阅读说明：本技术 一种阿利沙坦酯氨氯地平复方药物组合物的新应用 (New application of compound medicinal composition of allisartan isoproxil and amlodipine ) 是由 孙晶超 景小龙 肖瑛 程涛 王�琦 张雪静 吴芳 于 2021-11-11 设计创作，主要内容包括：本发明提供了一种阿利沙坦酯和/或其盐与氨氯地平和/或其盐的复方药物组合物的新应用,即在制备用于治疗对肾素-血管紧张素-醛固酮系统抑制剂单药控制不佳的高血压患者的药物中的应用。(The invention provides a new application of a compound pharmaceutical composition of allisartan isoproxil and/or salt thereof and amlodipine and/or salt thereof, namely the application in preparing a medicine for treating a hypertension patient with poor control on single medicine of a renin-angiotensin-aldosterone system inhibitor.)

1. The new application of the compound pharmaceutical composition of the alisartan medoxomil and/or the salt thereof and the amlodipine and/or the salt thereof is characterized in that the new application is the application of the compound pharmaceutical composition of the alisartan medoxomil and/or the salt thereof and the amlodipine and/or the salt thereof in preparing a medicine for treating hypertension patients with poor single-drug control of a renin-angiotensin-aldosterone system inhibitor, and the renin-angiotensin-aldosterone system inhibitor is the alisartan medoxomil.

2. The new application of the compound pharmaceutical composition of the allisartan isoproxil and/or the salt thereof and the amlodipine and/or the salt thereof according to claim 1 is characterized in that the mass ratio of the allisartan isoproxil and/or the salt thereof to the amlodipine and/or the salt thereof in the compound pharmaceutical composition is 24:1, 48:1 or 96: 1.

3. The new use of the compound pharmaceutical composition of the allisartan isoproxil and/or the salt thereof and the amlodipine and/or the salt thereof according to any one of claims 1 to 2, characterized in that the compound pharmaceutical composition of the allisartan isoproxil and/or the salt thereof is a compound pharmaceutical composition containing the allisartan isoproxil, or containing the allisartan isoproxil salt, or containing a mixture obtained by mixing the allisartan isoproxil and the allisartan isoproxil salt in any proportion.

4. The new application of the compound pharmaceutical composition of the allisartan isoproxil and/or the salt thereof and the amlodipine and/or the salt thereof according to claim 3, is characterized in that the allisartan isoproxil salt refers to a pharmaceutically acceptable salt of the allisartan isoproxil, and the pharmaceutically acceptable salt is sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, aluminum salt or ammonium salt.

5. The new use of the compound pharmaceutical composition of the alisartan ester and/or the salt thereof and the amlodipine and/or the salt thereof according to any one of claims 1 to 4, wherein the amlodipine refers to one or more of amlodipine, levamlodipine or pharmaceutically acceptable salts thereof, which are mixed in any ratio to obtain a mixture; the pharmaceutically acceptable salt is inorganic acid salt such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like, and a mixture obtained by mixing one or more than two of methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, malate, fumarate, hemifumarate, succinate, citrate, ascorbate, tartrate, trifluoroacetate and lactate according to any proportion.

6. The new use of the compound pharmaceutical composition of alisartan medoxomil and/or the salt thereof and amlodipine and/or the salt thereof according to claim 2, characterized in that the alisartan medoxomil and/or the salt thereof is alisartan medoxomil, and amlodipine and/or the salt thereof is amlodipine besylate.

7. The novel use of the compound pharmaceutical composition of alisartan ester and/or salt thereof and amlodipine and/or salt thereof according to any one of claims 1 to 6, wherein the compound pharmaceutical composition is divided into clinical administration doses and prepared into specific dosage administration units, and the dosage administration units can contain alisartan ester and/or salt thereof (calculated as alisartan ester) in an amount of 240mg, or 210mg, or 200mg, or 180mg, or 160mg, or 150mg, or 120mg, or 100mg, or 90mg, or 80mg, or 60mg, or 50mg, or 30mg, or 20mg, or 15mg, or 10 mg; the using amount of the amlodipine and/or the salt thereof (calculated by amlodipine) is 10mg, or 8mg, or 5mg, or 2.5mg, or 1.25mg, or 1mg, or 0.5 mg.

