CN110801452B - Pharmaceutical composition containing allisartan isoproxil hydrolysate or hydrolysate salt thereof and application thereof - Google Patents
Pharmaceutical composition containing allisartan isoproxil hydrolysate or hydrolysate salt thereof and application thereof Download PDFInfo
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Abstract
Compared with the existing allisartan cilexetil on the market, the pharmaceutical composition has the beneficial effects of reducing the using amount of the medicament, reducing side effects, being beneficial to large-scale production and the like, so that the pharmaceutical composition has better clinical application prospect.
Description
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, along 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 to be taken for a long time or even for life, the development of cardiovascular disease medicines is one of the hot spots in the field of medicine 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 can be hydrolyzed into EXP3174 after entering a human body to achieve the effect of reducing blood pressure.
The Chinese patent CN200610023991.0 firstly discloses the structural formula of allisartan isoproxil 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 (angiotensin converting enzyme) inhibition effects are the key points for drug development, such as omatralat (Omapatrilat), which is considered to play an important role in treatment of cardiovascular diseases such as hypertension and heart failure, but the drugs have adverse reactions which are easy to cause angioedema, so that the application prospect of the drugs is influenced, and pure NEP inhibitors cannot be developed into drugs finally because of poor blood pressure reduction effects.
AHU377 (CAS: 149709-62-6) is a brain neutral endopeptidase inhibitor, which was first disclosed in the 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 good 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:
a pharmaceutical composition is characterized by comprising alisartan medoxomil or a salt thereof, or a hydrolysate of alisartan medoxomil or a salt thereof, 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 a combination 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, 56zxft 5623, 6262 zxft 62, 1:3, 3456, 3438 zxft 3838, 1:6, 1:7, 3498, 3476, and the like, preferably has the advantages of drug properties of the alisartan medoxoft.
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 can be a series of NEP inhibitors disclosed in US5217996, and preferably, the brain neutral endopeptidase inhibitor is AHU377. The brain neutral endopeptidase inhibitor salt is a 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 filler and the lubricant are all pharmaceutical excipients commonly used 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 a pharmacodynamic study of a mixture of alisartan ester and an AHU377 calcium salt on a heart failure model, when the mass ratio of alisartan ester and AHU377 calcium salt is 1:8-3562, better drug synergy is shown, and the results are 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 acquisition left ventricular systolic pressure (mLVSP), the left ventricular diastolic terminal pressure (mLVDP) are significantly improved compared with an untreated animal group, the advantages of the 10.
The mass ratio of the alisartan medoxomil 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, 1:1, 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 test animals. The mass ratio of the alisartan ester to the calcium salt of AHU377 can be any value between 1:5 and 5:1, such as 5:1, 4.5, 8652 zxft 322, 3.5.
In the case of hypertension, which is another specific indication, the pharmaceutical composition also shows drug synergy. Specifically, taking a mixture of EXP3174 and AHU377 calcium salt as an example, in a 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 shown, which is shown that the mean arterial pressure (mAP) and mean left ventricular pressure (mLVP) of test animals in a corresponding treatment group are significantly improved compared with those in an untreated animal group, and compared with a treatment group of a pharmaceutical composition of 10:1, 10, which presents a data leap with the adjacent ratio group, and does not show a significant improvement with the untreated group. It can be seen that: in a hypertension drug effect test with relatively short administration time, the drug composition has better drug synergy when the mass ratio is 1:8-8:1.
The mass ratio of the EXP3174 and the calcium salt 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, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 and 1:8.
Furthermore, when the mass ratio of the EXP3174 calcium salt 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 and the AHU377 calcium salt can be any value between 1:5 and 5:1, such as 5:1, 4.5, 8652 zxft 322, 3.5.
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 the change pattern of mSP in each group of test animals in the pharmacodynamic study of heart failure model
FIG. 2 mDP variation of various groups of test animals in pharmacodynamic study of heart failure model
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.
Example 1
Taking 1 kg of allisartan isoproxil and 1 kg of AHU377 calcium salt, and mixing by using a multidirectional motion mixer to obtain the pharmaceutical composition of the allisartan isoproxil and the AHU377 calcium salt with the mass ratio of 1:1.
Mixing EXP3174 kg and AHU377 calcium salt 1 kg by using a multidirectional motion mixer to obtain the pharmaceutical composition with the mass ratio of EXP3174 to AHU377 calcium salt 1:1.
