WO2020169041A1 - Pharmaceutical composition containing amlodipine, chlorthalidone and aldosterone receptor antagonists - Google Patents

Abstract

Provided by the present invention is a pharmaceutical composition for treating refractory hypertension, which is composed of amlodipine, chlorthalidone and aldosterone receptor antagonists. The pharmaceutical composition provided by the present invention provides an effective anti-hypertension drug for patients suffering from resistant hypertension, especially patients suffering from low renin/normal aldosterone or low renin/high aldosterone resistant hypertension. The pharmaceutical composition provided by the present invention can also enhance the protective effect on target organs of patients suffering from resistant hypertension and reduce the risk of cerebrovascular events.

Description

Pharmaceutical composition containing amlodipine, chlorthalidone and aldosterone receptor antagonist Technical field

The invention provides a pharmaceutical composition for treating refractory hypertension, which is composed of amlodipine, chlorthalidone and an aldosterone receptor antagonist. It belongs to the field of pharmacy.

Background technique

Acute regulation of blood pressure is mainly achieved through baroreceptors and sympathetic nerve activity, while chronic regulation is mainly achieved through the renin-angiotensin-aldosterone system (RAAS) and the regulation of body fluid volume by the kidneys. Renin secreted by the kidney acts on the angiotensinogen synthesized by the liver to produce angiotensin I, which is converted into angiotensin II under the action of angiotensin-converting enzyme. Angiotensin II combines with effector receptors to make small arteries smooth muscle Contraction increases peripheral vascular resistance; stimulates the adrenal glands to secrete aldosterone, which causes water and sodium retention and increases blood volume; in addition, angiotensin II also promotes the release of norepinephrine from sympathetic nerve endings. The above effects can increase blood pressure, which is an important mechanism involved in the onset of hypertension and its persistence. In recent years, studies have found that RAAS in the organization is a self-contained system and may have a greater role in the formation of hypertension [Zhou Xianliang, Yang Tao Editor. Internal Medicine (3rd edition), Beijing: People's Medical Publishing House, 2014, 11, 259-260] . Aldosterone has a variety of pathophysiological effects, by regulating the kidney's reabsorption of sodium ions, maintaining water and salt balance, and regulating blood volume. It can also cause central hypertension, accelerate endothelial damage, reduce heart rate variability, induce ventricular arrhythmia, promote sodium retention, potassium and magnesium loss, promote myocardial fibrosis, necrosis and inflammation, and damage the fibrinolytic system.

Refractory hypertension (resistant hypertension, RH) accounts for about 15-20% of all hypertension patients. On the basis of improving lifestyle, combined application of reasonable and sufficient 3 kinds of antihypertensive drugs (including diuretics) for a certain period of time (≥1 month), blood pressure still does not reach the target, or taking ≥4 kinds of antihypertensive drugs Effective control is called RH [Chinese Expert Consensus on Diagnosis and Treatment of Refractory Hypertension, Chinese Journal of Hypertension, 2013, 21(4), 321-326]. The etiology and pathophysiological mechanisms of RH are multifaceted. There are basic causes, as well as central and local neurohumoral mechanisms. High salt intake, obesity, and decreased carotid baroreflex are the basic reasons why it is difficult to control blood pressure in hypertensive patients. On this basis, the activation of the rennin-angiotensin-aldosterone system (RAAS) in the circulation and tissues and the excessive increase in the activity of the central or local tissues (especially the kidneys) of sympathetic nerves will initiate inflammatory factors, The oxidative stress process also promotes the occurrence and progression of arteriosclerosis and atherosclerosis, and aggravates the abnormalities of blood vessel structure and function, making it difficult to control the increased blood pressure. RH not only has the "refractory" characteristic of lowering blood pressure, it is more likely to be combined with target organ damage and increase the prevalence of heart, cerebrovascular and kidney diseases. Daugherty et al. conducted a large-scale clinical trial. After 3.8 years of follow-up, it was found that 1972 (11%) patients developed chronic kidney disease, 344 patients died, and 234 had cardiovascular and cerebrovascular events (90 cases had non-fatal Myocardial infarction, 91 cases of stroke, 53 cases of congestive heart failure) [Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients.Circulation, 2012, 125(13): 1635-1642].

In addition to correcting bad lifestyles (such as weight loss, salt restriction, moderate alcohol intake, increased exercise, etc.) for the treatment of RH, the usual three-drug combination program recommends renin-angiotensin system inhibitors. RASI) [angio-tensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)]) + calcium antagonist + thiazide diuretic. When blood pressure is still not up to standard, you can consider adding spironolactone (need to assess the risk of renal function and potential hyperkalemia), or combined with β-blockers, αβ-blockers or α-blockers. When the blood pressure still fails to reach the target, clonidine, proserpine and central nervous system inhibitory drugs can be used as the fifth antihypertensive drug choice in the combined program. For the treatment of RH, there are currently no targeted drugs. The treatment of RH drugs is still in the development stage. The drugs in the patents for the treatment of RH that have been published in China all contain traditional Chinese medicine ingredients. For example, Chinese patent application 201710585463.2 combines Ganoderma lucidum polysaccharides with multiple antihypertensive drugs in conventional multi-therapy. A compound preparation that can be taken conveniently; Chinese patent 201110086573.7 discloses a Chinese patent medicine for the treatment of refractory hypertension, which is composed of sea buckthorn, thyme, periwinkle, ganoderma, black fungus, amla root, rhodiola, and Rauvolu , Pueraria lobata, Hawthorn, Cassia seed. As we all know, the mechanism of action of traditional Chinese medicine is complex, usually slow and effective, and the treatment period is longer. However, if the blood pressure of RH patients remains high for a long time, it will cause greater harm, which is inconsistent with the characteristics of traditional Chinese medicine treatment.