8. The new application of the compound pharmaceutical composition of the alisartan ester and/or the salt thereof and the amlodipine and/or the salt thereof according to claim 7, wherein the amlodipine and/or the salt thereof is amlodipine besylate, and the quality of the amlodipine besylate is calculated by amlodipine.

9. The novel use of the compound pharmaceutical composition of alisartan ester and/or salt thereof and amlodipine and/or salt thereof according to claim 8, wherein the compound pharmaceutical composition is divided and prepared into specific dosage units according to clinical administration dosage, the alisartan ester and/or salt thereof is alisartan ester, the dosage units can contain 80mg, 90mg, 120mg, 160mg, 180mg, 210mg and 240mg of the alisartan ester, the amlodipine besylate is used in 2.5mg, 5mg and 10mg, and the amlodipine besylate is used in amlodipine.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a new application of a compound pharmaceutical composition of alisartan medoxomil and/or salt thereof and amlodipine and/or salt thereof.

Background

At present, the estimated number of hypertension patients worldwide is l0 hundred million, the hypertension can cause the damage of organs such as heart, brain, kidney and the like of the patients, and has close relation with sugar, lipid metabolism disorder and diabetes, thereby obviously reducing the life quality of the patients and even endangering the life in severe cases. There are six general categories of therapeutic agents for hypertension: beta receptor blockers, angiotensin ii receptor Antagonists (ARBs), Angiotensin Converting Enzyme Inhibitors (ACEi), diuretics, calcium channel antagonists (CCBs), peripheral vasodilators, wherein both angiotensin ii receptor antagonists and angiotensin converting enzyme inhibitors are renin-angiotensin-aldosterone system (RASS) inhibitors. However, the current treatment of hypertension is in the bottleneck period that 60% of patients are not controlled by single medicine, and under the condition, the simultaneous use of two or more antihypertensive medicines has the requirements and values, so the research on the combined application of the antihypertensive medicines increasingly draws more attention to the medical field at home and abroad.

Angiotensin II produces a vasoconstrictive effect through its action on striatless smooth muscle cells, stimulating the formation of the adrenergic hormones epinephrine and norepinephrine, and an increase in sympathetic nervous system activity due to the production of norepinephrine. Angiotensin II also has an effect on electrolyte balance, for example in the kidneys to produce anti-natriuretic and antidiuretic effects and thereby on the one hand promotes the release of vasopressin peptides from the pituitary gland and on the other hand promotes the release of aldosterone from the adrenal glomeruli. All these effects play an important role in regulating blood pressure, increasing circulation volume and peripheral resistance. Angiotensin II is also involved in cell growth and migration and extracellular matrix formation. Allisartan isoproxil (CAS: 947331-05-7), chemical name: 2-butyl-4-chloro-1- [2 '- (1H-tetrazol-5-yl) -1, 1' -biphenyl-methyl ] -imidazole-5-carboxylic acid, 1- [ (isopropoxy) -carbonyloxy ] -methyl ester, trade name: xinritan is a novel angiotensin II receptor antagonist. Chinese patent CN200680000397.8 discloses the structural formula of an allisartan isoproxil compound, the allisartan isoproxil has low toxicity and the blood pressure reducing effect is better than that of the same type of products (such as losartan), and the allisartan isoproxil compound generates an active metabolite (EXP3174) through metabolism in vivo so as to play the role of reducing the blood pressure.

Amlodipine (amlodipine), the benzenesulfonate of which is commonly used, i.e., amlodipine besylate, belongs to a Calcium Channel Blocker (CCB) and exerts an antihypertensive effect mainly by blocking calcium channels outside cardiac muscle and vascular smooth muscle cells.

In clinical practice, part of hypertension patients have poor control on the single drug effect of the alisartan medoxomil, the condition of hypertension diseases of patients with poor clinical treatment effect on ARB/ACEi can be better reflected due to the fact that a DOCA-saline hypertension model has poor sensitivity on an RAAS system in the research, the blood pressure reducing effect of a DOCA-saline hypertension rat model animal with poor curative effect on the alisartan medoxomil after the alisartan medoxomil/amlodipine composition is used is investigated in the research, and meanwhile, the blood pressure reducing effect of the alisartan medoxomil/amlodipine composition and the valsartan/amlodipine composition is compared.