The medicinal composition of each proportion can select the corresponding weight of the allisartan isoproxil or the salt thereof, or the allisartan isoproxil hydrolysate or the salt of the allisartan isoproxil hydrolysate and the brain neutral endopeptidase inhibitor or the salt thereof according to the proportion, and the medicinal composition of the allisartan isoproxil or the salt thereof, or the allisartan isoproxil hydrolysate or the salt of the allisartan isoproxil hydrolysate and the brain neutral endopeptidase inhibitor or the salt thereof in the corresponding mass ratio is obtained by mixing the components by using a multi-directional movement mixer.
Example 2
By the same method as in example 1, pharmaceutical compositions of alisartan medoxomil and AHU377 calcium salt with mass ratios of 10, 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5 and 1.
The bulk density and the flowability of the powder, the allisartan isoproxil and the AHU377 calcium salt powder in each proportion are respectively measured by adopting a tap method and a repose angle method, and the following steps are carried out:
it can be known that the mass ratio of the allisartan cilexetil to the AHU377 calcium salt is 5:1-1:5, the bulk density and the flowability of the composition powder are better in preparation performance, and experiments also find that the mass ratio of the allisartan cilexetil to the AHU377 calcium salt is consistent in the mass ratio range of 8:1-1:8, so that the composition has the beneficial effects.
Further experiments prove that the mixture of the metabolite of the allisartan isoproxil (EXP 3174) and the AHU377 has the beneficial effect consistent with the mixture of the calcium salt of the allisartan isoproxil and the AHU377 in the mass ratio of 8:1 to 1:8.
In addition, repeated experiments prove that the composition of the potassium salt, the metabolite (EXP 3174) and the sodium salt, the potassium salt and the calcium salt of the allisartan isoproxil metabolite (EXP 3174) and the sodium salt, the potassium salt and the calcium salt of AHU377 have the beneficial effects consistent with the experiments in the aspects of powder bulk density and flowability.
Example 3 (tablet)
| Components | Mass (mg/tablet) |
| Allisartan isoproxil | 80.0 |
| AHU377 calcium salt | 80.0 |
| Microcrystalline cellulose | 120.0 |
| Silica gel micropowder | 10.8 |
| Croscarmellose sodium | 20.0 |
| Magnesium stearate | 3.6 |
| Is totaled | 314.4 |
The allisartan isoproxil and the calcium salt AHU377 are mixed, then microcrystalline cellulose, croscarmellose sodium, superfine silica powder, magnesium stearate and the like are sequentially added and uniformly mixed, and the obtained powder is directly tabletted to obtain the pharmaceutical composition with the mass ratio of the allisartan isoproxil to the calcium salt AHU377 being 1:1.
Example 4 (tablet)
| Components | Mass (mg/tablet) |
| Allisartan isoproxil | 160.0 |
| AHU377 calcium salt | 80.0 |
| Microcrystalline cellulose | 80.0 |
| Lactose | 60.0 |
| Croscarmellose sodium | 15.0 |
| Magnesium stearate | 5.0 |
| Is totaled | 400.0 |
The preparation method comprises the steps of mixing allisartan isoproxil with AHU377 calcium salt, adding microcrystalline cellulose, lactose and part of magnesium stearate, uniformly mixing, granulating mixed powder by using a dry granulator, uniformly mixing obtained granules with croscarmellose sodium and magnesium stearate, and tabletting the total mixed granules to obtain the pharmaceutical composition with the mass ratio of the allisartan isoproxil to the AHU377 calcium salt of 2:1.
Example 5 (tablet)
| Components | Mass (mg/tablet) |
| Allisartan isoproxil | 80.0 |
| AHU377 calcium salt | 160.0 |
| Microcrystalline cellulose | 60.0 |
| Lactose | 60.0 |
| Cross-linked polyvidone | 10.0 |
| Talcum powder | 12.0 |
| Magnesium stearate | 3.8 |
| Is totaled | 385.8 |
The allisartan isoproxil and the calcium salt AHU377 are mixed, then microcrystalline cellulose, lactose, crospovidone, talcum powder, magnesium stearate and the like are sequentially added and uniformly mixed, and the obtained powder is directly tabletted to obtain the pharmaceutical composition of the allisartan isoproxil and the calcium salt AHU377 with the mass ratio of 1:2.
Example 6 (tablet)
| Components | Mass (mg/tablet) |
| EXP3174 | 80.0 |
| AHU377 calcium salt | 80.0 |
| Microcrystalline cellulose | 120.0 |
| Silica gel micropowder | 10.8 |
| Croscarmellose sodium | 20.0 |
| Magnesium stearate | 3.6 |
| Total up to | 314.4 |
Mixing EXP3174 and AHU377 calcium salt, sequentially adding microcrystalline cellulose, croscarmellose sodium, aerosil, magnesium stearate and the like, uniformly mixing, and directly tabletting the obtained powder to obtain the pharmaceutical composition with the mass ratio of EXP3174 to AHU377 calcium salt of 1:1.