At present, there is no single antihypertensive drug or compound antihypertensive drug approved for the treatment of RH at home and abroad.

Amlodipine belongs to the long-acting dihydropyridine calcium channel blocker. It blocks the extracellular calcium ion of vascular smooth muscle from entering the cell through the calcium ion channel of the cell membrane, directly relaxes the vascular smooth muscle, expands peripheral blood vessels, and reduces peripheral resistance. It is clinically used Treat high blood pressure and angina pectoris. Compared with similar drugs, amlodipine lasts for a long time, has fewer side effects and is mild, and is the first-line drug for the clinical treatment of hypertension.

Chlorthalidone inhibits the Na ⁺ -Cl ^- symporter at the beginning of the distal convoluted tubules of the kidney, reduces the reabsorption of Na ⁺ , Cl ^- and water, and excretes excessive sodium and water in the body to reduce the volume of extracellular fluid. Reduce swelling. The causes of edema include congestive heart failure, acute emphysema, liver disease, ascites, nephrotic syndrome, acute and chronic nephritis, etc. Chlorthalidone is an auxiliary drug for the treatment of these diseases. In terms of lowering blood pressure, chlorthalidone is mainly used to treat mild and moderate hypertension, elderly hypertension complicated by heart failure and other diseases.

Aldosterone receptor antagonists are divided into non-selective aldosterone receptor antagonists (such as spironolactone) and selective aldosterone receptor antagonists (such as eplerenone). They antagonize aldosterone receptors and inhibit aldosterone in the epithelial cells of the distal convoluted tubule and collecting duct. It promotes the exchange of K ⁺ -Na ⁺ , increases the excretion of Na ⁺ and Cl ^- , reduces the excretion of K ⁺ , and plays a role in maintaining potassium, excreting sodium and diuresis. Eplerenone selectively acts on mineralocorticoid receptors and has little effect on androgen and progesterone receptors. It is clinically well tolerated. Except for elevated serum potassium, there are almost no sex hormone-related side effects of spironolactone. It is clinically used to treat congestive heart failure and essential hypertension after acute myocardial infarction.

The existing antihypertensive compound drugs are mainly for hypertension, not RH. At present, the compound products composed of three antihypertensive drugs on the domestic and foreign markets include amlodipine, valsartan, hydrochlorothiazide, amlodipine, telmisartan, hydrochlorothiazide, etc., and their indications are essential hypertension and are not used for hypertension. Initial treatment. There are also many compound or combination drugs in the research stage. For example, Chinese Patent 201010116867.5 discloses a compound pharmaceutical composition containing levalamlodipine for the treatment of hypertension, which includes levalamlodipine or its pharmaceutically acceptable Salt, and chlorthalidone. US Patent 20070287690 discloses a low-dose composition composed of a thiazide diuretic and an aldosterone receptor antagonist and its patented use for hypertension and related diseases. Du Jun published on December 1, 2018, a doctoral document of China Medical University: A study on the mechanism of action of amlodipine and eplerenone in alleviating kidney damage caused by salt-sensitive hypertension. The conclusion is: through different mechanisms of action The combined application of amlodipine and eplerenone can significantly improve renal podocyte damage and renal interstitial hypoxia caused by salt-sensitive hypertension, thereby inhibiting renal damage represented by glomerulosclerosis and renal interstitial fibrosis . The above-mentioned single drugs or compound prescriptions are used to treat hypertension, and have no effect on RH. Providing an effective and economical treatment drug for RH patients has become the research goal of scientific research

Summary of the invention

Under the development trend of precision medicine, individualized analysis of RH patients should be carried out. Renin and aldosterone should be regarded as biomarkers, and their plasma concentrations in RH patients should be measured. According to the difference between the two, the pathophysiological analysis of RH can be carried out. Type, so that clinical medication is more targeted. According to plasma renin and aldosterone levels, RH patients can be divided into low renin/aldosterone normal and elevated, low renin/low aldosterone and high renin/high aldosterone.

The purpose of the present invention is to provide a pharmaceutical composition with significant curative effect for refractory hypertension, especially refractory hypertension patients with low renin/normal aldosterone or low renin/increased aldosterone.

In order to achieve the above objectives, the present invention adopts the following technical solutions:

A pharmaceutical composition for refractory hypertension, the composition of which is:

(1) 2.5-10mg of amlodipine;

(2) 12.5-100mg of chlorthalidone;

(3) Medicinal dose of aldosterone receptor antagonist;

(4) Pharmaceutically acceptable carrier.

In the pharmaceutical composition provided by the present invention, amlodipine may exist in the form of salts, esters, active metabolites, or pharmaceutical precursors. The amlodipine provided by the present invention is used as a pharmaceutical ingredient, and its salt, ester, active metabolite or medicinal precursor and other forms of amlodipine are also within the protection scope of this application. In the present invention, the pharmaceutical dosage of amlodipine is selected from 2.5-10 mg, preferably 5-10 mg. The medicinal dosage of amlodipine in the form of salts, esters, active metabolites or medicinal precursors can be converted accordingly.