Disclosure of Invention

The invention aims to provide a new application of a compound pharmaceutical composition containing an angiotensin receptor Antagonist (ARB) alisartan medoxomil or a salt thereof and a calcium channel antagonist (CCB) amlodipine or a salt thereof, and the new application is the application of the compound pharmaceutical composition containing the alisartan medoxomil and/or the salt thereof and amlodipine and/or the salt thereof in preparing a medicine for treating hypertension patients with poor single-drug control on a renin-angiotensin-aldosterone system inhibitor, wherein the renin-angiotensin-aldosterone system inhibitor is alisartan medoxomil.

Another aspect of the invention is to provide a method of treating a hypertensive patient with poor monotherapy of alisartan medoxomil, which may be further accompanied by conditions such as heart failure, angina pectoris, diabetes, hypertension in, for example, diabetic patients, diabetic nephropathy, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, and renovascular hypertension. The method comprises administering to a hypertensive patient in need of such treatment a therapeutically effective amount of a combination of the angiotensin receptor antagonist alisartan ester or a pharmaceutically acceptable salt thereof and the ion channel antagonist amlodipine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The mass ratio of the allisartan isoproxil and/or the salt thereof to the amlodipine and/or the salt thereof in the compound pharmaceutical composition is 24:1, 48:1 or 96: 1.

The allisartan isoproxil and/or the salt thereof in the compound pharmaceutical composition refers to a mixture obtained by mixing the allisartan isoproxil, the allisartan isoproxil or the allisartan isoproxil with the compound pharmaceutical composition in any proportion; the aforementioned allisartan isoproxil salt refers to pharmaceutically acceptable salts of allisartan isoproxil including, but not limited to, sodium, potassium, calcium, magnesium, zinc, aluminum, ammonium salts and the like; the mass of the allisartan isoproxil and/or the salt thereof described in the present invention is calculated as allisartan isoproxil, unless otherwise specified.

The amlodipine in the compound pharmaceutical composition is amlodipine, levamlodipine or a mixture obtained by mixing one or more than two of pharmaceutically acceptable salts of amlodipine and levamlodipine in any proportion; the pharmaceutically acceptable salt includes but is not limited to inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like, and a mixture obtained by mixing one or more than two organic acid salts such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, malate, fumarate, hemifumarate, succinate, citrate, ascorbate, tartrate, trifluoroacetate, lactate and the like in any proportion; the pharmaceutically acceptable salt is preferably a benzene sulfonate, and the mass of the amlodipine, the levamlodipine or the pharmaceutically acceptable salt of the amlodipine and the levamlodipine is calculated by the amlodipine unless particularly specified.

In a preferred example of the aforementioned technical solution, the alisartan ester and/or the salt thereof is alisartan ester, and the amlodipine and/or the salt thereof is amlodipine besylate.

In a preferred example of the foregoing technical solution, the compound pharmaceutical composition is a combination of alisartan medoxomil and amlodipine racemate or levorotatory benzenesulfonate, and the mass ratio thereof is 24:1, 48:1 or 96: 1; further, the combination of the alisartan medoxomil and the amlodipine besylate is preferably 24:1, 48:1 or 96:1 in mass ratio, and the quality of the amlodipine besylate is calculated by amlodipine.

Further, the aforementioned compound pharmaceutical composition may be dispensed according to a clinical administration dose and prepared into an administration unit of a specific specification, for example, the aforementioned compound pharmaceutical composition may be dispensed and prepared into an administration unit containing alisartan medoxomil and/or a salt thereof 240mg, or 210mg, or 200mg, or 180mg, or 160mg, or 150mg, or 120mg, or 100mg, or 90mg, or 80mg, or 60mg, or 50mg, or 30mg, or 20mg, or 15mg, or 10mg, respectively, more specifically and preferably, when the amlodipine is amlodipine besylate, the content of amlodipine besylate (calculated as amlodipine) in the aforementioned administration unit may be 0.02 to 10mg, and specifically may be: 10mg, or 8mg, or 5mg, or 2.5mg, or 1.25mg, or 1mg, or 0.5mg, etc.

Further, when the specific content of the alisartan medoxomil and/or the salt thereof (calculated by alisartan medoxomil) in the administration unit of the compound pharmaceutical composition is 240mg, the specific content of the amlodipine besylate is as follows: 10mg, or 5mg, or 2.5mg, wherein the amlodipine besylate is used in an amount of amlodipine.

