Pharmaceutical composition for treating hypertension secondary heart failure

Abstract

The invention provides a pharmaceutical composition. The pharmaceutical composition is prepared from enalapril, indapamide, metoprolol, amlodipine, folic acid and pharmaceutically acceptable auxiliary materials. The composition provided by the invention has the advantages that the composition has remarkable beneficial effects of reducing blood pressure and improving cardiac hemodynamics, and is particularly suitable for patients with hypertension secondary left ventricular hypertrophy and chronic heart failure. Meanwhile, 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 enalapril, indapamide, metoprolol, amlodipine and folic acid, which is used for treating hypertension, and is particularly suitable for patients with hypertension-induced left ventricular hypertrophy and chronic heart failure. The present invention belongs to the field of pharmacy. Background Art

[0002] Hypertension is the most common chronic cardiovascular disease and a major risk factor for chronic heart failure. Due to the presence of long-term hypertension, the patient's peripheral blood vessels are in a state of high resistance, the systolic load of the heart continues to increase, and the initial compensatory myocardial structural remodeling forms myocardial (mainly left ventricle) hypertrophy to meet the functional needs of the circulatory system. If long-term hypertension is not effectively controlled, myocardial hypertrophy and myocardial structural changes will continue to intensify, leading to cardiac systolic and diastolic dysfunction. When the ejection fraction (EF) drops below 40%, peripheral vascular resistance increases reactively, further deteriorating cardiac function, forming a pathophysiological vicious circle, and eventually forming chronic heart failure, which is one of the important causes of death in patients with hypertension. Studies have shown that heart failure caused by hypertension is different from other types of heart failure, and most of them are ejection fraction preserved. Exploring comprehensive intervention measures for hypertension and its heart failure is an effective way to reduce the mortality rate of patients with hypertension.

[0003] There are many drugs available for the treatment of hypertension in clinical practice. Commonly used antihypertensive drugs include angiotensin II receptor antagonists (ARB, including losartan, valsartan, etc.), angiotensin converting enzyme inhibitors (ACEI, including captopril, enalapril, perindopril, etc.), beta-blockers (metoprolol, propranolol, atenolol, etc.), calcium channel blockers (CCB, including nifedipine, nitrendipine, amlodipine, etc.), diuretics (furosemide, hydrochlorothiazide, indapamide) and other drugs. Studies have found that ventricular remodeling caused by hypertension directly affects the occurrence and development of heart failure, and abnormal activation of the renin-angiotensin-aldosterone system (RAAS) plays a leading role in ventricular remodeling. After angiotensin II (AngII) binds to angiotensin II receptors on cardiomyocytes, it can not only stimulate cardiomyocyte proliferation and hypertrophy, but also enhance the synthesis of myocardial interstitial collagen fibers. Aldosterone not only directly participates in the formation of cardiomyocyte hypertrophy, but also regulates the gene expression of myocardial collagen at the transcriptional level, increasing collagen synthesis. ACEI can effectively block RAAS, antagonize AngII and aldosterone in the circulation and local tissues, reduce left ventricular preload and postload and ventricular wall tension, reduce myocardial interstitial fibrosis, reverse ventricular remodeling, improve hemodynamics, and thus improve cardiac function. It is clinically suitable for the treatment of various levels of heart failure or asymptomatic left ventricular dysfunction, delay the progression of heart failure, reduce hospitalization due to heart failure, and improve patient survival. It is the first choice of antihypertensive drug for hypertension combined with chronic heart failure.

[0004] However, in many patients with chronic heart failure secondary to hypertension and patients with hypertensive heart disease, the use of ARB or ACEI drugs alone not only fails to control blood pressure ideally, but also worsens the condition of myocardial hypertrophy and heart failure in patients with persistent hypertension. At present, the principle of combining commonly used compound antihypertensive drugs in clinical practice is to enhance the synergistic effect of antihypertensive drugs, and does not consider how to synergistically control the patient's myocardial hypertrophy and the gradually evolving chronic heart failure. Therefore, existing treatment technologies and corresponding drug products need to be improved, including improving the ingredients of compound drugs and reducing the dosage of one or more active ingredients, so as to improve the clinical benefits of drug treatment and reduce adverse reactions. Summary of the invention

[0005] In order to overcome the shortcomings of the current compound antihypertensive drugs on the market for treating hypertension and better prevent or improve complications of heart failure caused by 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) Enalapril and its derivatives; b) Indapamide and its derivatives; c) Metoprolol and its derivatives; d) Amlodipine and its derivatives; e) Folic acid substances; f) 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 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 effective amount is 0.2-5 mg.