In the pharmaceutical composition provided by the present invention, chlorthalidone can exist in the form of salts, esters, active metabolites, or pharmaceutical precursors. The chlorthalidone provided by the present invention is used as a pharmaceutical ingredient, and the existing forms of chlorthalidone salts, esters, active metabolites or pharmaceutical precursors are also within the protection scope of the application. In the present invention, the pharmaceutical dosage of chlorthalidone is selected from 12.5-100 mg, preferably 12.5-50 mg. The medicinal doses of chlorthalidone in the form of salts, esters, active metabolites or medicinal precursors can be converted.

In the pharmaceutical composition provided by the present invention, the aldosterone receptor antagonist includes a non-selective aldosterone receptor antagonist and a selective aldosterone receptor antagonist, the non-selective aldosterone receptor antagonist is spironolactone, and the selective aldosterone receptor antagonist The agent is eplerenone. In the present invention, the aldosterone receptor antagonist can exist in the form of salts, esters, active metabolites, or pharmaceutical precursors, so the above-mentioned forms of the aldosterone receptor antagonist are also within the scope of protection of the present application. In the present invention, the pharmaceutical dosage of spironolactone is selected from 12.5-100 mg, preferably 25-50 mg. The pharmaceutical dosage of eplerenone is selected from 25-100 mg, preferably 50-100 mg. The medicinal dosage of the salt, ester, active metabolite or medicinal precursor of the aldosterone receptor antagonist can be converted accordingly.

In the present invention, the medicinal dose of the active ingredient of the composition refers to the range of the dose of the medicinal medicinal ingredient in the composition that makes the composition exert medicinal effects after being combined with other medicinal ingredients. The preferred dose is the preferred medicinal dose of the active ingredient of the composition, and the medicinal effect of the preferred dose is better than that of the medicinal dose. Generally, the pharmaceutical dosage of the active ingredient of the composition includes the optimal dosage or optimal dosage range that maximizes the efficacy of the composition, and the optimal dosage or optimal dosage range will benefit the patient more.

When the aldosterone receptor antagonist is spironolactone:

As a preference, the composition of the pharmaceutical composition provided by the present invention is 5 mg amlodipine, 12.5 mg chlorthalidone and 25 mg spironolactone.

As another preference, the composition of the pharmaceutical composition provided by the present invention is 5 mg amlodipine, 25 mg chlorthalidone and 25 mg spironolactone.

As another preference, the composition of the pharmaceutical composition provided by the present invention is 5 mg amlodipine, 25 mg chlorthalidone and 50 mg spironolactone.

As another preference, the composition of the pharmaceutical composition provided by the present invention is 5 mg amlodipine, 50 mg chlorthalidone and 50 mg spironolactone.

As another preference, the composition of the pharmaceutical composition provided by the present invention is 10 mg amlodipine, 12.5 mg chlorthalidone and 25 mg spironolactone.

As another preference, the composition of the pharmaceutical composition provided by the present invention is 10 mg amlodipine, 25 mg chlorthalidone and 25 mg spironolactone.

As another preference, the composition of the pharmaceutical composition provided by the present invention is 10 mg amlodipine, 25 mg chlorthalidone and 50 mg spironolactone.

As another preference, the composition of the pharmaceutical composition provided by the present invention is 10 mg amlodipine, 50 mg chlorthalidone and 50 mg spironolactone.

When the aldosterone receptor antagonist is eplerenone:

As a preference, the composition of the pharmaceutical composition provided by the present invention is 5 mg amlodipine, 25 mg chlorthalidone and 50 mg eplerenone.

As another preference, the composition of the pharmaceutical composition provided by the present invention is 10 mg amlodipine, 25 mg chlorthalidone and 50 mg eplerenone.

As another preference, the composition of the pharmaceutical composition provided by the present invention is 10 mg amlodipine, 25 mg chlorthalidone and 100 mg eplerenone.

The pharmaceutical composition also contains a pharmaceutically acceptable carrier, which can be made into ordinary oral preparations, including ordinary tablets, ordinary capsules, granules, etc., when the pharmaceutical composition is made into tablets, the pharmaceutically acceptable carriers include The compound is formulated into excipients and adjuvants for medicinal preparations, such as a combination of one or more substances such as microcrystalline cellulose, inorganic salts, lactose, sodium chloride, citric acid and sodium sulfite, which belongs to common knowledge in the art.

The pharmaceutical composition provided by the present invention provides an effective antihypertensive drug for RH patients, especially low renin/aldosterone normal or elevated RH patients. The medicinal active ingredients of the pharmaceutical composition provided by the present invention are amlodipine, chlorthalidone and an aldosterone receptor antagonist. The composition is fast in treating RH and has significant curative effect, and is especially suitable for low renin/aldosterone normal or elevated Patients with high RH. Amlodipine, chlorthalidone, and aldosterone receptor antagonists are all commonly used antihypertensive drugs. As described in the background art, the above drugs can be used alone or in combination or in combination with other antihypertensive drugs. Treatment of blood pressure, but for RH, the above-mentioned drugs cannot play an effective role. The combination of amlodipine, chlorthalidone and aldosterone receptor antagonist has a significant effect in the treatment of RH, which cannot be exerted by a single drug or a combination of two drugs. Secondly, the antihypertensive effect of the pharmaceutical composition provided by the present invention lasts for a long time, the blood pressure fluctuations are small throughout the day after the patient takes it, and once a day is taken, the blood pressure can be stabilized for 24 hours.