The compound pharmaceutical composition is a solid preparation suitable for oral administration, preferably an oral tablet or capsule, and the total amount of the medicines of a plurality of tablets and a plurality of capsules is 60mg to 300 mg.

The compound pharmaceutical composition can be obtained by the methods known in the prior art, wherein the composition disclosed in CN109865139A and the preparation method thereof are introduced into the invention.

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

1. the compound medicine composition containing the angiotensin receptor Antagonist (ARB) allisartan cilexetil or the salt thereof and the calcium channel antagonist (CCB) amlodipine or the salt thereof is applied to preparing the medicine for treating the hypertension patient with poor curative effect on the allisartan cilexetil single drug, has obvious blood pressure reducing effect on a DOCA hypertension animal model with poor control on the allisartan cilexetil single drug treatment, and is superior to the blood pressure reducing effect of a losartan/amlodipine group and a valsartan/amlodipine group;

2. the statistics of clinical efficacy shows that the compound medicine composition of the invention has obvious blood pressure reducing effect when being used for treating hypertension patients with poor control of the single drug therapy of the allisartan isoproxil.

Drawings

Figure 1 is a graph of the trend of different doses of the alisartan ester/amlodipine besylate composition on mean arterial pressure of a DOCA-salt hypertension model;

FIG. 2 is a comparison of the area under the mean arterial pressure curves for the DOCA-saline hypertension model for different doses of the composition of alisartan medoxomil/amlodipine besylate;

figure 3 is a graph of the trend of the effect of the alisartan ester/amlodipine composition on the mean arterial pressure of the DOCA-salt hypertension model compared to other compositions;

figure 4 is a comparison of the area under the mean arterial pressure curve for the DOCA-salt hypertension model for the alisartan ester/amlodipine composition compared to other compositions.

Detailed Description

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

Example 1 preparation of Allisartan medoxomil amlodipine besylate Compound pharmaceutical composition

Adding allisartan isoproxil (120g) into a 0.5% CMCNa solution, fully stirring, adding amlodipine besylate (5g, calculated as amlodipine), fully stirring, and fixing the volume to the required volume to obtain the compound medicinal composition of the allisartan isoproxil-amlodipine besylate with the mass ratio of 24: 1.

The compound medicinal composition of the allisartan isoproxil-amlodipine besylate with the rest mass ratio, such as the compound medicinal composition of the allisartan isoproxil besylate with the mass ratio of 48:1, 96:1 and 192:1, can be prepared by adopting the same method.

Example 2 preparation of Allisartan medoxomil Potassium-amlodipine besylate Compound pharmaceutical composition

Adding allisartan isoproxil potassium (240g in terms of allisartan isoproxil) into a 0.5% CMCNa solution, fully stirring, adding amlodipine besylate (5g in terms of amlodipine), fully stirring, and fixing the volume to the required volume to obtain the compound pharmaceutical composition of the allisartan isoproxil potassium-amlodipine besylate with the mass ratio of 48: 1.

The compound medicinal composition of the alisartan medoxomil potassium-amlodipine besylate with the rest mass ratio can be prepared by adopting the same method, such as the alisartan medoxomil potassium-amlodipine besylate compound medicinal composition with the mass ratio of 24:1, 96:1 and 192: 1.

Example 3 preparation of Compound pharmaceutical composition of other Allisartan medoxomil salts

The compound pharmaceutical composition of the other salts of the alisartan medoxomil and the other salts of the amlodipine can be prepared by the same method as the embodiment 1 or 2, for example, the compound pharmaceutical composition of the other salts of the alisartan medoxomil and the other salts of the amlodipine with the mass ratio of 24:1, 48:1, 96:1 and 192: 1.

Example 4 Effect of different doses of Allisartan medoxomil/amlodipine besylate compositions on blood pressure in the DOCA-saline hypertension model

4.1 Experimental animals and instruments

Male SD rats, clean grade, weight 180-220 g, provided by Beijing Wittingle animal center. A Medlab biosignal collection and processing system, Nanjing Meiyi technology Ltd; a biological blood pressure sensor, model PT-100, Gendtis Union technologies, Inc.

4.2, making a mold

Alisartan ester was prepared according to the method of example 1 or 2, respectively: the mass ratio of the amlodipine besylate (calculated as amlodipine) is 192: 1. 96: 1. 48: 1. 24:1 of the compound medicine composition.