[0011] In the present invention, the dosage of enalapril is 1-5 mg, the dosage of indapamide is 0.1-1.25 mg, the dosage of metoprolol is 20-50 mg, the dosage of amlodipine is 0.5-2.5 mg, and the dosage of folic acid is 0.2-5 mg.

[0012] In the present invention, the dosage of enalapril is 1.25-5 mg, the dosage of indapamide is 0.3-1.25 mg, the dosage of metoprolol is 25-33 mg, the dosage of amlodipine is 0.625-1.25 mg, and the dosage of folic acid is 0.4-1.2 mg.

[0013] 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.

[0014] As a preferred embodiment, the pharmaceutical composition provided by the present invention contains 2.5 mg of enalapril, 0.625 mg of indapamide, 33 mg of metoprolol, 1.25 mg of amlodipine and 0.4 mg of folic acid.

[0015] As a preferred embodiment, the pharmaceutical composition provided by the present invention contains 5 mg of enalapril, 1.25 mg of indapamide, 50 mg of metoprolol, 2.5 mg of amlodipine and 1.2 mg of 5-methyltetrahydrofolate.

[0016] As a preferred embodiment, the pharmaceutical composition provided by the present invention contains 1.25 mg of enalapril, 0.3 mg of indapamide, 25 mg of metoprolol, 0.625 mg of amlodipine and 0.4 mg of 5-methyltetrahydrofolate.

[0017] 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.

[0018] 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.

[0019] In the present invention, the pharmaceutical dosage form of the pharmaceutical composition is an oral preparation, and is provided in one preparation.

[0020] In the present invention, the dosage form of the pharmaceutical composition is a pharmaceutically acceptable dosage form, including but not limited to ordinary tablets, double-layer tablets, multi-layer tablets, sustained-release tablets, single-chamber controlled-release tablets, double-chamber controlled-release tablets, microporous controlled-release tablets, sublingual tablets, orally rapidly disintegrating tablets, dispersible tablets, chewable tablets, enteric-coated tablets, granules, pills, enteric-coated capsules, delayed-release tablets, timed / positioned release tablets, ordinary capsules, sustained-release capsules, controlled-release capsules, capsules containing micropellets or small tablets, pH-dependent capsules containing micropellets or small tablets, liposomes, nanoformulations, microcapsules, microemulsions, porous polymer microspheres, oral liquids, syrups, powders, lyophilized powders, films, suspensions, emulsions, drops or patches, among which tablets, capsules, granules, pills, oral liquids, powders, liposomes, nanoformulations, microcapsules, microemulsions, and porous polymer microspheres are preferred.

[0021] In the present invention, the pharmaceutical composition is used in preparing a product for treating hypertension.

[0022] In the present invention, the pharmaceutical composition is used in preparing a product for treating heart failure secondary to hypertension.

[0023] In the present invention, the pharmaceutical composition is used in preparing a product for treating left ventricular hypertrophy secondary to hypertension.

[0024] In the present invention, heart failure mainly refers to congestive heart failure.

[0025] 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.

