyltetrahydrofolate. The dosage of the homocysteine ​​lowering drug is 0.2 to 1.6 mg, preferably 0.4 to 0.8 mg.

[0019] The pharmaceutical composition of the present invention comprises 0.5 mg of amlodipine, 16 mg of valsartan, 10 mg of metoprolol, 2.5 mg of hydrochlorothiazide and 0.4 mg of folic acid.

[0020] The pharmaceutical composition of the present invention comprises 1.25 mg of amlodipine, 40 mg of valsartan, 25 mg of metoprolol, 6.25 mg of hydrochlorothiazide and 0.8 mg of 5-methyltetrahydrofolate.

[0021] The pharmaceutical composition described in the present invention is in the form of an oral preparation, including tablets, capsules or granules.

[0022] The pharmaceutical composition provided by the present invention is used for preparing medicines for treating hypertension. The composition provided by the present invention is more suitable for preparing medicines for treating hypertension with elevated homocysteine ​​levels.

[0023] In the present invention, the pharmaceutical composition provided by the present invention is suitable for hypertensive patients complicated with heart failure. The heart failure described in the present invention includes heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, heart failure with intermediate ejection fraction, chronic heart failure, and acute heart failure. The pharmaceutical composition provided by the present invention can significantly reduce homocysteine ​​levels while lowering blood pressure and treating heart failure.

[0024] The advantage of the pharmaceutical composition of the present invention is that it uses drugs with different antihypertensive mechanisms for matching, and has an unexpected synergistic effect for hypertensive patients with heart failure and / or elevated homocysteine. Different from the known multi-hypertensive drug combinations on the market that use conventional doses, the present invention uses a minimum hypertension treatment dose of 20% to 50% of amlodipine, a minimum hypertension treatment dose of 20% to 50% of valsartan, a minimum hypertension treatment dose of 20% to 50% of metoprolol, and a minimum hypertension treatment dose of 20% to 50% of hydrochlorothiazide to achieve the purpose of blood pressure control and heart failure treatment. In addition, the formula also contains homocysteine-lowering drugs, which can effectively reduce homocysteine ​​levels and have a protective effect on vascular endothelial function. The homocysteine-lowering drugs are used in combination with the above-mentioned antihypertensive drugs to have the effect of synergistically treating hypertension combined with heart failure. The pharmaceutical composition has significant advantages in clinical application such as scientific component compatibility, precise dosage ratio, few side effects, and high compliance, and is an innovative intervention program in the field of hypertension-related disease treatment. DETAILED DESCRIPTION

[0025] 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.

[0026] Example 1: Effect of the composition of the present invention on a rat model of hypertension complicated with heart failure

[0027] Male SPF Dahl salt-sensitive rats weighing (220±10) g were provided by Beijing Weitonglihua Animal Company.

[0028] Nine rats were randomly selected as the control group, with 3 rats in one cage. The rats in the control group were fed with a 0.3% NaCl low-salt diet, and the remaining rats were prepared into a hypertension complicated with heart failure model and fed with an 8% NaCl high-salt diet. Both diets did not contain folic acid. Each cage was fed with 60 g of diet and 450 mL of water per day for a total of 20 weeks.

[0029] After the modeling is completed,

[0030] 1. Blood pressure monitoring: Use a rat intelligent non-invasive sphygmomanometer to detect changes in rat blood pressure.

[0031] 2. Echocardiography: SonoScape-S2N color Doppler ultrasound diagnostic instrument, under the guidance of two-dimensional ultrasound, used M-mode ultrasound through the sternal long axis section of the left ventricle to measure the left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD), and the average value of three cardiac cycles was calculated, and the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were calculated according to the Teichholtz formula.

[0032] 3. Determination of heart failure indicators: Blood is collected from the orbital vein to measure serum amino-terminal pro-brain natriuretic peptide (NT-proBNP) as an indicator for diagnosing heart failure.

