Pharmaceutical composition for treating coronary heart disease

Abstract

The invention provides a pharmaceutical composition. The pharmaceutical composition comprises felodipine, atenolol, folic acid substances and pharmaceutically acceptable auxiliary materials. The composition provided by the invention can also comprise telmisartan. The pharmaceutical composition provided by the invention can be used for preparing medicines for treating coronary heart disease, and has the effects of improving myocardial ischemia and reducing the occurrence risk of cardiovascular events.

Description

Technical Field

[0001] The invention relates to a pharmaceutical composition, comprising felodipine, atenolol and folic acid substances and pharmaceutically acceptable adjuvant compositions thereof. The composition provided by the invention is used for treating coronary heart disease, and has the effects of improving myocardial ischemia and reducing the risk of cardiovascular events. The invention belongs to the field of pharmacy. Background Art

[0002] Coronary heart disease, also known as coronary atherosclerotic heart disease, ischemic heart disease, refers to heart disease caused by myocardial ischemia and hypoxia caused by coronary atherosclerosis. Coronary heart disease is a common disease in middle-aged and elderly people. There may be no symptoms in the early stage, and gradually develop into exertional angina pectoris. At this time, the basic pathological changes of coronary artery stenosis already exist. After that, as the disease progresses, the frequency of angina pectoris attacks increases, and variant angina pectoris may occur until acute myocardial infarction occurs. Ischemic cardiomyopathy is a common type of coronary heart disease, which refers to localized or diffuse myocardial fibrosis caused by long-term myocardial ischemia, resulting in impaired cardiac systolic and / or diastolic function, causing cardiac enlargement or stiffness, chronic heart failure, arrhythmia, etc. Acute coronary syndrome (ACS) is a group of clinical syndromes with complete or incomplete occlusive thrombosis caused by rupture or erosion of coronary atherosclerotic plaques as the pathological basis, including acute ST-segment elevation myocardial infarction, acute non-ST-segment elevation myocardial infarction and unstable angina pectoris. The condition is serious and life-threatening.

[0003] Treatment measures for coronary heart disease include anti-myocardial ischemia and anti-thrombosis. Currently, drugs that improve myocardial ischemia and relieve angina symptoms mainly include nitrates, beta-blockers and calcium channel blockers (CCBs). In acute attacks of angina, sublingual nitroglycerin can be taken for emergency treatment; anti-thrombotic drugs include aspirin, clopidogrel, tirofiban, cilostazol, etc., which are used to prevent myocardial infarction at an early stage; in addition, statins can also be used clinically for lipid-lowering therapy to alleviate the progression of coronary atherosclerosis. But overall, these treatment measures lack protection for the vascular endothelium.

[0004] As mentioned above, the occurrence of ACS is closely related to thrombosis caused by rupture of coronary atherosclerotic plaques, and vascular endothelial integrity is a prerequisite for preventing plaque rupture or erosion. Studies have found that elevated levels of homocysteine ​​(Hcy) in the blood are an important pathological factor inducing vascular endothelial damage. Hcy is a sulfur-containing amino acid and an intermediate product of methionine metabolism. It is generated in the body after methionine is transmethylated and is a non-essential amino acid. Under normal circumstances, the generation and metabolism of Hcy in the human body maintain a dynamic balance, but when it is pathologically elevated, Hcy has a strong biological effect. It is speculated that several mechanisms may be the reason why Hcy accelerates vascular diseases, including vascular endothelial cell damage, vascular smooth muscle cell proliferation, lipid peroxidation, upregulation of prothrombotic factor levels, and downregulation of antithrombotic factors or endothelial-derived nitric oxide levels. Hcy may also promote atherosclerosis by stimulating the cell division effect of platelet-derived growth factor. Therefore, the treatment of coronary heart disease (including ACS prevention) needs to consider Hcy as a new risk factor. Summary of the invention

[0005] In view of the shortcomings of existing treatment measures for coronary heart disease, especially for patients with coronary heart disease accompanied by elevated homocysteine ​​levels (this phenomenon is relatively common, such as smoking, drinking, high methionine or low folic acid diet can lead to elevated Hcy), the present invention provides a novel pharmaceutical composition for treating coronary heart disease and preventing cardiovascular events.

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

[0007] A pharmaceutical composition comprising:

[0008] (a) 0.5-1.25 mg felodipine;

[0009] (b) 2.5-6.25 mg atenolol;

[0010] (c) 0.4-1.2 mg folic acid:

[0011] (d) Pharmaceutically acceptable excipients.

[0012] In the pharmaceutical composition of the present invention, the folic acid substance is selected from folic acid or 5-methyltetrahydrofolate.

[0013] The pharmaceutical composition described in the present invention comprises 0.5 mg of felodipine, 2.5 mg of atenolol and 0.4 mg of folic acid.