[0026] The inventors found in an animal model experiment of chronic heart failure caused by long-term hypertension that the use of lower doses of enalapril, indapamide, and metoprolol and amlodipine lower than the conventional treatment dose, as well as folic acid substances with the effect of reducing homocysteine ​​levels, can not only effectively reduce blood pressure, but also delay and improve heart function, and is particularly suitable for patients with left ventricular hypertrophy secondary to hypertension and heart failure secondary to hypertension. Based on this, the present invention provides a synergistic pharmaceutical composition containing enalapril, indapamide, metoprolol, amlodipine and folic acid substances through optimization, which still has beneficial effects when the dosage is lower than the minimum dosage of the components approved for the treatment of hypertension, and the multi-target and multi-component drug effects synergistically play a role in preventing and treating left ventricular hypertrophy and heart failure, providing a new solution for the long-term clinical treatment of hypertension. DETAILED DESCRIPTION

[0027] 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.

[0028] Example 1. Synergistic effect of the composition of the present invention on rats with heart failure induced by long-term spontaneous hypertension

[0029] I. Method

[0030] Experimental animals and grouping: Spontaneously hypertensive rats (SHR) of SPF grade, 16 weeks old, half male and half female, were purchased from Vital River Laboratories in Beijing. Wistar-Kyoto rats (WKY) of clean grade, 16 weeks old, half male and half female, were purchased from Vital River Laboratories in Beijing and used as the WKY control group. After purchase, the rats were raised 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. They were fed with normal feed for 16 weeks for adaptation. The SHR rats were randomly divided into the groups shown in Table 1 below (except the WKY control group), with 7 - 8 rats in each group, and were gavaged with drugs according to the doses in Table 1. The WKY control group and the SHR group were gavaged with normal saline once a day for 8 weeks.

[0031] Among them, "Ena" in the group represents enalapril, "Ind" represents indapamide, "Met" represents metoprolol, and "Aml" represents amlodipine.

[0032] After the last administration, the following indicators were measured: (1) Systolic blood pressure of the caudal artery (SBP): An non-invasive blood pressure measurement and analysis system was used to measure the systolic blood pressure of the caudal artery (SBP) of each group of rats, and it was measured continuously 3 times, and the average value was taken as the average blood pressure value; (2) Left ventricular posterior wall thickness (LVPWT), left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF): Each group of rats was anesthetized with medical pentobarbital, and ultrasonic examination was used to obtain LVPWT, LVEDD, and LVEF; (3) Content of NF-κB p65: The activity of NF-κB p65 in the nuclear protein of myocardial homogenate was detected by enzyme-linked immunosorbent assay (ELISA). The NF-κB signaling pathway plays an important role in the occurrence and development of myocardial hypertrophy and heart failure. Long-term increase and stimulation of NF-κB cause myocardial damage by upregulating pro-inflammatory factors, and inhibiting the activity of NF-κB in rats with myocardial infarction can significantly reduce the infarct area. Therefore, the inhibition of NF-κB has a positive effect on the structure and function of the heart.

[0033] Statistical method: The experimental data were expressed as . The t-test was used for comparison between groups. A significant statistical difference was considered when P < 0.05, and a very significant statistical difference was considered when P < 0.01.

[0034] In order to verify the scientific nature of the pharmaceutical composition provided by the present invention, and to illustrate that the 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.

[0035] 2. Results

[0036] As shown in Tables 1 and 2, compared with the WKY control group, the rats in the SHR control group had slow growth, messy fur, dull color, a small amount of hair loss, emaciation, irritability, etc. Some rats had tail edema, cyanosis of the lips and toes, etc., and the rats' tail artery systolic pressure, myocardial NF-κB p65, LVPWT, and LVEDD were significantly increased (P < 0.01), and LVEF was significantly decreased (P < 0.01), indicating that the rats' myocardial diastolic and systolic functions were significantly decreased, left ventricular remodeling occurred, cardiac function decreased, and obvious chronic heart failure appeared, indicating that the model was successfully established.

[0037] 1. Analysis of blood pressure reduction indicators:

[0038] Compared with the SHR control group, the systolic blood pressure of rats in the ammonia group, the quadruple drug group, and the quintuple drug group were significantly reduced (P < 0.05 or P < 0.01). The antihypertensive effect of the quadruple drug group was better than that of the conventional dose of amlodipine group. The systolic blood pressure of the quintuple drug group was further reduced on the basis of the quadruple drug, and the Q value analysis result was greater than 1.15, indicating that folic acid and the quadruple drug group produced a synergistic antihypertensive effect.

