CN101785858B - Medicine combination containing isosorbide mononitrate for treating high blood pressure - Google Patents

Abstract

The invention provides a pharmaceutical composition containing isosorbide mononitrate and angiotensin receptor antagonist. It is found through experiments that isosorbide mononitrate and angiotensin receptor antagonist can reduce blood pressure of patients and prevent hypertension. A good synergistic effect has been achieved in terms of patient complications, and the use of the pharmaceutical composition of the present invention can effectively protect the organ damage caused by hypertension, and effectively improve the long-term survival rate of hypertensive patients.

Description

Pharmaceutical composition containing isosorbide mononitrate for treating hypertension

technical field

This application is a divisional application of the patent application with the application number 200510125589.9 and the invention name "Pharmaceutical Composition Containing Isosorbide Mononitrate for Treating Hypertension" filed on November 23, 2005.

The invention belongs to the medical technology and relates to a new pharmaceutical composition for the treatment of elderly hypertension.

Background technique

New developments in the theory of drug therapy for hypertension

In the treatment of hypertensive patients, paying attention to whether the long-term survival rate of patients has been significantly improved is a great progress in the theory of hypertension treatment in recent years. Previously, it was thought that diastolic blood pressure (DBP) was a better indicator to determine the severity of hypertension, and the goal of drug treatment was to reduce DBP to less than 90, 85 or 80mmHg. Systolic blood pressure (SBP) is also reduced, but the degree of reduction is less than DBP, so PP cannot be reduced to normal. The results showed that although drug treatment normalized DBP, there was no further improvement in cardiovascular (CV) risk. Epidemiological studies in recent decades have shown that systolic blood pressure is a better predictor of CV risk, and widened pulse pressure (PP) is an independent CV risk factor. A widened PP may be the strongest predictor for identifying hypertensive patients at greatest risk for myocardial infarction, and PP has been shown to have prognostic value even in treated hypertensive patients. Pulse pressure has been recognized as the most powerful predictor for determining the risk of myocardial infarction, which is of great significance in the clinical treatment of hypertension and is a great progress in the understanding of hypertension treatment. This can also explain that blood pressure has been effectively controlled in clinical hypertension treatment for many years, but the long-term mortality of hypertensive patients has not improved, and some large-sample clinical surveys have even shown that the mortality rate has decreased. Three clinical trials of EWPHE, syst-Eur, and syst-China showed that when the systolic blood pressure was constant at 160mmHg, the incidence of cardiovascular events in patients with lower diastolic blood pressure (≤75mmHg) was higher than that of patients with high diastolic blood pressure (>95mmHg) in two years12 %. This shows that the higher the pulse pressure, the higher the mortality rate of hypertensive patients. A recently published survival analysis study of elderly hypertensive patients showed that the mortality rate of hypertensive patients with systolic blood pressure <130mmHg and diastolic blood pressure between 80 and 85mmHg was the lowest, while the group of patients with systolic blood pressure >160mmHg and diastolic blood pressure <70mmHg had the highest mortality rate. Mean arterial pressure and diastolic blood pressure were not associated with mortality, systolic and pulse pressure were strong predictors of mortality.

In patients with simple systolic hypertension, the arterial elasticity and compliance are significantly decreased, the velocity of the arterial wave and reflected wave is accelerated, and the reflected wave falls into the systolic period of the heart. The instantaneous blood pressure increase when the arterial wave and reflected wave meet is also the cause of cardiovascular events. Key factor.

Current status of clinical treatment of hypertension

In the population of hypertensive patients, diastolic blood pressure (DBP) is easier to control (≤90mmHg), and systolic blood pressure (SBP) is more difficult to control (≤140mmHg). In the traditional treatment of hypertension, diastolic blood pressure is regarded as an important goal of blood pressure control, which now seems to be incorrect. A new breakthrough in the concept. However, in the current clinical treatment, there is no ideal drug that has a good effect on systolic blood pressure and pulse pressure. For many hypertensive patients, the diastolic blood pressure is often easy to control, but the systolic blood pressure cannot be well controlled. For these hypertensive patients, as a result of traditional antihypertensive treatment, the diastolic blood pressure has been effectively controlled, the systolic blood pressure is still maintained at a high level, and the pulse pressure is increased, which relatively increases the risk of death of the patient.

Therefore, the traditional treatment of hypertension and cardiovascular diseases has been challenged, and clinical research on drugs that can improve arterial elasticity and compliance is being actively carried out at home and abroad. Looking for an ideal drug in line with the current concept of hypertension treatment, which can not only reduce and effectively lower blood pressure, prevent various complications that may be caused by long-term high blood pressure, but also effectively prevent the occurrence of cardiovascular events such as myocardial infarction, and effectively reduce mortality , in line with the interests of nearly 100 million hypertensive patients in our country.

Nitrate drugs such as isosorbide mononitrate are mainly used in the treatment of myocardial ischemic diseases in clinical practice. Previous pharmacological studies believed that the mechanism of anti-angina pectoris of nitrate drugs is mainly to expand small arteries and small veins, thereby reducing the In recent years, it has been found that the preload and afterload of the heart can enhance the elasticity of the atherosclerotic aorta, effectively restore the compliance of the aorta, and reduce the pulse pressure difference. In young adults, the reflected wave reaches the aorta after the aortic valve closes, so it only affects the DBP and not the SBP, contributing to an increase in coronary perfusion pressure. In patients with central arterial stiffness (hypertensive patients or the elderly), the pulse wave velocity is significantly increased, causing the reflected wave to fall into the systolic phase of the heart, which can increase the systolic pressure of the left ventricle and aorta and decrease the diastolic pressure of the aorta . During aging, the degree of sclerosis of the central artery increases, and the reflection coefficient increases. Clinical studies have shown that isosorbide mononitrate can reduce the enhancement coefficient of arterial waves and reflected waves by 50%, and has a significant effect on reducing systolic blood pressure. This may be one of the mechanisms of nitrates against angina.