Example 7
Pharmacodynamic study of allisartan isoproxil-AHU 377 calcium salt heart failure model
1. Experimental medicine, reagent and instrument
Molding medicine: doxorubicin (doxorubicin hydrochloride for injection);
and (3) testing a sample: allisartan isoproxil, AHU377 calcium salt;
other reagents: carboxymethyl cellulose (CMC) hydroxypropyl cellulose, sodium pentobarbital;
a detection instrument: a multi-channel physiological signal acquisition processing system;
2. laboratory animal
Male SD rats of 6 weeks of age;
3. experimental methods
Preparation before the test: dividing all animals into 16 groups according to a random grouping method, wherein each group comprises 8 animals, and adaptively feeding the animals for 1 week before test treatment;
molding adriamycin: 4mg/kg of Adriamycin (ADR) was intraperitoneally administered 1 time per week for 6 consecutive weeks for all groups; the preparation of the drug administration preparation is as follows: allisartan isoproxil was dissolved in 0.8% carboxymethylcellulose and AHU377 calcium salt was dissolved in 0.5% (w/v) hydroxypropyl cellulose aqueous solution.
Administration: beginning gavage at week 3 (i.e., two weeks after ADR injection) at a dose of 40mg/kg total dose once daily for 4 weeks; gavage the untreated group to 0.5% carboxymethylcellulose (CMC), the same dosing schedule as the treated group;
end point of experiment: after 4 weeks of dosing, animals were electrocardiogram measured the same day, arterial pressure and left ventricular pressure were measured the following day from the arterial cannula. Then CO 2 The animals were sacrificed and the heart and lungs were dissected and weighed;
4. data recording
Blood pressure (blood pressure): blood pressure including arterial pressure and left ventricular pressure were measured at the end of the experiment in animals under pentobarbital sodium anesthesia. Arterial pressure mean arterial systolic pressure (mSP) and mean arterial diastolic pressure (mDP) were collected. Left ventricular pressure acquisition left ventricular systolic pressure mLVSP (mean left ventricular systole pressure), left diastolic end pressure mlvdsp (mean left ventricular diastole pressure), each set of data is as follows:
the ratio # refers to alisartan medoxomil: mass ratio of AHU377 calcium salt
The combination of all indexes shows that the heart failure model induced by the adriamycin injection in the abdominal cavity is successfully modeled, and the mSP, mDP, mLVSP and mLVSP change graphs of all groups of tested animals in the test are respectively shown in figures 1-4;
from the obtained data, when the mass ratio of the alisartan medoxomil to the calcium salt of AHU377 is 1:8-8:1, a better drug synergistic effect is shown, the mean arterial systolic pressure (mSP), the mean arterial diastolic pressure (mDP), the left ventricular pressure acquisition left ventricular systolic pressure (mLVSP) and the left ventricular diastolic end pressure (mLVDP) of the corresponding treated group of test animals are obviously improved compared with those of untreated animals, the heart weight of the corresponding group of test animals is obviously increased compared with that of untreated groups of test animals in subsequent further tests, the lung weight is obviously reduced compared with that of untreated groups of test animals, and the heart failure symptom of the test animals is effectively improved from another angle;
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; in the case of mean systolic arterial pressure (mSP), the treatment groups with a mass ratio of the calcium salt of alisartan medoxomil to AHU377 of 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5 all exhibited an elevated pressure of at least about 10 mmHg; on the contrary, the effect of the treatment group with the pharmaceutical composition of 10;
for the treatment group using the allisartan isoproxil alone, the results show that the allisartan isoproxil does not show improvement of the untreated group, even the allisartan isoproxil has the function of reducing the blood pressure, so that mSP and mLVDP are reduced compared with the untreated group, and the aims of improving the symptoms of heart failure and increasing mSP and mLVDP are not achieved;
therefore, the allisartan isoproxil-AHU 377 calcium salt compatible 1:8-8:1 can show better drug synergistic effect, and the heart failure symptoms of the corresponding group of tested animals are obviously improved; when the alisartan medoxomil-AHU 377 calcium salt is compatible with 1:5-5:1, a relatively better medicament synergistic effect is shown, and heart failure symptoms such as the mean arterial systolic pressure (mSP), the mean arterial diastolic pressure (mDP), the left ventricular systolic pressure (mLVSP) acquired by the left ventricular pressure, the left ventricular end diastolic pressure (mLVDP) and the like of a tested animal are relatively better improved.