[0039] 2. Analysis of indicators for improving cardiac function

[0040] Compared with the SHR control group, the ammonia group had no significant effect on NF-κB p65, LVPWT, LVEDD and LVEF; the myocardial NF-κB p65, LVPWT and LVEDD of rats in the indole group and indole folic acid group were significantly decreased (P<0.05 or P<0.01), and LVEF was significantly increased (P<0.05 or P<0.01).

[0041] Q value analysis was performed on the pentavalent group, the corresponding quadruple group and the folic acid group, and the Q values ​​were 1.62, 1.50, 1.48 and 1.32, respectively, all greater than 1.15, indicating that the pentavalent group had extremely significant effects in lowering blood pressure and improving heart failure (P < 0.01), and both produced a synergistic effect (Q > 1.15), and can be used for patients with heart failure caused by aging due to spontaneous hypertension.

[0042] Table 1 Effect of the composition of the present invention on systolic blood pressure and myocardial NF-κB p65 content in spontaneously hypertensive rats ( n=7~8)

[0043]

[0044] Note: Compared with the WKY control group, aa P<0.01; compared with the SHR control group, b P<0.05, bb P<0.01.

[0045] Table 2 Effects of the composition of the present invention on cardiac morphological indicators in spontaneously hypertensive rats ( n=7~8)

[0046]

[0047]

[0048] Note: Compared with the WKY control group, aa P<0.01; compared with the SHR control group, b P<0.05, bb P<0.01.

[0049] Example 2. Synergistic hypotensive effect of the composition of the present invention on spontaneously hypertensive rats

[0050] 1. Methods

[0051] 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 3. WKY rats were also selected to set up a normal control group (n=7). The animals were gavaged once a day for 10 consecutive days. The blood pressure of the rats was measured before and after the last administration.

[0052] Statistical methods: The experimental data are The t test was used for comparison between groups. P<0.05 indicated a significant statistical difference, and P<0.01 indicated a very significant statistical difference. Q value analysis was performed.

[0053] 2. Results

[0054] As shown in Table 3, 5-methyltetrahydrofolate alone had no significant antihypertensive effect on spontaneously hypertensive rats. After the quadruple group was combined with 5-methyltetrahydrofolate, the antihypertensive effect on spontaneously hypertensive rats was enhanced, and the Q value was greater than 1.15, indicating that the combination of enalapril, indapamide, metoprolol, amlodipine and 5-methyltetrahydrofolate had a significant synergistic antihypertensive effect on spontaneously hypertensive rats.

[0055] Table 3 Antihypertensive effect of the composition of the present invention on spontaneously hypertensive rats ( n=7)

[0056]

[0057]

[0058] Note: Compared with the normal control group, aa P<0.01; compared with the model control group, b P<0.05, bb P<0.01.

Claims

1. A pharmaceutical composition, include: a) Enalapril; b) Indapamide; c) Metoprolol; d) amlodipine; e) Folic acid; f) pharmaceutically acceptable excipients.

2. 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.

3. The pharmaceutical composition according to claim 1, Features: The dosage of enalapril is 1-5 mg, the dosage of indapamide is 0.1-1.25 mg, the dosage of metoprolol is 20-50 mg, the dosage of amlodipine is 0.5-2.5 mg, and the dosage of folic acid is 0.2-5 mg.

4. The pharmaceutical composition according to claim 3, Features: The dosage of enalapril is 1.25-5 mg, the dosage of indapamide is 0.3-1.25 mg, the dosage of metoprolol is 25-33 mg, the dosage of amlodipine is 0.625-1.25 mg; and the dosage of folic acid is 0.4-1.2 mg.

5. The pharmaceutical composition according to claim 4, It is characterized in that The dosage of enalapril is 2.5 mg, the dosage of indapamide is 0.625 mg, the dosage of metoprolol is 33 mg, and the dosage of amlodipine is 1.25 mg.

6. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a product for treating hypertension.

7. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a product for treating chronic heart failure secondary to hypertension.

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