Nowadays, for the treatment of hypertension, a single drug often cannot achieve the desired effect. In clinical practice, two or more antihypertensive drugs are often used in combination to achieve better antihypertensive effect, but it still cannot overcome the arterial A phenomenon in which the pulse pressure increases while the pressure decreases.

Contents of the invention

We, Lunan Pharmaceutical Co., Ltd., keep up with the frontiers of research on the mechanism of action of nitrates against angina pectoris. According to recent clinical trials and the latest concept of hypertension treatment, we combine the curative effect characteristics of existing antihypertensive drugs, and creatively propose the Lunan Xinkang produced by our company is used in combination with other antihypertensive drugs for patients with refractory systolic blood pressure who are ineffective in traditional antihypertensive treatment, or reflex tachycardia after application of vasodilators For more serious patients, after years of large-sample clinical trials, good clinical efficacy has been achieved. Compared with the existing antihypertensive drugs, nitrate drugs such as isosorbide mononitrate have a unique mechanism of action, and are mainly used for the treatment of angina pectoris clinically. We found in clinical trials that isosorbide mononitrate and The combined application of almost all antihypertensive drugs has a synergistic effect in reducing systolic blood pressure, among which calcium ion antagonists, renin-angiotensin-aldosterone system antagonists, vasodilators, adrenoceptor blockers, etc. When antihypertensive drugs are used in combination, the effect is the most ideal, and unexpected effects have been achieved in terms of synergistically reducing systolic blood pressure, reducing adverse reactions caused by antihypertensive drugs, and effectively increasing the survival rate of hypertensive patients. The most significant is that their combined application can reduce the systolic blood pressure of hypertensive patients most obviously, effectively reduce the pulse pressure difference, and greatly reduce the risk of various cardiovascular events in hypertensive patients, which may have a long-term impact on patients. Survival rates are of great importance. Therefore, the antihypertensive pharmaceutical composition containing isosorbide mononitrate provided by the present invention breaks through a misunderstanding of clinical antihypertensive treatment for a long time, that is, simply pursuing the goal of lowering blood pressure, especially the lowering effect on diastolic blood pressure , while ignoring the long-term survival rate of hypertensive patients, making the treatment of hypertension lose its most fundamental significance. The advantage of composition of the present invention is embodied in following aspects:

1. Isosorbide mononitrate has a good synergistic antihypertensive effect with calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, vasodilators, and adrenoceptor blockers It has a good curative effect on clinically common patients with resistant hypertension.

2. Compared with traditional antihypertensive drugs, the composition of the present invention has a better effect on reducing systolic blood pressure and pulse pressure difference while significantly reducing mean arterial pressure. Increased pulse pressure following the drug.

3. While effectively reducing blood pressure, the composition of the present invention avoids the occurrence of adverse reactions such as reflex tachycardia, increased sympathetic activity, and edema in hypertensive patients.

4. Long-term use of the composition of the present invention has beneficial effects on the long-term survival rate of hypertensive patients, and positively affects the prognosis of patients. This is also the most meaningful clinical treatment problem solved by the present invention. In a word, the antihypertensive composition containing isosorbide mononitrate of the present invention has revolutionary significance for the treatment of hypertension, and the long-term clinical efficacy achieved by the composition of the present invention is unprecedented in the history of hypertension treatment.

Based on the results of previous clinical trials and the physical and chemical properties of various antihypertensive drugs, we selected starch, low-substituted hydroxypropyl cellulose (L-HPC), hydroxypropylmethyl Cellulose 4000 (HPMC--4M), HPMC--15M, microcrystalline cellulose, polyvinylpyrrolidone (PVP), micronized silica gel, magnesium stearate, lactose, sodium carboxymethyl starch, pregelatinized starch, mountain elm Glyceryl monostearate, glyceryl monostearate, talc, ethyl cellulose (EC), stearic acid, macrogol-6000, mannitol, crospovidone, sodium carboxymethyl cellulose (CMC -Na), polyvinyl alcohol (PVA), cetyl alcohol, stearyl alcohol, croscarmellose sodium, sodium alginate or ethylene-vinyl acetate copolymer, etc., and isosorbide mononitrate and nitrendipine , nifedipine, nicardipine, nisoldipine, felodipine, amlodipine, isradipine, captopril, enalapril, benazepril, perindopril, lisinopril, Fosinopril, trandolapril, ramipril, cilazapril, losartan, valsartan, irbesartan, eprosartan, candesartan, olmesartan medoxomil, timid Sartan, pinacidil, minoxidil, hydralazine, dihydralazine, cadralazine, butralazine, ketonserin, propranolol, timolol, nadolol, Antihypertensive drugs such as tavolol, atenolol, oxyprenolol, metoprolol, betaxolol, acebutolol, carvedilol, phentolamine and other antihypertensive drugs are prepared into long-term medication for patients Compound preparations, and preliminary animal tests have been carried out, and ideal results have been achieved.

Detailed ways

The following are prescription quantities of 1000 tablets.