[0033] Rats with hypertension complicated with heart failure (systolic blood pressure ≥ 140 mmHg, cardiac function parameters LVEF and LVFS significantly decreased compared with the control group, and NT-proBNP significantly increased, which was considered to cause hypertension complicated with heart failure) were randomly divided into a model group and 7 drug-administered groups (n = 8-10) according to the following table, and given the corresponding dose of drugs according to Table 1, once a day by oral gavage, and the gavage volume was calculated as 10 ml / kg body weight, and the drug was administered continuously for 8 weeks. Blood pressure was measured after 4 weeks and 8 weeks of administration, and left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) were measured after 8 weeks of administration, and the average values ​​of 3 cardiac cycles were calculated, and left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were calculated according to the Teichholtz formula. At the end of the experiment, the rats were killed and blood was collected, and serum NT-proBNP levels and homocysteine ​​(HCY) were measured.

[0034] 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.

[0035] In order to verify the scientific nature of the composition provided by the present invention, illustrate the compatibility advantages of the composition, and introduce the Jin Zhengjun Q value method for analysis. The Jin Zhengjun Q value method is also called 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: Ei = 1-Pi / P 模型组, Pi 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 or equal to 1.15, it is considered to be synergistic.

[0036] The experimental results are as follows:

[0037] Table 1: Changes in blood pressure and HCY levels of rats in each group after 8 weeks of administration ( n=8~10)

[0038]

[0039]

[0040] Note: Compared with the control group, # P<0.05, ## P<0.01; compared with the model group, * P<0.05, ** P<0.01.

[0041] From the above experimental results, it can be concluded that the blood pressure of Dahl salt-sensitive rats fed a high-salt diet was significantly increased compared with the control group 20 weeks after modeling (P<0.01), and the feed did not contain folic acid. After the modeling, their homocysteine ​​levels were significantly increased (P<0.01).

[0042] After modeling and grouping, different test substances were given. Except for the two groups using folic acid compounds alone, the other groups had significant blood pressure lowering effects. Compared with the amlodipine group (0.5) mg / kg, the combination of four antihypertensive drugs with different mechanisms of action at 20% of the lowest hypertension treatment dose: the low-dose group of amlodipine + valsartan + metoprolol + hydrochlorothiazide (0.05+1.6+1+0.25) mg / kg had a greater antihypertensive effect. Furthermore, the high-dose group of amlodipine + valsartan + metoprolol + hydrochlorothiazide (0.125+4+2.5+0.625) mg / kg, which was 50% of the lowest hypertension treatment dose, further enhanced the antihypertensive effect. On the basis of taking a combination of four antihypertensive drugs at 20% or 50% of the lowest hypertension treatment dose, adding folic acid (0.04) mg / kg or 5-methyltetrahydrofolate (0.08) mg / kg in combination has a synergistic effect in lowering blood pressure (Q>1.15), which is related to the fact that taking folic acid can effectively reduce homocysteine ​​levels and improve vascular endothelial function.

[0043] The groups supplemented with folic acid or 5-methyltetrahydrofolate had a significant effect on reducing homocysteine ​​levels, and 5-methyltetrahydrofolate (0.08) mg / kg had a better effect on reducing homocysteine ​​than folic acid (0.04) mg / kg, showing a dose effect. Whether 5-methyltetrahydrofolate (0.08) mg / kg or folic acid (0.04) mg / kg, when taken in combination with quadruple antihypertensive drugs, had a synergistic effect in reducing homocysteine ​​levels.

[0044] The composition provided by the present invention has been proven through experiments to have a significant combined drug effect in treating hypertension, especially for the characteristics of the hypertensive group with elevated homocysteine. The drug combination treatment scheme provided by the present invention has a targeted and unexpected synergistic blood pressure-lowering effect.

[0045] Table 2: Changes in cardiac function parameters of rats in each group after 8 weeks of administration ( n=8~10)

[0046]

[0047] Note: Compared with the control group, # P<0.05, ## P<0.01; compared with the model group, * P<0.05, ** P<0.01.