In addition, the pharmaceutical composition provided by the present invention can also enhance the protective effect on the target organs of patients with RH, while reducing the risk of cerebrovascular events. Target organ damage caused by RH includes left ventricular hypertrophy, benign arteriole nephrosclerosis, malignant arteriole nephrosclerosis, renal failure, retinal arteriosclerosis, or hypertensive fundus disease. When the above-mentioned damages cannot be effectively controlled, cerebrovascular events including cerebral infarction and cerebral hemorrhage will occur, that is, stroke. The pharmaceutical composition provided by the present invention not only effectively lowers blood pressure but also lowers blood pressure steadily within 24 hours. After the patient takes the medicine, blood pressure fluctuations throughout the day are small, and the damage to important organs caused by the increase in blood pressure and rapid blood pressure fluctuations is reduced. Secondly, RH easily induces vascular remodeling and endothelial dysfunction, as well as sympathetic nerve and renin-angiotensin system over-activation, metabolic abnormality and inflammation. The three medicinal components of the pharmaceutical composition provided by the present invention exert their respective mechanisms of action. Significantly synergistically improve these non-hemodynamic changes caused by elevated blood pressure, thereby effectively protecting the target organs of RH patients.

The present invention will be further described below in conjunction with the specific embodiments, which is not a limitation of the present invention. Any equivalent replacement in the field made in accordance with the content of the present invention belongs to the protection scope of the present invention.

detailed description

Example 1-Example 11 Preparation of amlodipine, chlorthalidone and spironolactone tablets (1000 tablets)

Preparation Process:

Mix amlodipine, chlorthalidone and spironolactone, add sodium starch glycolate, sodium lauryl sulfate and mix, then add microcrystalline cellulose and pregelatinized starch to mix evenly, use an appropriate amount of 10% povidone ethanol solution It is made into soft material, granulated, dried, and granulated. The granules with a water content of about 3% and an appropriate amount of magnesium stearate are mixed uniformly, and then compressed into 1000 tablets.

Example 12-Example 16 Preparation of amlodipine, chlorthalidone and eplerenone tablets (1000 tablets)

Formula composition Example 12 Example 13 Example 14 Example 15 Example 16 Amlodipine 2.5g 10g 5g 10g 10g Chlorthalidone 12.5g 50g 25g 25g 25g Eplerenone 25g 50g 50g 50g 100g Pregelatinized starch 59g 70g 68g 82g 99g Microcrystalline cellulose 90g 104g 101g 122g 149g Sodium starch glycolate 4g 6g 5g 6g 8g Sodium dodecyl sulfate 0.6g 1.2g 1.2g 1.2g 2.4g 5% hypromellose solution Right amount Right amount Right amount Right amount Right amount Magnesium stearate 1g 1.5g 1.25g 1.5g 2g

Preparation Process:

Mix amlodipine, chlorthalidone and eplerenone, add croscarmellose sodium and mix, pass through an 80-mesh sieve, then add microcrystalline cellulose and lactose to mix well, use an appropriate amount of 5% hypromellose The cellulose solution is made into a soft material, granulated, dried, and granulated. The granules with a water content of about 3% and an appropriate amount of magnesium stearate are uniformly mixed to make 1,000 tablets.

Example 17: Preparation of amlodipine, chlorthalidone and eplerenone capsules (1000 capsules)

Formula composition:

Preparation Process:

Pass the sodium carboxymethyl starch through a 100-mesh sieve, and pass the lactose and microcrystalline cellulose through an 80-mesh sieve for later use; mix the crude drug with croscarmellose sodium and sodium lauryl sulfate, and then add microcrystalline cellulose, Lactose is mixed, granulated with 5% hypromellose solution, dried at 50-60°C for 2h, the obtained can be mixed with magnesium stearate, and filled with No. 1 capsule. Get it when made into 1000 tablets.

Example 18: Effect of amlodipine/chlorothalidone/spironolactone compound preparation on lowering blood pressure and target organ protection in hyperaldosterone hypertensive rats

Model preparation and grouping administration: 128 SD rats, weighing 200-240g, males, fed with ordinary dietary feed and quarantined for 7 days. After measuring the basal blood pressure, 16 rats were randomly selected as the sham operation group and placed in the scapula A micro-osmotic pump was implanted in the subcutaneous space of the area, and only the solvent was pumped. The remaining 112 rats were implanted subcutaneously with a micro-osmotic pump (mini-osmoticpump, American AIZET company), and the aldosterone solution was pumped at 0.15ug/h. One week later, the blood pressure was measured. Randomly divided into model group and administration group according to blood pressure. See Table 1 for drug combination and dosage. Gavage lasts for 6 weeks, and then carry out index detection. The control drug was amlodipine, valsartan and hydrochlorothiazide tablets, the dual combination drug was a raw material, and the test drug was the compound preparation prepared in Example 5 and Example 11.

Table 1 Group design of hyperaldosteronism hypertension model test

Detection indicators: (1) 1 week after modeling, blood was collected to detect aldosterone (ALD) and renin activity (PRA) before grouping (Beijing North Biotechnology); (2) Blood pressure was measured for 3 weeks and 6 weeks after administration; 3) Observation of renal function after 6 weeks of administration: urine protein, urine microalbumin (MALB), urine creatinine and urea nitrogen detection (Xincheng Biotechnology); (4) 6 weeks of administration for endothelial function serum nitric oxide NO and endothelin Detection of ET-1 (Zurray Bio); (5) Cardioprotective effects of 6 weeks of administration: left ventricular index, cardiac index and CK-MB (Zray Bio).

result:

(1) Aldosterone (ALD) level and renin activity (PRA) in aldosterone-type hypertension model rats

One week after subcutaneous implantation of aldosterone, compared with the sham operation group, the ALD concentration of rats in the model group was significantly increased, and PRA activity was inhibited, resulting in a hypertensive rat model with high aldosterone and low renin. See Table 2.