Example 1

Isosorbide Mononitrate Nitrendipine Extended Release Tablets

Prescription A

Isosorbide Mononitrate 15g

Starch 50g

L--HPC 20g

10% Starch Slurry Appropriate amount

Magnesium stearate 1g

Prescription B

Nitrendipine 15g

HPMC--4M 20g

HPMC--15M 30g

Microcrystalline Cellulose 20g

PVP 8g

Micropowder silica gel 35g

8% PVPk30 absolute ethanol solution Appropriate amount

Magnesium stearate 2g

Preparation Process:

Pass the isosorbide mononitrate, starch, and L-HPC in prescription A through a 100-mesh sieve, mix well, add 10% starch slurry to granulate, dry below 50°C, granulate with a 18-mesh sieve, and add stearic acid Magnesium mix well; pass nitrendipine, HPMC--4M, HPMC--15M, microcrystalline cellulose, PVP, and micropowder silica gel in prescription B respectively through a 100-mesh sieve, mix well, add an appropriate amount of 8% PVPk30 absolute ethanol solution Granulating, drying, sizing, adding magnesium stearate, mixing, and compressing double-layer tablets.

Example 2

Isosorbide Mononitrate Captopril Tablets

Isosorbide Mononitrate 10g

Captopril 50g

Starch 60g

Microcrystalline Cellulose 100g

L-HPC 30g

10% Starch Slurry Appropriate amount

Magnesium stearate 2g

Preparation Process:

Pass the isosorbide mononitrate, captopril, starch, microcrystalline cellulose and L-HPC in the prescription through a 100-mesh sieve respectively, mix well, add 10% starch slurry to granulate in an appropriate amount, dry below 50°C, and dry for 18 Mesh sieve for granulation, add prescription amount of magnesium stearate, mix evenly, and compress into tablets.

Example 3

Isosorbide Mononitrate Nifedipine Extended Release Tablets

Prescription A

Isosorbide Mononitrate 20g

Starch 100g

Sodium Carboxymethyl Starch 10g

10% Starch Slurry Appropriate amount

Magnesium stearate 1g

Prescription B

Nifedipine 15g

Cetyl alcohol 10g

Glyceryl monostearate 20g

Microcrystalline Cellulose 40g

8% PVPk30 absolute ethanol solution Appropriate amount

Magnesium stearate 2g

Preparation Process:

Pass the isosorbide mononitrate, starch, and sodium carboxymethyl starch in prescription A through a 100-mesh sieve, mix well, add 10% starch slurry to granulate, dry below 50°C, granulate with a 18-mesh sieve, add hard Magnesium stearate and mix well; pass the nifedipine, cetyl alcohol, glyceryl monostearate and microcrystalline cellulose in prescription B respectively through a 100-mesh sieve, mix well, add 8% PVPk30 absolute ethanol solution to make granules , dried, granulated, added magnesium stearate, mixed evenly, and compressed into double-layer tablets.

Example 4

Isosorbide Mononitrate Enalapril Tablets

Isosorbide mononitrate 15g

Enalapril 10g

Lactose 20g

Microcrystalline Cellulose 30g

Cross-linked polyvinylpyrrolidone 5g

10% starch slurry Appropriate amount

Magnesium stearate 1g

Preparation Process:

Pass the isosorbide mononitrate, enalapril, lactose, microcrystalline cellulose and cross-linked polyvinylpyrrolidone in the prescription through a 100-mesh sieve, mix well, add 10% starch slurry to granulate, and dry below 60°C , 18-mesh sieve, add the prescribed amount of magnesium stearate, mix well, and tablet it.

Example 5

Isosorbide Mononitrate Metoprolol Tartrate Extended Release Tablets

Prescription A

Isosorbide Mononitrate 15g

Starch 100g

Sodium carboxymethyl starch 10g

8% PVPk30 ethanol solution Appropriate amount

Magnesium stearate 1g

Prescription B

Metoprolol Tartrate 100g

Octadecanol 10g

Glyceryl behenate 20g

Microcrystalline Cellulose 40g

3% Ethylcellulose absolute ethanol solution Appropriate amount

Magnesium stearate 2g

Preparation Process:

Pass the isosorbide mononitrate, starch, and sodium carboxymethyl starch in prescription A through a 100-mesh sieve, mix well, add 10% starch slurry to granulate in an appropriate amount, dry below 60°C, granulate through a 18-mesh sieve, add hard Magnesium fatty acid is mixed; Metoprolol tartrate, stearyl alcohol, glyceryl behenic acid, and microcrystalline cellulose in prescription B are passed through a 100-mesh sieve, mixed, and 5% ethyl cellulose absolute ethanol is added The solution is granulated in an appropriate amount, dried, granulated, added with magnesium stearate, mixed evenly, and compressed into a double-layer tablet.

Example 6

Isosorbide Mononitrate Carvedilol Extended Release Tablets

Prescription A

Isosorbide Mononitrate 20g

Microcrystalline Cellulose 100g

Yugelatinized starch 10g

10% starch slurry Appropriate amount

Talc powder 1g

Prescription B

Carvedilol 20g

Ethyl cellulose 8g

Glyceryl monostearate 20g

Microcrystalline Cellulose 40g

PVP 8g

8% PVPk30 absolute ethanol solution Appropriate amount

Magnesium stearate 2g

Preparation Process:

Pass isosorbide mononitrate, microcrystalline cellulose, and pregelatinized starch in prescription A through a 100-mesh sieve, mix well, add 10% starch slurry to granulate in an appropriate amount, dry below 50°C, and granulate with a 18-mesh sieve. Add magnesium stearate and mix well; pass carvedilol, ethyl cellulose, glyceryl monostearate, microcrystalline cellulose, and PVP in prescription B through a 100-mesh sieve, mix well, add 8% PVPk30 without An appropriate amount of water-ethanol solution is granulated, dried, granulated, added with magnesium stearate, mixed evenly, and compressed into a double-layer tablet.

