CN110801452A - 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 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.
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, 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.
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 with the mass ratio of the allisartan isoproxil to the AHU377 calcium salt being 1:1.
Mixing EXP 31741 kg and AHU377 calcium salt 1 kg by using a multidirectional motion mixer to obtain a pharmaceutical composition with the mass ratio of EXP3174 to AHU377 calcium salt being 1:1.
The pharmaceutical compositions of the respective proportions can be prepared by selecting corresponding weights 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 proportions, and mixing the selected weights by using a multidirectional motion mixer to obtain the pharmaceutical compositions 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 corresponding mass ratios.
Example 2
By the same method as in example 1, pharmaceutical compositions of alisartan medoxomil and AHU377 calcium salt in the mass ratios of 10:1, 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5 and 1:10 were obtained, respectively.
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:
the composition has better preparation performance in bulk density and flowability when the mass ratio of the allisartan isoproxil to the AHU377 calcium salt is 5: 1-1: 5, and experiments also find that the mass ratio of the allisartan isoproxil to the AHU377 calcium salt is in a mass ratio range of 8: 1-1: 8, and the composition has a consistent beneficial effect.
Further experiments prove that the mixture of the allisartan isoproxil metabolite (EXP3174) and the AHU377 has the beneficial effect consistent with the mixture of the allisartan isoproxil and the calcium salt of the AHU377 in the mass ratio of 8: 1-1: 8.
In addition, repeated experiments prove that the composition of the potassium salt, the metabolite (EXP3174) and the sodium salt, the potassium salt and the calcium salt of the allisartan isoproxil metabolite (EXP3174) 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 |
| Total up to | 314.4 |
The allisartan isoproxil and the calcium salt AHU377 are mixed, then microcrystalline cellulose, croscarmellose sodium, aerosil, 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 |
| Total up to | 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 being 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 |
| Total up to | 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 with the mass ratio of the allisartan isoproxil to the calcium salt AHU377 being 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 being 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 and 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 is dissolved in 0.8% carboxymethyl cellulose, and AHU377 calcium salt is 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 CO2The 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. The arterial pressure is collected as mean arterial systolic pressure mSP (mean arterial systolic pressure) and mean arterial diastolic pressure mDP (mean arterial diastolic pressure). Left ventricular pressure acquisition left ventricular systolic pressure mlvsp (mean left ventricular systole pressure), left diastolic end pressure mlvsp (mean left ventricular diastole pressure), the respective data are as follows:
the ratio # refers to alisartan medoxomil: mass ratio of AHU377 calcium salt
The comprehensive indexes show that the heart failure model induced by the intraperitoneal injection of adriamycin is successfully modeled, and mSP, mDP, mLVSP and mLVSP change graphs of all groups of tested animals in the test are respectively shown in figures 1-4;
the obtained data show that when the mass ratio of the allisartan isoproxil to the calcium salt of AHU377 is 1: 8-8: 1, a good drug synergistic effect is shown, the mean arterial systolic pressure (mSP), the mean arterial diastolic pressure (mDP) and the left ventricular pressure acquisition left ventricular systolic pressure (mLVSP) and the left ventricular end diastolic pressure (mLVDP) of the corresponding treatment group of test animals are obviously improved compared with those of untreated animal groups, the heart weight of the corresponding group of test animals is obviously increased compared with that of the untreated group of test animals and is obviously reduced compared with that of the untreated group of test animals in subsequent further tests, 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; taking mean systolic arterial pressure (mSP) as an example, the treatment groups with the mass ratio of alisartan medoxomil to AHU377 calcium salt of 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5 all showed an elevated pressure of at least about 10 mmHg; the adverse 10:1 and 1:10 pharmaceutical composition treatment groups have no obvious effect on improving the mean systolic arterial pressure, wherein the effect of the 1:10 pharmaceutical composition treatment group has no obvious advantage compared with the treatment group using the AHU377 calcium salt alone;
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 fulfilled;
the allisartan isoproxil-AHU 377 calcium salt can show better drug synergistic effect when being compatible between 1:8 and 8:1, and the heart failure symptoms of corresponding groups 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 realized, and heart failure symptoms such as mean arterial systolic pressure (mSP), mean arterial diastolic pressure (mDP), left ventricular pressure collection left ventricular systolic pressure (mLVSP), 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 allisartan isoproxil metabolite (EXP3174) and the AHU377 calcium salt has the heart failure resisting effect consistent with that of the mixture of the allisartan isoproxil 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 EXP 3174: AHU377 calcium salt mass ratio, each group total dose the same.