[0014] The pharmaceutical composition described in the present invention comprises 1.25 mg of felodipine, 6.25 mg of atenolol, and 0.8 mg of 5-methyltetrahydrofolate.

[0015] The pharmaceutical composition of the present invention may further contain 4 to 10 mg of telmisartan.

[0016] The pharmaceutical composition described in the present invention comprises 0.5 mg of felodipine, 2.5 mg of atenolol, 4 mg of telmisartan and 0.4 mg of folic acid.

[0017] The pharmaceutical composition described in the present invention comprises 1.25 mg of felodipine, 6.25 mg of atenolol, 10 mg of telmisartan, and 0.8 mg of 5-methyltetrahydrofolate.

[0018] The pharmaceutical composition described in the present invention is in the form of an oral preparation, including tablets, capsules or granules.

[0019] The present invention also provides the use of the pharmaceutical composition in preparing a product for treating coronary heart disease. The coronary heart disease includes: asymptomatic myocardial ischemia, angina pectoris, ischemic cardiomyopathy, and acute myocardial infarction.

[0020] In the present invention, patients with coronary heart disease accompanied by elevated homocysteine ​​levels are preferred.

[0021] The invention has the advantages of strengthening the protection of coronary vascular endothelium, and for the pathological characteristics of coronary heart disease and ACS, felodipine and atenolol with the effect of improving myocardial ischemia and protecting the heart and folic acid substances with the effect of reducing homocysteine ​​level and improving vascular endothelium are selected, and used in combination in the form of a compound medicine. The invention can also further add telmisartan for combined use as required. The composition provided by the invention has a good effect of treating coronary heart disease, especially for coronary heart disease patients with elevated homocysteine ​​levels, the composition of the invention has a significant synergistic effect, and is conducive to the primary and secondary prevention of cardiovascular events (ACS). DETAILED DESCRIPTION

[0022] 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.

[0023] Example 1: Effect of the composition of the present invention on rats with coronary heart disease accompanied by elevated homocysteine ​​levels

[0024] 150 SD rats, 8 weeks old, male, were purchased from Beijing Weitonglihua Biological Co., Ltd. and raised under standard conditions, with free access to food and water, suitable temperature and humidity, and artificial dark / light alternation.

[0025] 1. Preparation of High HCY Rat Model

[0026] Ten rats were selected as the sham operation group and fed with ordinary feed. All the remaining rats were used for modeling and fed with folic acid-free feed for 4 weeks to establish a high homocysteine ​​(HCY) rat model. Blood was collected and the HCY level was determined. A successful model was established when the rat plasma HCY was greater than 10 μmol / L. After the model was successfully established, the rats continued to be fed with folic acid-free feed until the end of the experiment.

[0027] 2. Preparation of rat model of high HCY combined with chronic ischemic coronary heart disease

[0028] Take the above-mentioned rats with successful modeling, use the BL-420E biological function experimental system, weigh the rats, anesthetize, subcutaneously inject atropine, and fix the rats in a supine position on a self-made wooden platform. The surgical sites of the neck and chest were trimmed and disinfected with iodine. Connect the BL-420E biological function experimental system and perform ECG monitoring on the rats. Lay a perforated towel, intubate the trachea, and connect the ventilator to assist breathing. Make a small incision parallel to the ribs at about the 4th intercostal space of the left anterior chest (the most obvious part of the heartbeat by hand), disconnect the two adjacent ribs to form an incision perpendicular to the ribs, 2.0 to 3.0 cm long. After separating the layers of tissue, enter the chest cavity and find the heart with strong beating. Use two small retractors to pull open and expose the heart. At this time, be careful to avoid the lungs to avoid damage. Tear the pericardium with tweezers, gently push the left atrial appendage with a cotton stick, expose the root of the aorta, and ligate the blood vessels between the left atrial appendage and the pulmonary artery cone approximately at the same level as the lower edge of the left atrial appendage, together with a small bundle of myocardial fibers. It can be seen that the color of the myocardium below the ligature becomes lighter and whiter. Use a retractor to gently lift the chest at the incision, try to place the heart in the original anatomical position, do not suture the pericardium, rub the wound with a cotton swab soaked in penicillin G solution to prevent wound infection, and quickly close the chest after inflating the lungs. After closing the chest, observe the respiratory recovery of the rat. If there is spontaneous breathing, it can be taken off the machine and put back into the cage. After the operation, blood was collected from the orbital venous plexus after 2 months of observation to measure the serum levels of HCY, creatine kinase isoenzyme (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH). Compared with the sham operation group, rats with significantly increased levels of HCY, CK-MB, AST, and LDH were selected as successful model rats.

[0029] After modeling, the test substances of the corresponding groups were gavaged according to the following table. The gavage volume was 10 ml / kg, and the drug was administered once a day for 8 consecutive weeks.