Table 2 Effects of ALD and PRA in aldosterone hypertensive rats

Compared with the sham operation group, ^# P<0.05, ^## P<0.01, compared with the model group ^* P<0.05, ^** P<0.01

(2) The effect of amlodipine/chlorthalidone/spironolactone compound preparation on rat blood pressure. The blood pressure of rats in the model group increased significantly, which was statistically different from the sham operation group, which proved that subcutaneous implantation and pumping of aldosterone can cause blood pressure to increase . Amlodipine, valsartan, hydrochlorothiazide, and hydrochlorothiazide tablets group can reduce blood pressure at the level of 11.7-16.5mmHg. Amlodipine and chlorthalidone spironolactone tablets can significantly reduce blood pressure in both low and high dose groups (P<0.05, P<0.01), and high doses The effect of the group is more obvious, and it has obvious advantages compared with the antihypertensive effect of the two-combination drug group, and the further antihypertensive range is 6.8-19.9mmHg. See Table 3.

n＝16) Table 3 Effects of amlodipine/chlorthalidone/spironolactone compound preparation on blood pressure in rats (

n=16)

Compared with the sham operation group, ^# P<0.05, ^## P<0.01; compared with the model group ^* P<0.05, ^** P<0.01; Amlodipine Chlorthalidone Spironolactone Tablets, Amlodipine Valsartan Hydrochlorothiazide Tablets Group comparison, ^■ P<0.05, ^■■ P<0.01, compared with amlodipine + chlorthalidone group ^△ P<0.05, ^△△ P<0.01, compared with amlodipine + spironolactone group ^▲ P<0.05, ^▲▲ P<0.01, compared with chlorthalidone spiro+lactone group ^★ P<0.05, ^★★ P<0.01

(3) Effect of amlodipine/chlorothiazide/spironolactone compound preparation on renal function of rats. After 6 weeks of administration, 24 hours of rat urine were collected for urine protein, urine microalbumin (MALB), and blood was taken to determine blood creatinine and urea nitrogen.

Urinary protein and MALB increased significantly in the model group, which was significantly different from the sham operation group. Urinary protein and MALB decreased in the amlodipine chlorthalidone spironolactone tablet administration group, and the triple drug combination was more effective than amlodipine, valsartan, hydrochlorothiazide tablets In the group (P<0.01, P<0.05), compared with the dual drug combination, the triple drug can further improve renal function, indicating that the compound preparation administration group has a significant protective effect on the kidney. See Table 4.

n＝16) Table 4 Effects of amlodipine/chlorthalidone/spironolactone compound preparation on renal function in rats (

n=16)

Compared with the sham operation group, ^# P<0.05, ^## P<0.01, compared with the model group ^* P<0.05, ^** P<0.01, compared with the amlodipine valsartan hydrochlorothiazide group, ^■ P<0.05, ^{■ ■} P<0.01, compared with amlodipine + chlorthalidone group ^△ P<0.05, ^△△ P<0.01, compared with amlodipine + spironolactone group ^▲ P<0.05, ^▲▲ P<0.01, compared with chlorthalidone +Lactone group comparison ^★ P<0.05, ^★★ P<0.01

The model blood creatinine and urea nitrogen increased significantly, which was significantly different from the sham operation group. The urine creatinine and urea nitrogen of the amlodipine chlorthalidone spironolactone tablet administration group decreased, and the triple drug combination was better than amlodipine, valsartan, and hydrochlorothiazide In the tablet group (P<0.05), compared with the dual drug combination, the triple drug can further improve renal function, indicating that the compound preparation administration group has a significant protective effect on the kidney. See Table 5.

n＝16) Table 5 Effects of amlodipine/chlorthalidone/spironolactone compound preparation on renal function in rats (

n=16)

Compared with the sham operation group, ^# P<0.05, ^## P<0.01, compared with the model group ^* P<0.05, ^** P<0.01, compared with the amlodipine valsartan hydrochlorothiazide group, ^■ P<0.05, ^{■ ■} P<0.01, compared with amlodipine + chlorthalidone group ^△ P<0.05, ^△△ P<0.01, compared with amlodipine + spironolactone group ^▲ P<0.05, ^▲▲ P<0.01, compared with chlorthalidone + Comparison of spironolactone group ^★ P<0.05, ^★★ P<0.01

(4) The effect of amlodipine/chlorthalidone/spironolactone compound preparation on rat vascular endothelial function. After 6 weeks of administration, compared with the sham operation group, the serum NO level of the model group was significantly reduced, and the ET-1 level was significantly increased. High, with significant difference (P<0.01). Compared with the model group, amlodipine, valsartan, hydrochlorothiazide, and hydrochlorothiazide tablets have a certain effect on improving the vascular endothelial function of aldosterone hypertension model animals, but the effect is not as good as that of amlodipine and chlorthalidone spironolactone tablets administration group (P<0.05), especially high dose The increase in NO (P<0.01) and the decrease in ET-1 (P<0.05) in the two groups have significant differences; compared with the dual drug combination, the Sanlian compound further increases the level of NO and lowers ET-1, indicating that the Sanlian The compound has a stronger protective effect on vascular endothelium. See Table 6.

n＝16) Table 6 Effects of amlodipine/chlorthalidone/spironolactone compound preparation on vascular endothelial function (

n=16)