Further experiments prove that the mixture of the alisartan medoxomil metabolite (EXP 3174) and the AHU377 calcium salt has the heart failure resisting effect consistent with that of the mixture of the alisartan medoxomil and the AHU377 calcium salt in the mass ratio of 8:1-1:8, and the heart failure resisting effect consistent with that of the mixture of different salts can be further inferred.
Example 8
EXP3174-AHU377 calcium salt coronary artery ligation rat hypertension model pharmacodynamics research
1. Experimental medicine, reagent and instrument
And (3) testing a sample: EXP3174, AHU377 calcium salt;
2. laboratory animal
Male SD rats of 6 weeks of age;
3. experimental methods
Preparation before the test: dividing all animals into 10 groups according to a random grouping method, wherein each group comprises 6 animals, and adaptively feeding the animals for 3 days before test treatment;
the experimental process comprises the following steps: the test animals were pre-gavage for 7 days once a day with therapeutic drug. And performing operation on the eighth day, anesthetizing the animal, connecting a trachea breathing machine, connecting an electrocardiograph for real-time recording, opening the chest between the third rib and the fourth rib, ligating the left anterior descending branch of the coronary artery, raising the ST segment of the electrocardiogram to represent that the ligation is successful, closing the chest and suturing the skin.
The animals were then continued to gavage for 3 consecutive days once a day with the therapeutic agent administered. Gastrodia elata Blume 11 animals were inebriated, electrocardiographic measurements were taken, and arterial pressure and left ventricular pressure were then measured from the carotid cannula.
4. Data recording
Blood pressure (blood pressure): mean arterial pressure (mAP) and mean left ventricular pressure (mLVP), and the data for each set were as follows:
the # ratio refers to EXP3174: AHU377 calcium salt mass ratio, each group total dose the same.
The combination of all indexes shows that the model building of the rat hypertension model is successful, and the change graphs of the mean arterial pressure (mAP) and the mean left ventricular pressure (mLVP) of all groups of tested animals in the test are respectively shown in figures 5-6;
in animals subjected to coronary artery ligation and modeling, compensatory blood pressure increase occurs due to partial myocardial function impairment. It can be understood by those skilled in the art that, unlike the drug efficacy test of the animal model of heart failure, the drug efficacy test of the animal model of hypertension has a significant effect on blood pressure within a short time after administration, so that from the obtained data, when the mass ratio of EXP3174 to AHU377 calcium salt is 1:8-8:1, a good synergistic effect of blood pressure reduction is shown, which is represented by that the mean arterial pressure (mAP) and the mean left ventricular pressure (mLVP) of the corresponding treated animal group are significantly improved compared with the untreated animal group, and the weight of the corresponding animal group is also significantly increased compared with the untreated animal group in the subsequent further tests;
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; for the example of mean arterial pressure (mAP), treatment groups with calcium salt mass ratios of EXP3174 and AHU377 of 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5 all exhibited a decrease of at least about 30 mmHg; in a backstage 10;
in conclusion, when the mass ratio of the EXP3174 to the AHU377 calcium salt is 1:8-8:1, a better synergistic effect of drug blood pressure reduction can be realized, and the hypertension symptoms of corresponding groups of tested animals are obviously improved; when EXP3174-AHU377 calcium salt is compatible with 1:5-5:1, the synergistic effect of drug pressure reduction is relatively better, and the blood pressure indexes such as mean arterial pressure (mAP) and mean left ventricular pressure (mLVP) of the tested animal are relatively better improved.
Further experiments prove that the mixture of the allisartan isoproxil and the calcium salt of AHU377 has the same antihypertensive effect as the mixture of EXP3174 and the calcium salt of AHU377 in the mass ratio of 8:1-1:8, and further deduces that the mixture also has the same antihypertensive effect in the combination of different salts.
In conclusion, by combining the previous investigation on bulk density and fluidity of the alisartan medoxomil-AHU 377 calcium salt powder, the comprehensive knowledge shows that when the alisartan medoxomil or the salt thereof, or the alisartan medoxomil hydrolysate or the salt of the alisartan medoxomil hydrolysate and the AHU377 or the salt thereof are compatible between 1:8-8:1, the bulk density and the fluidity of the medicinal composition powder are moderate, relatively good preparation performance is achieved, and meanwhile, a good medicinal synergistic effect is achieved in animal pharmacodynamic tests for treating cardiovascular diseases including heart failure and hypertension, and a good development prospect is achieved.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such modifications are intended to be included in the scope of the present invention.