[0030] After the administration, all rats were killed and blood was collected to measure serum HCY, CK-MB, AST, and LDH levels.

[0031] 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.

[0032] 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: 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 or equal to 1.15, it is considered to be synergistic.

[0033] Table 1: Changes in HCY levels in rats in each group after 8 weeks of administration ( n=8~10)

[0034]

[0035]

[0036] Note: Compared with the sham operation group, # P<0.05, ## P<0.01; compared with the model group, * P<0.05, ** P<0.01.

[0037] Table 2: Changes in CK-MB, AST, and LDH levels in rats in each group after 8 weeks of administration ( n=8~10)

[0038]

[0039]

[0040] Note: Compared with the sham operation 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 compared with the sham operation group, the HCY level of the model group rats after modeling was significantly increased (P<0.01), proving that a high HCY model has been created. On this basis, after chronic ischemic surgery modeling, the CK-MB, AST, and LDH levels in the model group were significantly higher than those in the sham operation group (P<0.01), proving that the model rats prepared by this method have obvious myocardial cell damage, and the model has met the characteristics of the drug evaluation experimental model for coronary heart disease.

[0042] From the experimental results, it can be concluded that each group supplemented with folic acid has a significant effect on reducing the homocysteine ​​level of rats (P<0.01), and has the effect of reducing CK-MB and AST levels in rats with coronary heart disease and elevated homocysteine. The two groups of combined use of felodipine + atenolol or two groups of telmisartan alone have different degrees of effects on reducing CK-MB, AST, and LDH, and there is an obvious dose-effect relationship from low dose to high dose, but only the high-dose group of felodipine + atenolol and the high-dose group of telmisartan have significant differences in reducing CK-MB (P<0.05).

[0043] At the same dosage, compared with taking felodipine + atenolol alone, the triple combination with added folic acid: felodipine + atenolol + folic acid, has a greater effect on reducing CK-MB, AST, and LDH in both the low-dose group and the high-dose group, and has a synergistic effect (Q≥1.15), which proves that this combination has significantly better improvement of the symptoms of chronic myocardial ischemic cardiomyocyte injury than the double combination of folic acid alone or the corresponding dose of felodipine + atenolol.

[0044] At the same dose, compared with the triple combination of felodipine + atenolol + folic acid, the quadruple combination of telmisartan has the effect of further reducing CK-MB, AST, and LDH at both low and high doses, but the reduction effect is limited, and the Q values ​​are between (0.85 and 1.15), which proves that it has an additive effect.

[0045] The composition provided by the present invention has significant therapeutic effects on high homocysteine ​​combined with coronary heart disease. It can reduce homocysteine ​​levels, improve myocardial cell function, and has a synergistic improvement effect on coronary heart disease symptoms, especially symptoms caused by chronic ischemic coronary heart disease. Patients have high medication compliance and have significant clinical treatment advantages.

Claims

1. A pharmaceutical composition, include: (1) 0.5-1.25 mg felodipine; (2) 2.5-6.25 mg atenolol; (3) 0.4-1.2 mg of folic acid; (4) Pharmaceutically acceptable excipients.

2. The pharmaceutical composition according to claim 1, It is characterized in that The folic acid substance is selected from folic acid or 5-methyltetrahydrofolate.

3. The pharmaceutical composition according to claim 1, It is characterized in that The pharmaceutical composition comprises 0.5 mg of felodipine, 2.5 mg of atenolol and 0.4 mg of folic acid.

4. The pharmaceutical composition according to claim 1, It is characterized in that The pharmaceutical composition comprises 1.25 mg of felodipine, 6.25 mg of atenolol and 0.8 mg of 5-methyltetrahydrofolate.

5. The pharmaceutical composition according to claim 1, It is characterized in that The composition contains 4-10 mg of telmisartan.

6. The pharmaceutical composition according to claim 5, It is characterized in that The pharmaceutical composition comprises 0.5 mg of felodipine, 2.5 mg of atenolol, 4 mg of telmisartan and 0.4 mg of folic acid.

7. The pharmaceutical composition according to claim 5, It is characterized in that The pharmaceutical composition comprises 1.25 mg of felodipine, 6.25 mg of atenolol, 10 mg of telmisartan and 0.8 mg of 5-methyltetrahydrofolate.

8. Use of the pharmaceutical composition according to claims 1 to 7 in the preparation of medicines for treating coronary heart disease.

9. The use according to claim 8, It is characterized in that The coronary heart disease includes: asymptomatic myocardial ischemia, angina pectoris, myocardial infarction, and ischemic cardiomyopathy.

10. The use according to claim 8, It is characterized in that The coronary heart disease patients have elevated homocysteine ​​levels.

Images