Example 7

Isosorbide Mononitrate Losartan Capsules

Isosorbide mononitrate 15g

Losartan 20g

Lactose 20g

Microcrystalline Cellulose 30g

Sodium carboxymethyl starch 5g

10% starch slurry Appropriate amount

Preparation Process:

Pass the isosorbide mononitrate, losartan, lactose, microcrystalline cellulose and sodium carboxymethyl starch in the prescription through a 100-mesh sieve, mix well, add 10% starch slurry to make granules, and dry below 60°C. Sieve through a 18-mesh sieve and fill the capsules.

Example 8

Isosorbide Mononitrate, Lisinopril, and Pinacidil Extended-Release Capsules

Prescription A

Isosorbide Mononitrate 15g

Lisinopril 5g

Blank ball core 200g

Sodium carboxymethyl cellulose 10g

Sodium carboxymethyl starch 40g

7% PVP alcohol solution Appropriate amount

Preparation Process:

Isosorbide mononitrate and lisinopril are passed through a 160 mesh sieve, sodium carboxymethyl cellulose and sodium carboxymethyl starch are passed through a 100 mesh sieve, the prescription quantity is weighed, and they are miscible in 7% PVP ethanol solution (solvent is 60-70% ethanol). Turn on the granulation coating machine, the air inlet pressure is 0.5 bar, the CYL (air inlet damper pressure) is 3 bar, and the CAP1 (atomization pressure) is 0.8 bar, pour blank pellet cores, and granulate. The feeding speed is 4 rpm, the peristaltic pump is 12%, the rotating speed of the turntable is 145 rpm, and it is dried at 50°C.

Prescription B

(1) Preparation of pill core

Pinacidil 80g

Blank ball core 200g

7% PVP solution (solvent is 90% ethanol) Appropriate amount

Preparation Process:

Pass the pinacidil through a 160 mesh sieve, weigh the prescription amount, and pour it into the lower hopper. Turn on the granulation coating machine, the air inlet pressure is 0.5bar, the CYL is 2bar, and the CAP is 10.6bar, pour blank pellet cores, and granulate. The feeding speed is 4 rpm, the peristaltic pump is 12%, the rotation speed of the turntable is 145 rpm, spray 7% PVP solution (the solvent is 90% ethanol), and dry at 50°C. The granulation is finished.

Containing pill core 500g

Acrylic resin RS100 10g

Acrylic resin RL 100 10g

Polyethylene Glycol-6000 2g

Talc powder 3g

95% Ethanol Appropriate amount

Preparation process: Weigh out the prescription amount to take the pill core containing medicine, and pour it into the lower hopper. Turn on the granulation coating machine, inlet air pressure 0.5bar, CYL 3bar, CAP10.9bar, inlet air temperature 30°C, turntable speed 180rpm, peristaltic pump 7%, spray the ethanol solution of acrylic resin RS 100 and acrylic resin RL 100. Coating is complete.

The drug-containing pellets obtained from prescription A and prescription B can be filled into capsules according to the weight ratio of 1:1.

The acrylic resin in this embodiment can be replaced by the same amount of polyvinyl alcohol or ethylene-vinyl acetate copolymer.

Example 9

Clinical Trial of Combined Application of Lunan Xinkang and Other Antihypertensive Drugs in the Treatment of Hypertension

The R&D and production of Lunan Xinkang (isosorbide mononitrate) by Lunan Pharmaceutical Co., Ltd. has always been at the leading level in China. The production of raw materials has filled the domestic gap. In recent years, it has closely followed the anti-anginal effect of nitrate drugs At the forefront of mechanism research, in cooperation with many hospitals, we creatively proposed to use Lunan Xinkang produced by our company in combination with other antihypertensive drugs for refractory systolic blood pressure elevation that traditional antihypertensive treatment fails clinically For patients with severe reflex tachycardia after the application of vasodilators, after years of large-scale clinical trials, good clinical efficacy has been achieved. Compared with the existing antihypertensive drugs, nitrate drugs such as isosorbide mononitrate have a unique mechanism of action, and are mainly used for the treatment of angina pectoris clinically. We found in clinical trials that isosorbide mononitrate and Calcium ion antagonists, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, vasodilators, adrenergic receptor blockers and other antihypertensive drugs combined to reduce systolic blood pressure synergistically; Adverse reactions caused by antihypertensive drugs; effectively increasing the survival rate of hypertensive patients, etc., achieved unexpected results. Some of the test data are now published as follows.

1. Case selection

Elderly hypertensive patients between 60 and 70 years old, without other obvious history of cardiovascular and cerebrovascular diseases, and patients with poor clinical efficacy after traditional antihypertensive treatment are eligible to participate in this trial.

2. Medication plan

All the patients participating in this experiment were randomly divided into two groups according to the level of systolic blood pressure and age level. Before the combined use of Lunan Xinkang and other antihypertensive drugs, the experimental group received the same dose of Lunan Xinkang for 2 weeks and Other antihypertensive drugs were used for 2 weeks, and the first two drugs were used in combination with the same dose as before from the fifth week; the control group only used corresponding antihypertensive drugs except Lunan Xinkang. In order to achieve the purpose of effectively lowering blood pressure, the other The dose used was higher than that of the test group.

3. Observation indicators

In the trial, we mainly observed the systolic blood pressure, pulse pressure, heart rate increase after drug use, the patient's 8-year survival rate and the incidence of adverse reactions of some drugs. The blood pressure of the patients was measured at 10:30 in the morning 2 weeks after the medication.

