阅读说明：本技术 一种含有阿利沙坦酯水解产物或其水解产物盐的药物组合物及其用途 (Pharmaceutical composition containing allisartan isoproxil hydrolysate or hydrolysate salt thereof and application thereof ) 是由 颜杰 许文杰 李松 邓运 于 2016-03-11 设计创作，主要内容包括：提供了一种含有阿利沙坦酯水解产物或阿利沙坦酯水解产物的盐与脑中性内肽酶抑制剂或其盐的药物组合物,与现有上市的阿利沙坦酯相比,所述药物组合物具有降低药物使用量、减少副作用、有利于规模化生产等有益效果的有益效果,使得所述药物组合物具有更好的临床应用前景。(Compared with the existing allisartan isoproxil on the market, the pharmaceutical composition has the beneficial effects of reducing the using amount of the drug, reducing side effects, being beneficial to large-scale production and the like, so that the pharmaceutical composition has better clinical application prospect.)

1. The pharmaceutical composition is characterized by comprising an allisartan isoproxil hydrolysate or a salt of the allisartan isoproxil hydrolysate and a brain-neutral endopeptidase inhibitor or a salt thereof, wherein the brain-neutral endopeptidase inhibitor is AHU377, the allisartan isoprox hydrolysate is EXP3174, and the mass ratio of the allisartan isoproxil hydrolysate or the salt of the alisartan isoproxil hydrolysate to the brain-neutral endopeptidase inhibitor or the salt thereof is 8: 1-1: 8.

2. The pharmaceutical composition according to claim 1, wherein the mass ratio of the allisartan isoproxil hydrolysate or the salt of the allisartan isoproxil hydrolysate to the brain neutral endopeptidase inhibitor or the salt thereof is 5: 1-1: 5.

3. The pharmaceutical composition according to claim 1, characterized in that the mass ratio of the alisartan ester hydrolysate or the salt of alisartan ester hydrolysate to the brain neutral endopeptidase inhibitor or the salt thereof is 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1: 8.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the salt of the alisartan medoxomil hydrolysate is selected from any one of sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt and ammonium salt.

5. The pharmaceutical composition according to any of claims 1-4, wherein said AHU377 salt is selected from the group consisting of sodium, potassium, calcium, magnesium, zinc, and ammonium salts.

6. The pharmaceutical composition according to claim 1, wherein the brain neutral endopeptidase inhibitor salt is AHU377 calcium salt, the alisartan ester hydrolysate is EXP3174, the pharmaceutical composition consists of EXP3174 and AHU377 calcium salt, and the mass ratio of the EXP3174 to the AHU377 calcium salt is 5: 1-1: 5.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition comprises EXP3174 and AHU377 calcium salt in a ratio of 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5 by weight.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises a mixture of one or more of lactose, mannitol, dextrin, starch, pregelatinized starch, microcrystalline cellulose, calcium sulfate, calcium phosphate and calcium hydrogen phosphate; the adhesive is one or a mixture of more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, povidone, starch slurry and gelatin; the disintegrant is one or more of croscarmellose sodium, dry starch, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, starch, and pregelatinized starch; the lubricant is one or a mixture of magnesium stearate, superfine silica gel powder, talcum powder and polyethylene glycol.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is a powder, a granule, a tablet, a capsule, an effervescent, an injection.

10. Use of the pharmaceutical composition according to any one of claims 1 to 9 for the preparation of a medicament for the treatment of hypertension, heart failure and complications thereof.

Technical Field

The invention belongs to the field of medicines, and particularly relates to a pharmaceutical composition containing an allisartan isoproxil hydrolysate or a salt of the allisartan isoproxil hydrolysate and application thereof.

Background

Cardiovascular diseases are considered as the first killers threatening human health, with the improvement of living standard of people in China and the aging of population, the population suffering from cardiovascular diseases (such as hypertension, diabetes, heart failure, coronary heart disease and the like) in China is growing, and because most cardiovascular diseases need long-term medication or even lifetime medication, the development of cardiovascular disease drugs is one of the hot spots in the field of drug research and development.

Allisartan isoproxil, CAS: 947331-05-7, which is a novel AT1 inhibitor for treating hypertension, is a derivative of losartan metabolite EX3174, and achieves the effect of reducing blood pressure by entering human body to be hydrolyzed into EXP 3174.