The comprehensive indexes show 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 each group of tested animals in the test are respectively shown in figures 5-6;
the blood pressure of the animals after coronary artery ligation and modeling is increased complementarily due to the damaged function of part of cardiac muscle. The technical personnel in the field can understand that, different from the drug effect test of an animal model of heart failure, the drug effect test of an animal hypertension model has obvious influence on blood pressure in a short time after administration, so that the obtained data shows that when the mass ratio of EXP3174 to AHU377 calcium salt is 1: 8-8: 1, a better blood pressure reduction synergistic effect is shown, the mean arterial pressure (mAP) and the mean left ventricular pressure (mLVP) of the tested animals in a corresponding treatment group are obviously improved compared with those in an untreated animal group, and the weight of the tested animals in the corresponding group is also obviously increased in a subsequent further test compared with that of the untreated animal group;
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; in the case of mean arterial pressure (mAP), the treatment groups with calcium salts of EXP3174 and AHU377 at mass ratios of 5:1, 4:1, 3:1, 2:1, 1:2, 1:3, 1:4, 1:5 all showed a decrease of at least about 30 mmHg; the adverse 10:1 and 1:10 pharmaceutical composition treatment groups have unobvious blood pressure reduction effects, and the mean arterial pressure reduction value is about 10mmHg, wherein the 10:1 pharmaceutical composition treatment group is similar to EXP3174 with the same dosage and fails to show the drug synergistic effect;
in conclusion, when the mass ratio of the EXP3174 to the AHU377 calcium salt is 1: 8-8: 1, a better medicine blood pressure reduction synergistic effect can be realized, and the hypertension symptoms of corresponding groups of tested animals are obviously improved; when the EXP3174-AHU377 calcium salt is compatible with 1: 5-5: 1, the synergistic effect of relatively better medicine pressure reduction is shown, 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 AHU377 has the same antihypertensive effect as the mixture of the calcium salts EXP3174 and AHU377 in the mass ratio of 8: 1-1: 8, and further the combination of different salts shows that the mixture has the same antihypertensive effect.
In summary, 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 in a ratio of 1: 8-8: 1, the bulk density and the fluidity of the medicinal composition powder are moderate, the medicinal composition powder has relatively good preparation performance, and simultaneously, the medicinal composition powder embodies a good medicament synergistic effect in animal pharmacodynamic tests for treating cardiovascular diseases including heart failure and hypertension, and has a good development prospect.
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 changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
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.
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| CN201510109026 | 2015-03-12 | ||
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| CN2016100727689 | 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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| WO2021254409A1 (en) * | 2020-06-18 | 2021-12-23 | 深圳信立泰药业股份有限公司 | Pharmaceutical composition of complex and preparation method therefor |
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| US11026925B2 (en) | 2016-01-20 | 2021-06-08 | Shenzhen Salubris Pharmaceuticals Co. Ltd. | Angiotensin II receptor antagonist metabolite and NEP inhibitor composite and preparation method thereof |
| WO2018196860A1 (en) * | 2017-04-28 | 2018-11-01 | 武汉朗来科技发展有限公司 | 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 |
| CN113289023B (en) * | 2017-11-24 | 2023-02-28 | 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 |
| CN113286789B (en) * | 2019-05-30 | 2022-03-11 | 深圳信立泰药业股份有限公司 | New use of compound of angiotensin II receptor antagonist metabolite and NEP inhibitor |
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| 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 |
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| CN105963296B (en) | 2020-01-21 |
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