[0048] From the above experimental results, it can be seen that after the modeling, compared with the control group, the LVEF (P<0.05) and LVFS (P<0.01) of the model group were significantly reduced, and the NT-proBNP (P<0.05) was significantly increased, indicating that the model rats prepared by this method have developed a relative degree of heart failure symptoms.

[0049] Compared with the model group, each drug-administered group showed a trend of improving heart failure indicators, and the efficacy of the 5-methyltetrahydrofolate group and the folic acid group was milder. Compared with the amlodipine group (0.5) mg / kg, the combination of four antihypertensive drugs with different mechanisms of action, which was 20% of the lowest hypertension treatment dose: the low-dose group of amlodipine + valsartan + metoprolol + hydrochlorothiazide (0.05 + 1.6 + 1 + 0.25) mg / kg, had a greater effect of increasing LVEF, LVFS and reducing NT-proBNP. Furthermore, the high-dose group of amlodipine + valsartan + metoprolol + hydrochlorothiazide (0.125 + 4 + 2.5 + 0.625) mg / kg, which was 50% of the lowest hypertension treatment dose, further enhanced the effect of increasing LVEF, LVFS and reducing NT-proBNP. On the basis of taking a combination of four antihypertensive drugs at 20% or 50% of the lowest hypertension treatment dose, adding folic acid (0.04) mg / kg or 5-methyltetrahydrofolate (0.08) mg / kg in combination has the effect of synergistically increasing LVEF, LVFS and reducing NT-proBNP.

Claims

1. A pharmaceutical composition, include: (1) 20% to 50% of the minimum hypertension treatment dose of amlodipine; (2) 20% to 50% of the minimum hypertension treatment dose of valsartan; (3) 20% to 50% of the minimum hypertension treatment dose of metoprolol; (4) 20% to 50% of the minimum hypertension treatment dose of hydrochlorothiazide; (5) Homocysteine-lowering drugs; (6) Pharmaceutically acceptable excipients.

2. The pharmaceutical composition according to claim 1, It is characterized in that The dosage of 20% to 50% of the minimum hypertension treatment dose of amlodipine is 0.5 to 1.25 mg; the dosage of 20% to 50% of the minimum hypertension treatment dose of valsartan is 16 to 40 mg; the dosage of 20% to 50% of the minimum hypertension treatment dose of metoprolol is 10 to 25 mg; the dosage of 20% to 50% of the minimum hypertension treatment dose of hydrochlorothiazide is 2.5 to 6.25 mg.

3. The pharmaceutical composition according to claim 1, It is characterized in that The homocysteine ​​lowering drug is selected from folic acid or 5-methyltetrahydrofolate.

4. The pharmaceutical composition according to claim 1, It is characterized in that The dosage of the homocysteine ​​lowering drug is 0.2 to 1.6 mg, preferably 0.4 to 0.8 mg.

5. The pharmaceutical composition according to claim 1, It is characterized in that The pharmaceutical composition comprises 0.5 mg of amlodipine, 16 mg of valsartan, 10 mg of metoprolol, 2.5 mg of hydrochlorothiazide and 0.4 mg of folic acid.

6. The pharmaceutical composition according to claim 1, It is characterized in that The pharmaceutical composition comprises 1.25 mg of amlodipine, 40 mg of valsartan, 25 mg of metoprolol, 6.25 mg of hydrochlorothiazide and 0.8 mg of 5-methyltetrahydrofolate.

7. Use of the pharmaceutical composition according to any one of claims 1 to 6 in preparing a drug for treating hypertension.

8. The use according to claim 7, It is characterized in that The hypertension is hypertension with elevated homocysteine.

9. The use according to claim 7, It is characterized in that The hypertensive patient suffers from heart failure.

10. The use according to claim 9, It is characterized in that The heart failure includes heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, heart failure with mid-range ejection fraction, chronic heart failure, and acute heart failure.

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