4. Test results

1. Clinical trials of combined use of isosorbide mononitrate and nitrendipine on hypertensive patients

A total of 160 patients participated in this experiment, who were randomly divided into two groups according to age and systolic blood pressure level, 89 cases in the test group and 71 cases in the control group. The experimental group first used Lunan Xinkang for 2 weeks, 20mg/day, taking it in the morning and at 2 o'clock in the afternoon respectively; after stopping the drug for 1 week, used nitrendipine for 2 weeks, 15mg/day, taking it three times, the use of the two drugs The doses were all lower than the usual clinical doses, and the above two drugs were used in combination from the 7th week, and the daily doses were the same as before. The control group took 30 mg of nitrendipine every day, and took it three times. The patients in the test group and the control group were followed up for a long time, and the patients who died of non-cardiovascular and cerebrovascular diseases or those who failed to adhere to the medication were excluded from the trial, and the 8-year survival rate was calculated. The results showed that in the patients in the test group, the combination of isosorbide mononitrate and nitrendipine had a significant synergistic antihypertensive effect on the systolic blood pressure, but had no significant effect on the diastolic blood pressure. At the same time as the systolic blood pressure, the pulse pressure also decreased significantly, achieving an ideal antihypertensive effect, while both the subclinical dose and the conventional clinical dose of nitrendipine increased the pulse pressure. The combined application of subclinical doses of isosorbide mononitrate and nitrendipine significantly corrected the adverse reaction of reflex tachycardia that occurred during the use of nitrendipine, lowered blood pressure, and did not cause significant sympathetic activity. This may have a beneficial effect on the long-term survival of patients. The 8-year survival rate of the combined treatment group was significantly higher than that of the nitrendipine control group alone.

Table 1. Comparison of antihypertensive efficacy of isosorbide mononitrate combined with nitrendipine

^** Compared with before medication, P<0.01, ^* Compared with before medication, P<0.05.

^&& Compared with the experimental group at the fifth week, P<0.01.

^$$ Compared with the control group in the second week, P<0.01.

2. Clinical trials of combined use of isosorbide mononitrate and nifedipine on hypertensive patients

A total of 150 patients participated in this experiment, which were randomly divided into two groups according to age and systolic blood pressure level, 79 cases in the test group and 71 cases in the control group. The experimental group first used Lunan Xinkang for 2 weeks, 20mg/day, taking it in the morning and at 2 o'clock in the afternoon respectively; after stopping the drug for 1 week, used nifedipine for 2 weeks, 15mg/day, taking it three times, the use of the two drugs The doses were all lower than the usual clinical doses, and the above two drugs were used in combination from the 7th week, and the daily doses were the same as before. The control group took 45 mg of nifedipine every day, and took it three times. The patients in the test group and the control group were followed up for a long time, and the patients who died of non-cardiovascular and cerebrovascular factors or those who failed to adhere to the medication were excluded from the trial, and the 8-year survival rate was calculated. The results showed that in the patients in the test group, the combination of isosorbide mononitrate and nifedipine had a significant synergistic effect on systolic blood pressure, but had no significant effect on diastolic blood pressure. At the same time as the systolic blood pressure, the pulse pressure also decreased significantly, achieving an ideal antihypertensive effect, while both the subclinical dose and the conventional clinical dose of nidipine increased the pulse pressure. The combined application of subclinical doses of isosorbide mononitrate and nifedipine significantly corrected the adverse reactions of reflex tachycardia that occurred during the use of high-dose nifedipine, and lowered blood pressure without causing sympathetic activity. significantly increased, which may have a beneficial impact on the long-term survival of patients. The 8-year survival rate of the combination group was significantly higher than that of the nifedipine control group alone.

Table 2. Comparison of antihypertensive efficacy of isosorbide mononitrate combined with nifedipine

^** Compared with before medication, P<0.01.

^&& Compared with the experimental group at the fifth week, P<0.01.

^$$ Compared with the control group in the second week, P<0.01, ^$ Compared with the control group in the second week, P<0.05.

3. Clinical trials of combined use of isosorbide mononitrate and enalapril on hypertensive patients

A total of 165 patients participated in this experiment, who were randomly divided into two groups according to age and systolic blood pressure level, 86 cases in the test group and 79 cases in the control group. The experimental group first used Lunan Xinkang for 2 weeks, 20mg/day, taking it in the morning and at 2 o'clock in the afternoon respectively; after stopping the drug for 1 week, they used enalapril for 2 weeks, 10mg/day, taking it once in the morning, the two drugs The doses used were lower than the commonly used clinical doses, and the above two drugs were used in combination from the 7th week, and the daily doses were the same as before. The control group was given 30 mg of enalapril every day, divided into two doses. Long-term follow-up was carried out on the patients in the test group and the control group to observe the drug efficacy and adverse reactions. The results showed that in the patients in the test group, the combination of isosorbide mononitrate and enalapril had a significant synergistic effect on systolic blood pressure, but had no significant effect on diastolic blood pressure. While reducing the systolic blood pressure, the pulse pressure also decreased significantly, achieving an ideal antihypertensive effect, but the clinical dose of enalaprilia failed to produce a significant antihypertensive effect, because the cases selected in this test were all For patients with refractory hypertension who are difficult to treat, high-dose clinical use has not been able to achieve ideal curative effect, and the incidence of adverse reactions such as dry cough is relatively high. The combined application of isosorbide mononitrate and subclinical dose of enalapril has obviously corrected the adverse reactions such as rash and dry cough during the use of high-dose enalapril. The results of the long-term follow-up survey showed that the patients in the combined medication group had better medication compliance, and most patients could persist in medication, while the high-dose enalapril control group had more serious adverse reactions, and many patients could not persist in medication for more than 1 year.

Table 3. Comparison of antihypertensive efficacy of isosorbide mononitrate combined with enalapril

^** Compared with before medication, P<0.01, ^* Compared with before medication, P<0.05.

^&& Compared with the experimental group at the fifth week, P<0.01.

^$$ Compared with the control group in the second week, P<0.01.