The Chinese patent CN200610023991.0 discloses the structural formula of allisartan isoproxil for the first time and discloses the application of allisartan isoproxil in the preparation of hypertension drugs. Compared with other antihypertensive products (such as losartan) of the same type, the allisartan isoproxil has the characteristics of low toxicity, excellent antihypertensive effect and the like. In addition, patent cn200880018830.x discloses that allisartan isoproxil can be used for treating target organ injuries such as heart, brain, kidney, blood vessel and the like caused by hypertension.

The brain Neutral Endopeptidase (NEP) is an important enzyme with metal in vivo, and has the effects of inhibiting NEP, increasing the level of natriuretic factor, and thus playing roles in expanding blood vessels, expelling sodium, promoting urination, inhibiting cell proliferation, inhibiting sympathetic nerve, etc. NEP inhibitors with ACE inhibitory action are the key points for the development of the drugs, such as omatralat (Omapatrilat), which is considered to play an important role in the treatment of cardiovascular diseases such as hypertension and heart failure, but the drugs have adverse reactions which are easy to cause angioedema, which affect the application prospect, while simple NEP inhibitors cannot be developed into drugs due to poor blood pressure reducing effect.

AHU377 (CAS: 149709-62-6) is a brain neutral endopeptidase inhibitor, which was first disclosed in patent US 5217996.

Because the etiology and pathogenesis of hypertension are various, the structure and function of a plurality of organs of a body are affected by the incapability of controlling the blood pressure, and patients with hypertension are accompanied by diseases or pathological changes of other organs, such as cardiovascular and cerebrovascular diseases, hyperlipidemia and the like. In the aspect of treatment, the combined use of the antihypertensive drugs with different mechanisms is beneficial to better controlling blood pressure, and more importantly, the combined use of the drugs with different antihypertensive mechanisms may have a synergistic effect, thereby being beneficial to reducing the use amount of the drugs and further achieving the purpose of reducing the side effects of the drugs. At present, the compound antihypertensive drugs approved in China include olmesartan medoxomil/hydrochlorothiazide tablets, losartan potassium/hydrochlorothiazide tablets, enalapril maleate/folic acid tablets, enalapril/hydrochlorothiazide tablets, amlodipine/benazepril tablets and the like, and compared with single active ingredients, the compound preparation has obvious advantages in the aspects of treatment effect and the like.

Heart failure (heart failure for short) is a complex group of clinical syndromes in which ventricular filling or the ability to eject blood is impaired due to any structural or functional abnormality of the heart. The major clinical manifestations of heart failure are dyspnea and weakness (limited exercise tolerance), and fluid retention (pulmonary congestion and peripheral edema). Hypertension is one of the main risk factors of heart failure, Angiotensin Converting Enzyme Inhibitors (ACEIs), such as enalapril, are the first class of drugs which are proved to reduce the fatality rate of patients, are also the drugs which accumulate the most according to evidence of medicine and are the first choice drugs for treating heart failure, but the Angiotensin Converting Enzyme Inhibitors (ACEIs) have dry cough, vascular edema and the like.

Chinese patent CN1615134A discloses a pharmaceutical composition of valsartan and brain Neutral Endopeptidase (NEP), which shows better drug synergy when treating or preventing cardiovascular diseases including hypertension, heart failure and other indications, and has certain prospects for drug development. However, the patent does not disclose the specific ratio range of valsartan and brain Neutral Endopeptidase (NEP) which produce the drug synergistic effect, and does not integrate the pharmaceutical prospect of the pharmaceutical composition in consideration of other aspects of the drug property such as flowability and the like.

It can be seen that the search for drug synergism among known compounds, the optimization of the treatment effect of cardiovascular diseases including hypertension, heart failure and other indications, the reduction of the drug usage amount, and the improvement of the drug compliance are still the technical problems to be solved in the prior art.

Disclosure of Invention

The invention aims to provide a pharmaceutical composition of alisartan medoxomil or salt thereof, or alisartan medoxomil hydrolysate or salt of alisartan medoxomil hydrolysate and a brain neutral endopeptidase inhibitor or salt thereof, wherein the pharmaceutical composition can be used for treating cardiovascular diseases such as hypertension and heart failure and complications thereof, and has the beneficial effects of reducing the usage amount of drugs, reducing side effects, facilitating large-scale production and the like.