80 male SD rats were taken and animals were surgically implanted with hypertensive implants. Nursing for 7 days after operation, and performing operation modeling after the wound is basically healed. The rat is weighed and then is subjected to intraperitoneal injection of pentobarbital sodium for anesthesia, then hair is cut in a back operation area, the rat is fixed on an operation plate in a prone position, an incision with the length of about 2cm is made at the left side of the spinal column and the lower edge of the twelfth rib after strict disinfection, muscles are separated, the kidney envelope is dissociated, the left kidney is exposed, the renal artery and vein are tied closely to the renal hilum, the left kidney is cut off, and the muscle layer and the skin are sutured after blood stasis is removed. Penicillin sodium was given intraperitoneally for 5 days after surgery, and the surgically alive rats were divided into three groups 1 week later: one group was sham-operated control group (8), injected with vegetable oil subcutaneously, drunk water normally, and administered with vehicle by intragastric administration every day; one group was model group (8), DOCA oil solution was injected once per week subcutaneously, drinking water contained 1% NaCl and 2% KCl, and molding was continued for 4 weeks; one group was an alisartan medoxomil administration group (54 individuals), which was administered by gavage with alisartan medoxomil at 25mg/kg for 4 weeks while DOCA-high salt molding was performed.

4.3 grouping and administration

Animals are monitored for 24 hours of blood pressure and heart rate through a DSI remote measuring system, animals which are screened for 24h MAP (mean arterial pressure) and model group mean value +/-5 mmHg in an allisartan cilexetil administration group after 4 weeks of model administration are considered as model animals with poor curative effect, 40 animals are screened in total, random grouping is carried out according to 24h MAP, each group comprises 8 animals, and the conditions of each group are shown in the following table 1:

table 1: grouping and administration of drugs

Note: amlodipine besylate was used on average as amlodipine in the table, and the dosages administered were all in terms of amlodipine.

The administration was performed once a day, and the Mean Arterial Pressure (MAP) at 24 hours on the 14 th day of the administration was observed after two weeks of continuous administration, and the area under the curve AUC was calculated by the trapezoidal method_0～24hAUC was calculated by normalization processing with the sham surgical group data and inhibition (%) was calculated.

4.4 Experimental results and conclusions

The experimental results are shown in the following table 2 and fig. 1-2, after the pseudo-surgery group data is standardized, the alisartan medoxomil 25mpk group has no obvious blood pressure reduction effect compared with a model group, and the model can simulate the symptoms of clinical hypertension patients with poor efficacy of alisartan medoxomil. The alisartan ester/amlodipine 25mpk/0.13mpk group and the alisartan ester/amlodipine 25mpk/0.26mpk group show certain blood pressure reduction effects, but have no significant difference compared with the alisartan ester 25mpk single drug group; the alisartan ester/amlodipine 25mpk/0.52mpk group and the alisartan ester/amlodipine 25mpk/1.04mpk group both show obvious blood pressure reducing effects, and have obvious difference compared with the model group and the alisartan ester 25mpk group, and meanwhile, the alisartan ester/amlodipine 25mpk/0.52mpk group and the alisartan ester/amlodipine 25mpk/1.04mpk group have similar blood pressure reducing effects, which shows that the blood pressure reducing effects in the model are close to a platform, and the alisartan ester/amlodipine 25mpk/1.04mpk group has more obvious clinical adverse reactions (gastrointestinal adverse reactions and edema) in consideration of high-dose amlodipine, and the subsequent experiments adopt the alisartan ester/amlodipine 25mpk/0.52mpk combination for further and deeply research.

TABLE 2 results of the experiment

Note: amlodipine besylate was used on average as amlodipine in the table, and the dosages administered were all in terms of amlodipine.

Example 5 Effect of different doses of Allisartan medoxomil/amlodipine besylate compositions on blood pressure in the DOCA-saline hypertension model

5.1 Experimental animals and instruments

Male SD rats, clean grade, weight 180-220 g, provided by Beijing Wittingle animal center. A Medlab biosignal collection and processing system, Nanjing Meiyi technology Ltd; a biological blood pressure sensor, model PT-100, Gendtis Union technologies, Inc.