Compared with the sham operation group, ^# P<0.05, ^## P<0.01, compared with the model group ^* P<0.05, ^** P<0.01, compared with the amlodipine valsartan hydrochlorothiazide group, ^■ P<0.05, ^{■ ■} P<0.01, compared with amlodipine + chlorthalidone group ^△ P<0.05, ^△△ P<0.01, compared with amlodipine + spironolactone group ^▲ P<0.05, ^▲▲ P<0.01, compared with chlorthalidone + Comparison of spironolactone group ^★ P<0.05, ^★★ P<0.01

(5) Cardioprotective effect of amlodipine/chlorthalidone/spironolactone compound preparation on rats

After 6 weeks of administration, the animals were sacrificed and blood was collected for CK-MB detection. The heart was weighed, and the left ventricle was separated and weighed. The left ventricular index and cardiac index of each group of rats were calculated ((left ventricular weight*1000)/body weight) . Compared with the sham operation group, the left ventricular index and heart index of the model group increased significantly, indicating that there is left ventricular hypertrophy. Amlodipine, valsartan, hydrochlorothiazide, and hydrochlorothiazide tablets have a certain improvement, but the effect is not as good as amlodipine and chlorthalidone spironolactone tablets. Administration group (P<0.05). The increase in CK-MB was used as a specific indicator of myocardial damage. The CK-MB in the model group was significantly increased, indicating the presence of myocardial damage. The CK-MB in the amlodipine and chlorthalidone spironolactone tablets administration group was significantly reduced (P<0.01), Compared with the dual drug combination, the cardioprotective effect is more obvious. See Table 7.

n＝16) Table 7 Effects of amlodipine/chlorthalidone/spironolactone compound preparation on the cardiac function of rats (

n=16)

Compared with the sham operation group, ^# P<0.05, ^## P<0.01, compared with the model group ^* P<0.05, ^** P<0.01, compared with the amlodipine valsartan hydrochlorothiazide group, ^■ P<0.05, ^{■ ■} P<0.01, compared with amlodipine + chlorthalidone group ^△ P<0.05, ^△△ P<0.01, compared with amlodipine + spironolactone group ^▲ P<0.05, ^▲▲ P<0.01, compared with chlorthalidone + Comparison of spironolactone group ^★ P<0.05, ^★★ P<0.01

Example 19: Synergistic hypotensive effect of amlodipine/chlorthalidone/spironolactone compound preparation on hyperaldosterone hypertensive rats

The model preparation method is the same as in Example 18. The animal groups are shown in Table 8. 12 animals in each group were given by intragastric administration once a day for 4 consecutive weeks. The systolic blood pressure of the rats was measured 2 to 4 hours after the last administration.

The Jinzheng average Q value method is also called the probability addition method. According to the pharmacological effects of two drugs in combination and the pharmacological effects of two drugs in the dose-effect curve area, the following 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", the denominator represents the "expected combined effect", and Q is the ratio of the two. When the Q value is less than 0.85, the combination of the two drugs is considered to be antagonistic, when 0.85 is less than Q value is less than 1.15, it is considered to be additive, and when Q value is greater than 1.15, it is considered to be synergistic. In order to satisfy the analysis of the relationship between the pharmacological effects, the blood pressure value is converted into an effect that can directly reflect the strength of the pharmacological action. The calculation formula is: Ei=(1-Pi/P _{model group} )×100%, Pi is the blood pressure value of each group, P _{The model group} is the blood pressure value of the model group. The results are shown in Table 8.

Amlodipine, chlorthalidone, and spironolactone combined medication group, three comparison methods, the Q value of the effect on the systolic blood pressure of hyperaldosterone hypertensive rats are 1.253, 1.378, 1.245, all> 1.15, indicating the drug combination of the present invention The substances are synergistic with each other, and the compatibility of the three drugs is reasonable, which can enhance the antihypertensive effect of the drugs on hyperaldosterone hypertensive rats. The Q value of amlodipine, chlorthalidone, and eplerenone in the combined medication group for the systolic blood pressure of hyperaldosterone hypertensive rats is 1.226,> 1.15, indicating that the pharmaceutical composition provided by the present invention has a synergistic effect. The compatibility of the three drugs can enhance the antihypertensive effect of the drugs on hyperaldosterone hypertensive rats.

Amlodipine, hydrochlorothiazide, and spironolactone combination group, three comparison methods, the Q value of the effect on the contractile fluid of hyperaldosterone hypertensive rats were 1.037, 0.996, 0.997, between 0.85 and 1.15, indicating amlodipine The three drugs, hydrochlorothiazide, and spironolactone are additive to each other. The Q value of amlodipine, hydrochlorothiazide, and eplerenone combination group on the systolic blood pressure of hyperaldosterone hypertensive rats was 0.996, ranging from 0.85 to 1.15, indicating that amlodipine, hydrochlorothiazide, and eplerenone The three drugs are additive to each other.

n＝12) Table 8 Synergistic effect of amlodipine/chlorthalidone/spironolactone compound preparations on hyperaldosterone-type hypertensive rats (

n=12)

Example 20: Clinical trial of amlodipine + chlorthalidone + aldosterone receptor antagonist on antihypertensive efficacy and safety in patients with refractory hypertension

Selection criteria: Subjects who meet all of the following criteria and no one of the exclusion criteria can be selected.

Male and female hypertensive patients aged 40 to 75; insist on using 3 or more antihypertensive drugs for more than one month, sitting blood pressure (average of 3 measurements) meets the following standards: diastolic blood pressure ≥90mmHg or systolic blood pressure ≥140mmHg, And diastolic blood pressure <110mmHg and systolic blood pressure <180mmHg; volunteer to participate and sign the informed consent form.