The beneficial effects of the invention are realized by the following technical scheme:

the pharmaceutical composition is characterized by comprising alisartan medoxomil or a salt thereof, or a hydrolysate of alisartan medoxomil or a salt of alisartan medoxomil hydrolysate, and a brain neutral endopeptidase inhibitor or a salt thereof, wherein the mass ratio of the alisartan medoxomil or the salt thereof, or the hydrolysate of alisartan medoxomil or the salt thereof to the brain neutral endopeptidase inhibitor or the salt thereof is 8: 1-1: 8.

The mass ratio of the alisartan medoxomil or the salt thereof, or the alisartan medoxomil hydrolysate or the salt of the alisartan medoxomil hydrolysate to the brain neutral endopeptidase inhibitor or the salt thereof is any one of the ratio of 8: 1-1: 8, for example, the mass ratio of the alisartan medoxomil or the salt thereof, or the alisartan medoxomil hydrolysate or the salt of the alisartan medoxomil hydrolysate to the brain neutral endopeptidase inhibitor or the salt thereof can be 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, and the advantages of comprehensive drug effect, patent property, powder physical and chemical properties and the like are achieved, and the mass ratio is preferably 5: 1-1: 5.

The allisartan isoproxil salt is common pharmaceutically acceptable salt, such as sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, ammonium salt and the like, preferably, the salt is one of sodium salt, potassium salt and calcium salt.

The hydrolysis product of the allisartan isoproxil can be EXP3174, the corresponding salt of the allisartan isoproxil hydrolysis product can be EXP3174 salt, the salt is common pharmaceutically acceptable salt, such as sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, ammonium salt and the like, and preferably, the salt is one of sodium salt, potassium salt and calcium salt.

The brain neutral endopeptidase inhibitor may be a series of NEP inhibitors disclosed in US5217996, preferably the brain neutral endopeptidase inhibitor is AHU 377. The brain neutral endopeptidase inhibitor salt is common pharmaceutically acceptable salt, such as sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, ammonium salt and the like, preferably, the salt is one of sodium salt, potassium salt and calcium salt, and the formula is AHU377 calcium salt.

The pharmaceutical composition can be obtained by physically mixing the allisartan isoproxil or the salt thereof, or the allisartan isoproxil hydrolysate or the salt of the allisartan isoproxil hydrolysate with a brain neutral endopeptidase inhibitor or the salt thereof, and can further contain pharmaceutically acceptable carriers such as a filler, a binder, a disintegrant, a lubricant and the like on the basis. The disintegrating agent, the adhesive, the filling agent and the lubricant are all common pharmaceutic adjuvants in the field. Specifically, the filler is selected from one or more of lactose, mannitol, dextrin, starch, pregelatinized starch, microcrystalline cellulose, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, etc.; the adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, polyvidone, starch slurry, gelatin, etc.; the disintegrant can be selected from one or more of croscarmellose sodium, dry starch, crospovidone, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, microcrystalline cellulose, starch, pregelatinized starch, etc.; the lubricant is selected from one or more of magnesium stearate, silica gel micropowder, talcum powder, polyethylene glycol and the like.

The pharmaceutical composition can be powder, granule, tablet, capsule, effervescent, injection and other conventional administration forms, preferably tablet and capsule.

The mass percentage of the mixture of the alisartan medoxomil or the salt thereof, or the alisartan medoxomil hydrolysate or the salt of the alisartan medoxomil hydrolysate and the brain neutral endopeptidase inhibitor or the salt thereof in the pharmaceutical composition, which is obtained by physically mixing the alisartan medoxomil or the salt thereof and the brain neutral endopeptidase inhibitor or the salt thereof, in the pharmaceutical composition, can be 1-99%, preferably 10-90%.

The pharmaceutical composition can be used for treating cardiovascular diseases such as hypertension, heart failure and the like and complications thereof, wherein the complications comprise but are not limited to damage of target organs such as heart, brain, kidney, blood vessel and the like, such as left ventricular hypertrophy, renal function damage, aorta thickening, congestive heart failure, coronary atherosclerosis, acute congestive heart failure, chronic congestive heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy and the like. Compared with the independent use of the allisartan isoproxil or the salt thereof, or the allisartan isoproxil hydrolysate or the salt of the allisartan isoproxil hydrolysate, after a certain amount of brain neutral endopeptidase inhibitor or the salt thereof is added, the pharmaceutical composition has the beneficial effects of reducing the use amount of the medicine, reducing side effects, being beneficial to large-scale production and the like, so that the pharmaceutical composition has better clinical application prospect.