4. Clinical trial of combined use of isosorbide mononitrate and valsartan on hypertensive patients

A total of 156 patients participated in this experiment, who were randomly divided into two groups according to age and systolic blood pressure level, 79 cases in the test group and 77 cases in the control group. The experimental group first used Lunan Xinkang for 2 weeks, 20mg/day, taking it in the morning and at 2 o'clock in the afternoon respectively; after stopping the drug for 1 week, used valsartan for 2 weeks, 40mg/day, taking it every morning, the use of the two drugs The doses were all lower than the usual clinical doses, and the above two drugs were used in combination from the 7th week, and the daily doses were the same as before. The control group received 120 mg of valsartan per day, once a day in the morning. Long-term follow-up was carried out on the patients in the test group and the control group to observe the drug efficacy and adverse reactions. The results showed that in the patients in the test group, the combination of isosorbide mononitrate and valsartan had a significant synergistic antihypertensive effect on the systolic blood pressure of the patients, but had no significant effect on the diastolic blood pressure. At the same time as the systolic blood pressure, the pulse pressure also decreased significantly, and the ideal antihypertensive effect was achieved, but the subclinical dose of valsartan failed to produce a significant antihypertensive effect. In the treatment of refractory hypertension patients, the clinical use of large doses of valsartan has reduced the blood pressure of the patients to a certain extent, but it has not been able to achieve an ideal effect in reducing the systolic blood pressure. The combined application of subclinical doses of isosorbide mononitrate and valsartan achieved an ideal antihypertensive effect that could not be achieved by using valsartan or isosorbide mononitrate alone. Be able to adhere to medication.

Table 4. Comparison of antihypertensive efficacy of combined use of isosorbide mononitrate and valsartan

^** Compared with before medication, P<0.01, ^* Compared with before medication, P<0.05.

^&& Compared with the experimental group at the fifth week, P<0.01.

^$$ Compared with the control group in the second week, P<0.01.

5. Clinical trial of combined use of isosorbide mononitrate and pinacidil on hypertensive patients

A total of 168 patients participated in this experiment, who were randomly divided into two groups according to age and systolic blood pressure level, 91 cases in the test group and 77 cases in the control group. The experimental group first used Lunan Xinkang for 2 weeks, 20mg/day, taking it in the morning and at 2 o'clock in the afternoon respectively; after stopping the drug for 1 week, used pinacidil sustained-release capsules for 2 weeks, 25mg/day, taking it twice , the doses of the two drugs were lower than the usual clinical doses, and the above two drugs were used in combination from the 7th week, and the daily doses were the same as before. The control group took 75 mg of pinacidil sustained-release capsules twice a day. Long-term follow-up was carried out on the patients in the test group and the control group to observe the curative effect and adverse reactions of the medication. The results showed that in the patients in the test group, the combination of isosorbide mononitrate and pinacidil had a significant synergistic antihypertensive effect on the systolic blood pressure of the patients, but had no obvious effect on the diastolic blood pressure. While reducing the systolic blood pressure, the pulse pressure also decreased significantly, achieving an ideal antihypertensive effect, while both the subclinical dose and the conventional clinical dose of pinacidil increased the pulse pressure. The combined application of subclinical doses of isosorbide mononitrate and pinacidil significantly corrected the adverse reaction of reflex tachycardia during the use of pinacidil, and reduced blood pressure without causing sympathetic activity. significantly increased, which may have a beneficial impact on the long-term survival of patients. In addition, the dosage of pinacidil in the control group was relatively large, and the incidence of edema was relatively high. The combined medication significantly reduced the incidence of edema while achieving an effective antihypertensive effect. The 8-year survival rate of the combination group compared with the control group is currently under observation.

Table 5. Comparison of antihypertensive efficacy of isosorbide mononitrate combined with pinacidil

^** Compared with before medication, P<0.01.

^&& compared with the 5th week of the test group, P<0.01, ^& compared with the 5th week of the test group, P<0.05.

^$$ Compared with the control group in the second week, P<0.01, ^$ Compared with the control group in the second week, P<0.05.

6. Clinical trial of combined use of isosorbide mononitrate and metoprolol on hypertensive patients

A total of 180 patients participated in this experiment, who were randomly divided into two groups according to age and systolic blood pressure level, 81 cases in the test group and 99 cases in the control group. The experimental group first used Lunan Xinkang for 2 weeks, 20mg/day, taking it in the morning and at 2 o'clock in the afternoon respectively; after stopping the drug for 1 week, used metoprolol for 2 weeks, 100mg/day, taking it twice, the two drugs The doses used are lower than the usual clinical doses, and the above two drugs are used in combination from the 7th week, and the daily doses are the same as before. The control group was given 300 mg of metoprolol per day, divided into two doses, and the initial dose could be appropriately reduced according to the specific situation. The patients in the test group and the control group were followed up for a long time, and the patients who died of non-cardiovascular and cerebrovascular factors or those who failed to adhere to the medication were excluded from the trial, and the 8-year survival rate was calculated. The results showed that in the patients in the test group, the combination of isosorbide mononitrate and metoprolol had a significant synergistic effect on systolic blood pressure, but had little effect on diastolic blood pressure. At the same time, the pulse pressure has also been significantly reduced, and an ideal blood pressure reduction effect has been achieved. The combined application of subclinical doses of isosorbide mononitrate and metoprolol has obviously corrected the adverse reactions such as dizziness, headache, and fatigue during the use of high-dose metoprolol. The 8-year survival rate of the combination group was slightly higher than that of the metoprolol control group alone, and there was no statistical difference, but the quality of life of patients in the control group decreased significantly.

Table 6. Comparison of antihypertensive efficacy of isosorbide mononitrate combined with metoprolol

^** Compared with before medication, P<0.01.