Exclusion criteria: Exclude those who meet any of the following.

(1) Pregnant and lactating women; (2) Those with a history of allergies to the ingredients in the medicine; (3) Those with a clear allergic constitution; (4) White coat hypertension; (5) Those with poor medication compliance; (6) Known to have serious medical diseases; (7) Those with obvious laboratory examinations or abnormal signs, according to the judgment of the investigator, this abnormality indicates that the patient has a serious disease, or according to the judgment of the investigator, may affect the efficacy of the drug Or the observation and evaluation of adverse events are not suitable for participants in the research; (8) Those who have participated in any trial drug that has not been officially approved for marketing by the state within 4 weeks before the first visit.

The subjects were randomly divided into groups and controlled in parallel. The blood pressure of the patients was measured at the 4th weekend and the 8th weekend respectively. The systolic blood pressure/diastolic blood pressure <140/90mmHg was regarded as the blood pressure compliance standard, and the compliance rate was calculated. Safety indicators include: blood and urine routine, electrocardiogram, liver and kidney function, and adverse events.

The treatment plan is as follows:

Group A: Continue the original treatment plan;

Group B: Stop the original drug and switch to amlodipine/valsartan/hydrochlorothiazide tablets (10/160/25mg);

Group C: Stop the original drug and switch to amlodipine 5mg or 10mg + chlorthalidone 12.5mg, 25mg or 50mg + spironolactone 25mg or 50mg

Group D: Stop the original drug and switch to amlodipine 5mg or 10mg + chlorthalidone 12.5mg, 25mg or 50mg + eplerenone 50mg or 100mg

result:

The blood pressure of most patients in group A could not reach the target, and the rate of blood pressure in group B increased, and the difference was significant in the fourth week. Compared with group A, patients in the amlodipine + chlorthalidone + spironolactone treatment group (group C) and amlodipine + chlorthalidone + eplerenone treatment (group D) have significantly improved blood pressure compliance rates. The difference between week and 8th week was significant. Compared with group B, the blood pressure compliance rate of patients in the amlodipine + chlorthalidone + spironolactone treatment group (group C) further improved, and the difference between the 4th and 8th weeks was significant, amlodipine + chlorthalidone + epro The blood pressure compliance rate of patients in the ketone treatment (group D) group was further improved, and the difference was significant at the 8th week. See Table 9.

Common adverse events (incidence rate> 1%) include: upper respiratory tract symptoms, pain, abnormal liver function, gastrointestinal symptoms, abnormal lipid metabolism, dizziness, skin itching, urinary system symptoms, cardiovascular symptoms, oral symptoms, abnormal glucose metabolism And facial flushing. The overall incidence of adverse events in group A was 22.0%, group B was 19.8%, group C was 13.5%, group D was 17.7%, and group C had the lowest incidence of adverse events.

Table 9 Amlodipine + chlorthalidone + aldosterone receptor antagonist treatment, blood pressure compliance rate and adverse event rate in patients with refractory hypertension

Compared with group A, ^* P<0.05, ^** P<0.01; compared with group B, ^# P<0.05, ^## P<0.01

Example 21: Amlodipine + chlorthalidone + aldosterone receptor antagonist on the antihypertensive efficacy and safety of patients with low renin/aldosterone normal or elevated refractory hypertension: a randomized parallel controlled clinical trial

Selection criteria: Subjects who meet all of the following criteria and no one of the exclusion criteria can be selected.

Male and female patients aged 40 to 75; insist on using 3 or more antihypertensive drugs for more than one month, sitting blood pressure (average of 3 measurements) meets the following criteria: diastolic blood pressure ≥90mmHg or systolic blood pressure ≥140mmHg, and diastolic Patients with blood pressure <110mmHg and systolic blood pressure <180mmHg; fasting blood taken in the morning is determined to be normal or elevated low renin/aldosterone; voluntary participation and signed informed consent.

Exclusion criteria: Exclude those who meet any of the following.

(1) Pregnant and lactating women; (2) Those with a history of allergies to the ingredients in the medicine; (3) Those with a clear allergic constitution; (4) White coat hypertension; (5) Those with poor medication compliance; (6) Known to suffer from serious medical diseases; (7) There are obvious laboratory examinations or abnormal signs, and according to the judgment of the investigator, this abnormality indicates that the patient has a serious disease, or according to the judgment of the investigator, it may affect the drug Observation and evaluation of efficacy or adverse events is not suitable for participants; (8) Those who have participated in any trial drug that has not been officially approved for marketing by the state within 4 weeks before the first visit; (9) Take it on an empty stomach in the morning Patients with high renin type or normal renin level in blood test; (10) Patients with low aldosterone level in the morning with fasting blood.

The subjects in the classification group were randomly divided into groups, and the antihypertensive treatment plan of each group was controlled in parallel as follows:

Group A: Continue the original treatment plan;

Group B: Stop the original drug and switch to amlodipine/valsartan/hydrochlorothiazide tablets (10/160/25mg);

Group C: Stop the original drug and switch to amlodipine 5mg or 10mg + chlorthalidone 12.5mg, 25mg or 50mg + spironolactone 25mg or 50mg;

Group D: Discontinue the original drug and switch to amlodipine 5mg or 10mg + chlorthalidone 12.5mg, 25mg or 50mg + eplerenone 50mg or 100mg.