Claims (9)
1. The pharmaceutical composition is characterized in that the active ingredients of the pharmaceutical composition are 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 isoproxil hydrolysate is EXP3174, and the mass ratio of the allisartan isoproxil hydrolysate or the salt of the alisartan isoproxft hydrolysate to the brain-neutral endopeptidase inhibitor or the salt thereof is 5:1-1:5.
2. The pharmaceutical composition according to claim 1, wherein the mass ratio of the alisartan medoxomil hydrolysate or the salt of alisartan medoxomil hydrolysate to the brain neutral endopeptidase inhibitor or the salt thereof is 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5.
3. The pharmaceutical composition according to any one of claims 1 to 2, wherein 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.
4. The pharmaceutical composition of any of claims 1-2, wherein said AHU377 salt is selected from any of sodium, potassium, calcium, magnesium, zinc, and ammonium salts.
5. The pharmaceutical composition of 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.
6. The pharmaceutical composition of claim 5, wherein the mass ratio of EXP3174 and AHU377 calcium salt in the pharmaceutical composition is 5:1, 4.5.
7. The pharmaceutical composition of any one of claims 1-2,5-6 further comprising a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises a mixture of one or more of lactose, mannitol, dextrin, 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, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and starch; the lubricant is one or a mixture of magnesium stearate, superfine silica gel powder, talcum powder and polyethylene glycol.
8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is a powder, a granule, a tablet, a capsule, an effervescent, an injection.
9. Use of a pharmaceutical composition according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of hypertension or heart failure.
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| CN2015101090264 | 2015-03-12 | ||
| CN201510109026 | 2015-03-12 | ||
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| CN201610072768 | 2016-02-02 | ||
| CN201610140591.1A CN105963296B (en) | 2015-03-12 | 2016-03-11 | Pharmaceutical composition containing allisartan isoproxil or salt thereof or hydrolysate thereof or salt of hydrolysate thereof and application thereof |
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| CA3016258A1 (en) | 2016-01-20 | 2017-07-27 | Jie Yan | Compounds of angiotensin ii receptor antagonist metabolite and nep inhibitor, and preparation methods thereof |
| EP3611160B1 (en) * | 2017-04-28 | 2023-03-29 | Wuhan LL Science And Technology Development Co., Ltd. | Ammonium carboxylate compound, crystal form and amorphous substance thereof, and preparation method therefor |
| CN107188817A (en) * | 2017-05-22 | 2017-09-22 | 杭州瑞法康科技有限公司 | A kind of husky storehouse of high-purity is than novel crystal forms of bent half calcium salt monohydrate and preparation method thereof |
| CN107602410A (en) * | 2017-09-13 | 2018-01-19 | 浙江三门恒康制药有限公司 | Sha Ku is than crystal formation II of bent sodium salt and preparation method thereof |
| CN109833481B (en) * | 2017-11-24 | 2021-07-27 | 深圳信立泰药业股份有限公司 | Medicinal composition of allisartan isoproxil or salt thereof and diuretic |
| CN113230411B (en) * | 2017-12-04 | 2023-04-11 | 深圳信立泰药业股份有限公司 | Compound pharmaceutical composition of allisartan isoproxil or salt thereof and calcium channel antagonist |
| CN114452287B (en) * | 2019-05-30 | 2023-05-12 | 深圳信立泰药业股份有限公司 | New use of complexes of metabolites of angiotensin II receptor antagonists and NEP inhibitors |
| WO2021093697A1 (en) * | 2019-11-11 | 2021-05-20 | 深圳信立泰药业股份有限公司 | Composite of angiotensin ii receptor antagonist and nep inhibitor and preparation method therefor |
| CN116036079A (en) * | 2020-06-18 | 2023-05-02 | 深圳信立泰药业股份有限公司 | Pharmaceutical composition of compound and preparation method thereof |
| WO2022037512A1 (en) * | 2020-08-17 | 2022-02-24 | 深圳信立泰药业股份有限公司 | Use of complex of angiotensin ii receptor antagonist metabolite and nep inhibitor in treatment of heart failure |
| CN115461052B (en) * | 2020-11-25 | 2023-12-22 | 深圳信立泰药业股份有限公司 | Pharmaceutical use of complexes of ARB metabolites with NEP inhibitors for the prevention and/or treatment of kidney disease |
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| CN105963296A (en) | 2016-09-28 |
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