^&& compared with the 5th week of the test group, P<0.01, ^&& compared with the 5th week of the test group, P<0.01.

^$$ Compared with the control group in the second week, P<0.01.

7. Clinical trial of combined use of isosorbide mononitrate, felodipine and enalapril on hypertensive patients

Calcium ion antagonists and angiotensin-converting enzyme inhibitors have a good synergistic effect in lowering blood pressure. Compound preparations have long been on the market in foreign countries. A total of 215 patients participated in this test. They were randomly divided into two groups according to age and systolic blood pressure level. There were 90 cases in the test group and 125 cases in the control group. The experimental group used Lunan Xinkang 20mg/day, taking it in the morning and at 2 o'clock in the afternoon; felodipine 10mg/day, taking it twice, enalapril 5mg/day, taking it once in the morning, the use of three drugs Doses were lower than those commonly used in clinical practice. The control group received felodipine 10mg/day, taken twice, and enalapril 5mg/day, once in the morning. Blood pressure was measured at the 2nd week and 10th week after medication, and patients were followed up for a long time. Patients who died due to non-cardiovascular and cerebrovascular factors or patients who failed to adhere to medication were excluded from this trial, and the calculation was 8 years. survival rate. The results showed that in the patients of the test group, after 2 weeks of use, the addition of isosorbide mononitrate further reduced the systolic blood pressure of the patients and achieved a significant synergistic antihypertensive effect. In the 20th week of medication, patients in the control group developed a certain degree of drug resistance, and the addition of isosorbide mononitrate in the test group effectively prevented the emergence of drug resistance in patients. The 8-year survival rate of the experimental group was significantly higher than that of the control group.

Table 7. Comparison of antihypertensive efficacy of isosorbide mononitrate combined with felodipine and enalapril

^** Compared with before medication, P<0.01, ^* Compared with before medication, P<0.05.

^$$ Compared with the control group at the 20th week, P<0.01.

Example 10

Comparison and Screening of Curative Effects of Combined Application of Lunan Xinkang and Angiotensin Converting Enzyme Inhibitors on Hypertensive Rats

On the basis of the clinical trial results of Lunan Xinkang (isosorbide mononitrate) combined with enalapril, and according to the new progress of the current concept of clinical hypertension treatment, we have studied the combination of angiotensin-converting enzyme inhibitors and isosorbide mononitrate. The effect of combined use of sorbide was further screened, and some indicators related to the long-term survival rate of patients and the organ damage caused by hypertension were investigated in clinical hypertension treatment.

The specific experimental data are as follows:

Experimental animals: Spontaneous hereditary hypertensive rats (SHR), purchased from Shanghai Slack Experimental Animal Co., Ltd.

experimental method:

Grouping of animals: 165 SHR rats of 200-250 g were randomly divided into 11 groups according to blood pressure level, 15 rats in each group. Followed by model control group, captopril group, enalapril group, benazepril group, perindopril group, lisinopril group, fosinopril group, ramipril group, quinapril group, Puril group, cilazapril group and trandolapril group. Another 10 SD rats were used as normal blood pressure control group.

The normal control group and the model control group were intragastrically given 5ml/kg of normal saline every day;

The captopril group was given captopril 8.2mg/kg and isosorbide mononitrate 2.8mg/kg by intragastric administration every day;

The enalapril group was given enalapril 2.8mg/kg and isosorbide mononitrate 2.8mg/kg by intragastric administration every day;

The Benazepril group was given Benazepril 2.8mg/kg and Isosorbide Mononitrate 2.8mg/kg by intragastric administration every day;

The perindopril group was given perindopril 1.4mg/kg and isosorbide mononitrate 2.8mg/kg by intragastric administration every day;

The lisinopril group was given lisinopril 2.8mg/kg and isosorbide mononitrate 2.8mg/kg by intragastric administration every day;

The fosinopril group was given fosinopril 2.8mg/kg and isosorbide mononitrate 2.8mg/kg by intragastric administration every day;

The ramipril group was given ramipril 0.7mg/kg and isosorbide mononitrate 2.8mg/kg by intragastric administration every day;

The quinapril group was given quinapril 2.8 mg/kg and isosorbide mononitrate 2.8 mg/kg by intragastric administration every day;

Cilazapril group was given cilazapril 0.7mg/kg and isosorbide mononitrate 2.8mg/kg by intragastric administration every day;

The trandolapril group was given 0.28 mg/kg trandolapril and 2.8 mg/kg isosorbide mononitrate by intragastric administration every day.

After 15 weeks of intragastric administration to the rats in each group, the urine of the rats was inoculated with metabolic cages, and the microalbumin content in the urine of the rats in each group was measured according to the bromophenol blue method to reflect the kidney damage of hypertensive rats (SHR) Degree. Inject 1.5 ml of 1 mol/L potassium chloride through the arterial cannula to stop the heart of the animal in a diastolic state. Immediately remove the heart and aorta (from the ascending aorta to the thoracic aorta), weigh the wet weight of the left ventricle and aorta, and calculate the weight of the left ventricle per unit body weight and the weight of the aorta per unit length. The concrete method of bromophenol blue method determination microalbumin content in rat urine is as follows:

various reagents

1. 10% (v/v) glacial acetic acid solution (pH2.8).

2. 0.303mol/L glycine-glacial acetic acid buffer solution (pH3.0): Weigh 22.72g glycine, dilute it with 10% glacial acetic acid solution to 1000ml, add NaN ₃ 100mg, seal at room temperature and be stable for 1 year.

3. Bromophenol blue (1.924mmol/L) stock solution: Accurately weigh 257.36mg of bromophenol blue (BPB), dissolve it with absolute ethanol to 200ml, and it can be stable for 1 year in a 4°C refrigerator.