The blood pressure of the patients in each group was measured at the 4th weekend and the 8th weekend respectively, and the systolic blood pressure/systolic blood pressure <140/90mmHg was regarded as the blood pressure compliance standard, and the compliance rate was calculated. Safety indicators include: blood and urine routine, electrocardiogram, liver and kidney function, and adverse events.

result:

The blood pressure of most patients in group A could not reach the target, and the rate of reaching the target of blood pressure in group B increased. The difference between the 4th week and the 8th week was significant. Compared with group A, patients in the amlodipine + chlorthalidone + spironolactone treatment group (group C) and amlodipine + chlorthalidone + eplerenone treatment (group D) have significantly improved blood pressure compliance rates. The difference between week and 8th week was significant. Compared with group B, the blood pressure compliance rate of patients with amlodipine+chlorthalidone+spironolactone treatment group (group C) and amlodipine+chlorthalidone+eplerenone treatment (group D) further increased. The differences at 8 weeks are all significant, see Table 10.

Common adverse events (incidence> 1%) include: upper respiratory tract symptoms, abnormal liver function, gastrointestinal symptoms, abnormal lipid metabolism, dizziness, skin itching, urinary system symptoms, cardiovascular symptoms, abnormal glucose metabolism and facial flushing. The total incidence of adverse events in group A was 25.0%, group B was 22.4%, group C was 19.2%, group D was 16.7%, and group D had the lowest incidence of adverse events.

Table 10 Amlodipine + chlorthalidone + aldosterone receptor antagonist for refractory hypertension patients with normal or elevated low renin/aldosterone and the incidence of adverse events

Compared with group A, ^* P<0.05, ^** P<0.01; compared with group B, ^# P<0.05, ^## P<0.01

Claims (23)

A pharmaceutical composition for refractory hypertension, the composition of which is: (1) 2.5-10mg of amlodipine; (2) 12.5-100mg of chlorthalidone; (3) Medicinal dose of aldosterone receptor antagonist; (4) Pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 1, wherein the content of amlodipine is 5-10 mg. The pharmaceutical composition according to claim 1, wherein the content of chlorthalidone is 12.5-50 mg. The pharmaceutical composition according to claim 1, wherein the aldosterone receptor antagonist is spironolactone and the content is 12.5-100 mg. The pharmaceutical composition according to claim 4, wherein the content of the spironolactone is 25-50 mg. The pharmaceutical composition according to claim 5, characterized in that the composition of the pharmaceutical composition is 5 mg amlodipine, 12.5 mg chlorthalidone and 25 mg spironolactone. The pharmaceutical composition according to claim 5, characterized in that the composition of the pharmaceutical composition is that the composition of the pharmaceutical composition is 5 mg amlodipine, 25 mg chlorthalidone and 25 mg spironolactone. The pharmaceutical composition according to claim 5, wherein the composition of the pharmaceutical composition is that the composition of the pharmaceutical composition is 5 mg amlodipine, 25 mg chlorthalidone, and 50 mg spironolactone. The pharmaceutical composition according to claim 5, wherein the composition of the pharmaceutical composition is that the composition of the pharmaceutical composition is 5 mg amlodipine, 50 mg chlorthalidone and 50 mg spironolactone. The pharmaceutical composition according to claim 5, wherein the composition of the pharmaceutical composition is that the composition of the pharmaceutical composition is 10 mg amlodipine, 12.5 mg chlorthalidone and 25 mg spironolactone. The pharmaceutical composition according to claim 5, wherein the composition of the pharmaceutical composition is that the composition of the pharmaceutical composition is 10 mg amlodipine, 25 mg chlorthalidone and 25 mg spironolactone. The pharmaceutical composition according to claim 5, wherein the composition of the pharmaceutical composition is that the composition of the pharmaceutical composition is 10 mg amlodipine, 25 mg chlorthalidone and 50 mg spironolactone. The pharmaceutical composition according to claim 5, characterized in that the composition of the pharmaceutical composition is that the composition of the pharmaceutical composition is 10 mg amlodipine, 50 mg chlorthalidone and 50 mg spironolactone. The pharmaceutical composition according to claim 1, wherein the aldosterone receptor antagonist is eplerenone and the content is 25-100 mg. The pharmaceutical composition according to claim 14, wherein the content of eplerenone is 50-100 mg. The pharmaceutical composition according to claim 15, characterized in that the composition of the pharmaceutical composition is that the composition of the pharmaceutical composition is 5 mg amlodipine, 25 mg chlorthalidone and 50 mg eplerenone. The pharmaceutical composition according to claim 15, wherein the composition of the pharmaceutical composition is that the composition of the pharmaceutical composition is 10 mg amlodipine, 25 mg chlorthalidone and 50 mg eplerenone. The pharmaceutical composition according to claim 15, characterized in that the composition of the pharmaceutical composition is that the composition of the pharmaceutical composition is 10 mg amlodipine, 25 mg chlorthalidone and 100 mg eplerenone. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is prepared as an oral preparation. Use of the pharmaceutical composition of claim 1 in the preparation of a medicine for treating refractory hypertension. The use according to claim 20, characterized in that the refractory hypertension is low renin/normal aldosterone or low renin/high aldosterone. Use of the pharmaceutical composition of claim 1 in the preparation of a medicament for treating target organ damage in patients with refractory hypertension. The use according to claim 22, characterized in that the target organ damage is left ventricular hypertrophy, benign arteriole nephrosclerosis, malignant arteriole nephrosclerosis, renal failure, retinal arteriosclerosis, or hypertension Fundus disease.