5.2, molding

Alisartan ester was prepared according to the method of example 1 or 2, respectively: the mass ratio of the amlodipine besylate (calculated as amlodipine) is 48:1, a compound pharmaceutical composition; the clinical dose of losartan serving as a medicine on the market is 50mg, the clinical dose of valsartan/amlodipine compound preparation serving as a medicine on the market is 80mg/5mg, and the losartan is prepared according to the daily administration dose conversion of the losartan and the valsartan: the mass ratio of the amlodipine besylate (calculated as amlodipine) is 10: 1, valsartan: the mass ratio of the amlodipine besylate (calculated as amlodipine) is 16: 1 of the compound medicine composition.

90 male SD rats were taken and animals were surgically implanted with hypertensive implants. Nursing for 7 days after operation, and performing operation modeling after the wound is basically healed. The rat is weighed and then is subjected to intraperitoneal injection of pentobarbital sodium for anesthesia, then hair is cut in a back operation area, the rat is fixed on an operation plate in a prone position, an incision with the length of about 2cm is made at the left side of the spinal column and the lower edge of the twelfth rib after strict disinfection, muscles are separated, the kidney envelope is dissociated, the left kidney is exposed, the renal artery and vein are tied closely to the renal hilum, the left kidney is cut off, and the muscle layer and the skin are sutured after blood stasis is removed. Penicillin sodium was given intraperitoneally for 5 days after surgery, and the surgically alive rats were divided into three groups 1 week later: one group was sham-operated control group (8), injected with vegetable oil subcutaneously, drunk water normally, and administered with vehicle by intragastric administration every day; one group was a model group (10), DOCA oil was injected once per week subcutaneously, drinking water contained 1% NaCl and 2% KCl, and molding was continued for 4 weeks; one group was an alisartan medoxomil administration group (58 individuals), which was administered continuously for 4 weeks by gavage together with the alisartan medoxomil at 25mg/kg while DOCA-high salt molding was performed.

5.3 grouping and administration

Animals are monitored for 24 hours of blood pressure and heart rate through a DSI remote measuring system, animals which are screened for 24h MAP (mean arterial pressure) and model group mean value +/-5 mmHg in an allisartan cilexetil administration group after 4 weeks of model administration are considered as model animals with poor curative effect, 40 animals are screened in total, random grouping is carried out according to 24h MAP, each group comprises 8 animals, and the conditions of each group are shown in the following table 3:

table 3: grouping and administration of drugs

Note: amlodipine besylate was used on average as amlodipine in the table, and the dosages administered were all in terms of amlodipine.

The administration was performed once a day, and the Mean Arterial Pressure (MAP) at 24 hours on the 14 th day of the administration was observed after two weeks of continuous administration, and the area under the curve AUC was calculated by the trapezoidal method_0～24hAUC was calculated by normalization processing with the sham surgical group data and inhibition (%) was calculated.

5.4 Experimental results and conclusions

The experimental results are shown in the following table 4 and fig. 3-4, after the pseudo-surgery group data is standardized, the alisartan medoxomil 25mg/kg group has no obvious blood pressure reduction effect compared with the model group, and the model can simulate the symptoms of clinical hypertension patients with poor efficacy of alisartan medoxomil. Compared with the model group and the alisartan ester monotherapy group, the alisartan ester/amlodipine group has significant differences (P <0.001, P <0.01), which shows that the model group and the alisartan ester monotherapy group can significantly control a DOCA hypertension animal model with poor control after the alisartan ester amlodipine composition is used; meanwhile, the losartan/amlodipine group and the valsartan/amlodipine group also show a certain blood pressure reduction effect, but the blood pressure reduction effect is inferior to that of the allisartan cilexetil/amlodipine group.

TABLE 4 results of the experiment

Group of	Normalized AUC (mmHg x h, mean + -SD))	Inhibition ratio (%)
			Model set	1245.4±177.1	-
Allisartan isoproxil 25mpk	1167.8±175.6	6.3％
			Allisartan cilexetil 25 mpk/amlodipine 0.52mpk	799.2±185.5	35.9％
Valsartan 8.3 mpk/amlodipine 0.52mpk	927.4±138.3	25.5％
			Losartan 5.2 mpk/amlodipine 0.52mpk	1010.3±166.9	19.9％

Note: amlodipine besylate was used on average as amlodipine in the table, and the dosages administered were all in terms of amlodipine.