4. Bromophenol blue (0.231mmol/L) chromogenic reagent: take 60ml of BPB stock solution, add 2.5ml of TritonX-100, dilute to 500ml with glycine-glacial acetic acid buffer solution, and seal it at room temperature for 1 year.

test methods

Take 2ml of rat urine sample (cloudy urine should be centrifuged to get the supernatant) into a cuvette, add 1ml of BPB color reagent, mix well, and use a 721-type spectrophotometer to measure color at 600nm with a 10mm optical path after 1min.

Experimental results

1. Effects of combined use of isosorbide mononitrate and angiotensin-converting enzyme inhibitors on left ventricular hypertrophy and aortic hypertrophy in hypertensive rats

The results showed that among all the angiotensin converting enzyme inhibitors, except for the effect of captopril which was not ideal, other angiotensin converting enzyme inhibitors combined with isosorbide mononitrate had a long-term effect on hypertensive rats. The left ventricular hypertrophy and aortic hypertrophy formed after hypertension have a very significant impact. The results of our animal experiments indicate that the combined use of angiotensin-converting enzyme inhibitors and isosorbide mononitrate has a clinical effect on the treatment of hypertensive patients in the future. The important impact will effectively prevent various complications of hypertensive patients and improve the long-term survival rate of patients. The specific results are shown in Table 8.

2. Effect of combined use of isosorbide mononitrate and angiotensin-converting enzyme inhibitor on urinary microalbumin in hypertensive rats

The results showed that among the tested angiotensin-converting enzyme inhibitors, the urinary microalbumin of hypertensive rats in each experimental group was significantly lower than that of the model group. Ideally, the combination of other ACE inhibitors and isosorbide mononitrate has a very significant effect on the increase of urinary microalbumin in hypertensive rats after long-term hypertension, which predicts the conversion of angiotensin The combined use of enzyme inhibitors and isosorbide mononitrate has a good preventive effect on kidney damage in hypertensive patients. The specific experimental results are shown in Table 8.

Table 8 Comparison of left ventricular mass index, aortic weight and urinary microalbumin in each group of rats

^* Compared with the model control group, p<0.05, ^** Compared with the model control group, p<0.01.

^& compared with captopril group, p<0.05., ^&& compared with captopril group, p<0.01.

Comparison and Screening of Curative Effects of Lunan Xinkang Combined with Angiotensin Receptor Antagonists on Hypertensive Rats

On the basis of the clinical trial results of combined use of Lunan Xinkang (isosorbide mononitrate) and valsartan, and according to the new progress of the current concept of clinical hypertension treatment, we have combined angiotensin receptor antagonists and isosorbide mononitrate A further screening study was carried out on the effect of combined use of esters, and some indicators related to the long-term survival rate of patients and the organ damage caused by hypertension were investigated in clinical hypertension treatment.

The specific experimental data are as follows:

The experimental animals and experimental methods are basically the same as above, and the dosage of each experimental drug is converted from the commonly used clinical dosage according to the body surface area.

Experimental results

1. Effects of combined use of isosorbide mononitrate and angiotensin receptor antagonist on left ventricular hypertrophy and aortic hypertrophy in hypertensive rats

The results showed that the combined use of all angiotensin receptor antagonists and isosorbide mononitrate has a very significant effect on the left ventricular hypertrophy and aortic hypertrophy formed after long-term hypertension in hypertensive rats. Our animal experiment results indicate that The combined use of angiotensin receptor antagonists and isosorbide mononitrate will have an important impact on the clinical treatment of hypertensive patients in the future. It will effectively prevent various complications of hypertensive patients and improve the long-term survival rate of patients. The specific results are shown in Table 9.

2. Effect of combined use of isosorbide mononitrate and angiotensin receptor antagonist on urinary microalbumin in hypertensive rats

The results show that the combination of angiotensin receptor antagonist and isosorbide mononitrate has a very significant effect on the increase of urinary microalbumin after long-term hypertension in hypertensive rats, which indicates that angiotensin receptor antagonist The combined use of the drug and isosorbide mononitrate has a good preventive effect on kidney damage in hypertensive patients. The specific experimental results are shown in Table 9.

Table 9 Comparison of left ventricular mass index, aortic weight and urinary microalbumin in each group of rats

^* Compared with the model control group, p<0.05, ^** Compared with the model control group, p<0.01.

Claims (1)

1. Use of a pharmaceutical composition containing isosorbide mononitrate and an angiotensin II receptor antagonist in the preparation of a drug for treating hypertension. the 2. as claimed in claim 1, it is characterized in that described angiotensin II receptor antagonist is losartan, valsartan, candesartan, olmesartan esters, irbesartan, telmisartan, or eprosartan. 3. The use for preparing medicine for treating hypertension as claimed in claim 1, characterized in that said angiotensin II receptor antagonist is losartan and valsartan. 4. as claimed in claim 1, is used for preparing the purposes of medicine for treating hypertension, it is characterized in that also containing one or more in the following inactive components in the described pharmaceutical composition, they are starch, low-substituted hydroxyl Propyl cellulose, hydroxypropyl methylcellulose 4000, hydroxypropyl methylcellulose 15000, microcrystalline cellulose, polyvinylpyrrolidone, micronized silica gel, magnesium stearate, lactose, sodium carboxymethyl starch, pregelatin Starch, Glyceryl Behenate, Glyceryl Monostearate, Talc, Ethylcellulose, Stearic Acid, Macrogol-6000, Mannitol, Crospovidone, Sodium Carboxymethylcellulose , polyvinyl alcohol, cetyl alcohol, stearyl alcohol, croscarmellose sodium, sodium alginate or ethylene-vinyl acetate copolymer.