Specifically, taking the heart failure indication as an example, blood pressure (including arterial pressure and left ventricular pressure) is an important index for measuring cardiac function, and represents that in pharmacodynamic research on a heart failure model of a mixture of alisartan ester and AHU377 calcium salt, when the mass ratio of alisartan ester to AHU377 calcium salt is 1: 8-8: 1, better drug synergy is shown, which is shown in that the heart weight ratio, the lung weight ratio, the mean arterial systolic pressure (mSP), the mean arterial diastolic pressure (mDP), the left ventricular pressure collection left ventricular systolic pressure (mLVSP) and the left diastolic terminal pressure (mLVDP) of corresponding tested animals in a treatment group are obviously improved compared with untreated animals, the advantages of the treatment group of the pharmaceutical composition 10, the treatment group of the pharmaceutical composition 1:10 and the treatment group of the calcium salt of U377 alone are obvious compared with the treatment group of the pharmaceutical composition 10:1, and the treatment group of the calcium salt of alisartan ester alone are not improved with the untreated animals, even as the allisartan isoproxil has the function of reducing blood pressure, mSP and mLVDP are reduced compared with untreated groups, and the aims of improving the symptoms of heart failure and increasing mSP and mLVDP are fulfilled.

The mass ratio of the allisartan isoproxil to the calcium salt of AHU377 can be any value between 1:8 and 8:1, such as 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 and 1: 8.

Furthermore, when the mass ratio of the allisartan isoproxil to the calcium salt of AHU377 is 1: 5-5: 1, the pharmaceutical composition shows better synergistic effect, and shows better heart failure symptom improvement effect on corresponding groups of tested animals. The mass ratio of the allisartan isoproxil to the calcium salt of AHU377 can be any value between 1:5 and 5:1, such as 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 and 1: 5.

In the case of hypertension, another specific indication, the pharmaceutical composition also shows drug synergy. Specifically, taking the mixture of EXP3174 and AHU377 calcium salt as an example, in the pharmacodynamic test of a rat hypertension model caused by coronary artery ligation, when the mass ratio of EXP3174 to AHU377 calcium salt is 1: 8-8: 1, a better drug synergistic effect is reflected, which is shown that the mean arterial pressure (mAP) and mean left ventricular pressure (mLVP) of the tested animals in the corresponding treatment group are obviously improved compared with the untreated animals, and the blood pressure reducing effect is obviously superior to that of the treatment group of the 10:1 pharmaceutical composition and that of the treatment group of the 1:10 pharmaceutical composition, while the adverse 10: the data of the 1 medicinal composition treatment group and the 1:10 medicinal composition treatment group are leaped with the adjacent proportion group, and the obvious improvement with the untreated group is not shown. It can be seen that: in a hypertension pharmacodynamic test with relatively short administration time, the pharmaceutical composition has a good drug synergistic effect when the mass ratio is 1: 8-8: 1.

The mass ratio of the EXP3174 to the AHU377 calcium salt can be any value between 1:8 and 8:1, such as 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 and 1: 8.

Furthermore, when the mass ratio of the EXP3174 to the AHU377 calcium salt is 1: 5-5: 1, the pharmaceutical composition shows better synergistic effect, and shows better heart failure symptom improvement effect on corresponding groups of test animals. The mass ratio of the EXP3174 to the AHU377 calcium salt can be any value between 1:5 and 5:1, such as 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 and 1: 5.

Compared with the prior art, the invention has the following advantages and beneficial effects:

compared with the existing marketed allisartan isoproxil, the pharmaceutical composition has the beneficial effects of reducing the usage amount of the drug, reducing side effects, being beneficial to large-scale production and the like, so that the pharmaceutical composition has better clinical application prospect.

Drawings

FIG. 1 shows mSP changes in various groups of test animals in pharmacodynamic studies of heart failure model

FIG. 2 mDP profiles of various groups of test animals in pharmacodynamic studies of heart failure models

FIG. 3 mLVSP variation diagram of each group of tested animals in pharmacodynamic study of heart failure model

FIG. 4 mLVDP variation of each group of test animals in pharmacodynamic study of heart failure model

FIG. 5 is a graph of mean arterial pressure (mAP) changes in groups of test animals in a pharmacodynamic study of hypertension model

FIG. 6 is a graph of mean left ventricular pressure (mLVP) changes in groups of test animals in a hypertension model pharmacodynamic study

Detailed Description

The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the invention are not limited thereto.