Comprehensively, the compound pharmaceutical composition consisting of the alisartan medoxomil and/or the salt thereof and the amlodipine and/or the salt thereof can obviously control a DOCA hypertension animal model with poor control of the alisartan medoxomil monotherapy, is superior to the antihypertensive effect of the losartan/amlodipine group and the valsartan/amlodipine group, and has a considerable patent medicine prospect.

Example 6 clinical pharmacodynamic test

The test is a multicenter, prospective, open phase IV clinical test.

The study was carried out in two stages:

the first stage is as follows: all patients were subjected to a 2-week placebo washout period (only 1 week placebo for naive patients), after which eligible patients were subjected to oral treatment with alisartan ester 240mg once daily for 4 weeks (placebo: tablet, specification 240 mg/tablet, manufactured and supplied by Shenzhen Xinritai pharmaceutical Co., Ltd., lot: 151101BL, DHA20160301, DHA17002, DHA 17003B).

And a second stage: treating with 240mg of allisartan isoproxil (Xin Li Tan) single drug for 4 weeks, and continuing the original dose treatment for 8 weeks if the blood pressure reaches the standard (the standard reaches SBP <140mmHg and DBP <90 mmHg); if the blood pressure is not up to the standard, the subjects are randomly divided into an alisartan ester tablet (Xin Li Tan) + calcium antagonist group (alisartan ester tablet (Xin Li Tan) 240mg + amlodipine besylate (calculated as amlodipine)) and continue to perform the treatment for 8 weeks.

In the clinical test process, 2874 subjects are screened by 44 research centers, 662 subjects are failed in screening and are grouped into 2212, 2015 subjects (91.09) in a 12-week treatment period are completed, 197 subjects (8.91) are not completed, the number of people with substandard blood pressure after the alisartan ester is treated for 4 weeks is 614, and 307 subjects are randomly selected to be grouped into an alisartan ester + amlodipine besylate group.

The therapeutic end point is as follows:

the main curative effect indexes are as follows: at 12 weeks of treatment, the achievement rate of the sitting blood pressure of the alisartan ester + amlodipine besylate group was 57.68% (169/293), as detailed in table 5 below.

TABLE 5 treatment of seat blood pressure achievement Rate at 12 weeks (FAS)

Note: the standard reaching means that the SBP/DBP of the sitting position is less than 140mmHg/90 mmHg; effective means that sitting blood pressure is normal (systolic/diastolic <140/90mmHg), or a reduction in systolic pressure of greater than 20mmHg, and/or a reduction in diastolic pressure of greater than 10 mmHg.

Secondary efficacy index: the standard reaching rate of the sitting blood pressure of the alisartan medoxomil and amlodipine besylate group is 57.38% (171/298).

Safety endpoint:

blood routine: the number and the proportion of subjects with clinical significance for the abnormal conventional index of the amlodipine besylate group blood at the treatment period of 12 weeks are as follows: 18 cases of white blood cells (11.11%), 23 cases of red blood cells (0%), 9 cases of neutrophil percentage (11.11%), 17 cases of lymphocyte percentage (5.88%), 12 cases of platelets (8.33%), 28 cases of hemoglobin (17.86%), 48 cases of packed red blood cells (10.42%).

The routine of urine: the number and the proportion of subjects with clinical significance for abnormal conventional index of amlodipine besylate in the group urine at 12 weeks of treatment are as follows: 33 cases of urine leucocyte (27.27%), 43 cases of urine erythrocyte (23.26%), 47 cases of urine protein (36.17%), 12 cases of urine glucose (58.33%), 52 cases of urine albumin/creatinine (51.92%).

Blood biochemistry: the number and the proportion of subjects with clinical significance for the abnormal blood biochemical index of the amlodipine besylate group at 12 weeks of treatment are as follows: 41 (34.15) alanine aminotransferase, 32 (28.13) aspartate aminotransferase, 29 total bilirubin (6.9), 19 blood urea nitrogen (15.79), 16 blood creatinine (25), 71 uric acid (45.07), 16 eGFR (31.25), 86 total cholesterol (66.28), 135 triglyceride (61.48), 83 high density lipoprotein cholesterol (19.28), 111 low density lipoprotein cholesterol (57.66) and 88 fasting blood glucose (63.64).

The statistics of the drug effect of the clinical tests show that the compound drug composition of the invention has a remarkable antihypertensive effect when being used for treating hypertension patients with poor control of the single drug therapy of the allisartan isoproxil.

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.