CN113876766A - New application of compound medicinal composition of allisartan isoproxil and indapamide - Google Patents
New application of compound medicinal composition of allisartan isoproxil and indapamide Download PDFInfo
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Abstract
The invention provides a new application of a compound medicine composition of allisartan isoproxil and/or salts thereof and indapamide, namely an application in preparing a medicine for treating a hypertension patient with poor control on a single medicine of a renin-angiotensin-aldosterone system inhibitor.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a new application of a compound pharmaceutical composition of allisartan isoproxil and/or salts thereof and indapamide.
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.
Indapamide (indapamide) belongs to sulfonamides, has diuretic and calcium antagonistic effects, and is a powerful and long-acting antihypertensive drug.
In clinical practice, part of hypertension patients have poor control on the single drug effect of the allisartan isoproxil, the research adopts a DOCA-salt hypertension model with poor sensitivity to a RAAS system, the hypertension disease condition of the patients with poor clinical treatment effect on ARB/ACEi can be better reflected, the blood pressure reducing effect of a DOCA-salt hypertension rat model animal with poor curative effect on the allisartan isoproxil after the allisartan isoproxil/indapamide composition is used is investigated in the research, and meanwhile, the blood pressure reducing effects of the allisartan isoproxil/indapamide composition and the losartan/indapamide group, the losartan/hydrochlorothiazide group and the allisartan isoproxil/hydrochlorothiazide composition are compared.
Disclosure of Invention
The invention aims to provide a new application of a compound pharmaceutical composition containing an angiotensin receptor Antagonist (ARB) allisartan cilexetil or a salt thereof and a diuretic indapamide, and the new application is the application of the compound pharmaceutical composition containing the allisartan cilexetil and/or the salt thereof and the indapamide in preparing a medicine for treating a hypertension patient with poor single-drug control on a renin-angiotensin-aldosterone system inhibitor, wherein the renin-angiotensin-aldosterone system inhibitor is the allisartan cilexetil.
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 allisartan cilexetil or a pharmaceutically acceptable salt thereof and the diuretic indapamide together with a pharmaceutically acceptable carrier.
The mass ratio of the allisartan isoproxil and/or the salt thereof to the indapamide in the compound pharmaceutical composition is 1: 3-300: 1, and specifically, the mass ratio of the allisartan isoproxil and/or the salt thereof to the indapamide can be any specific value between 1: 3-300: 1, such as: 1:3, 1: 1. 1.6:1, 3.2:1, 3.3:1, 4.8:1, 9.6:1, 10:1, 16:1, 30:1, 32:1, 33:1, 48:1, 60:1, 64:1, 72:1, 80:1, 84:1, 88:1, 96:1, 100:1, 160:1, 192:1, 300:1, etc.
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.
Further, the aforesaid compound pharmaceutical composition can be divided and prepared into specific dosage units according to clinical administration dosage, for example, the aforesaid compound pharmaceutical composition can be divided and prepared into dosage units respectively containing alisartan medoxomil and/or 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, more specifically and preferably, the content of indapamide in the aforesaid dosage units can be 0.03-7.5 mg, specifically, the content can be 7.5mg, or 5mg, or 2.5mg, or 1.5mg, or 1.25mg, or 1mg, or 0.75mg, or 0.625mg, or 0.5 mg.
Further, the compound pharmaceutical composition is subpackaged according to clinical administration dosage and prepared into an administration unit with a specific specification, wherein the administration unit can contain 80mg, 120mg, 240mg of the alisartan medoxomil and/or the salt thereof (calculated by alisartan medoxomil) and 2.5mg, or 1.5mg, or 1.25mg of the indapamide.
Furthermore, when the specific content of the allisartan isoproxil and/or the salt thereof (calculated by the allisartan isoproxil) in a unit of administration of the pharmaceutical composition is 240mg, the specific content of the indapamide is 2.5mg, or 1.5mg, or 1.25 mg.
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 CN109833481A 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 can have obvious blood pressure reducing effect on a DOCA hypertension animal model with poor control on the single drug therapy of the allisartan cilexetil, and is superior to the blood pressure reducing effect of a losartan/indapamide group, a losartan/hydrochlorothiazide group and an allisartan cilexetil/hydrochlorothiazide 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
FIG. 1 is a graph of the trend of different doses of the composition of alisartan medadamide on the mean arterial pressure of a DOCA-salt hypertension model;
FIG. 2 is the area under the curve of mean arterial pressure for the DOCA-saline hypertension model for different doses of the composition of alisartan medadamide;
FIG. 3 is a graph of the trend of the effect of the composition of indapamide allisartan cilexetil on the mean arterial pressure of the DOCA-salt hypertension model compared to other compositions;
figure 4 is the product of the mean arterial pressure curve of the alxosartan cilexetil indapamide composition compared to other compositions for the DOCA-salt hypertension model.
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 cilexetil-Indapamide pharmaceutical compositions
Adding allisartan isoproxil (480g) into 0.5% CMC-Na solution, fully stirring, adding indapamide (5g), fully stirring, and fixing the volume to the required volume to obtain the compound allisartan isoproxil-indapamide pharmaceutical composition with the mass ratio of 96: 1.
The alisartan medoxomil-indapamide medicine compositions with the rest mass ratio can be prepared by the same method, such as alisartan medoxomil-indapamide medicine compositions with the mass ratio of 48:1, 160:1, 320:1 and 640: 1.
EXAMPLE 2 preparation of a pharmaceutical composition of Allisartan medoxomil Potassium-Indapamide
Adding allisartan isoproxil potassium (160g, calculated as allisartan isoproxil) into 0.5% CMC-Na solution, fully stirring, adding indapamide (1g), fully stirring, and fixing the volume to the required volume to obtain the compound allisartan isoproxil-indapamide pharmaceutical composition with the mass ratio of 160: 1.
The alisartan medoxomil potassium-indapamide medicine compositions with the rest mass ratio can be prepared by the same method, such as alisartan medoxomil potassium-indapamide medicine compositions with the mass ratios of 48:1, 320:1 and 640: 1.
EXAMPLE 3 preparation of other Allisartan ester salt-Indapamide pharmaceutical compositions
The pharmaceutical composition of the other salts of the allisartan isoproxil and the indapamide can be prepared by the same method as the embodiment 1 or 2, for example, the pharmaceutical composition of the other salts of the allisartan isoproxil and the indapamide with the mass ratio of 48:1, 96:1 and 300: 1.
EXAMPLE 4 Effect of different doses of Allisartan cilexetil/Indapamide compositions on the blood pressure of the DOCA-salt hypertension model 4.1, laboratory 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 indapamide is 640: 1. 320, and (3) respectively: 1. 160: 1. 96:1 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 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 allisartan isoproxil administration group (62 individuals), which was administered continuously for 4 weeks by gavage together with allisartan isoproxil 25mg/kg 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: all doses were calculated as alisartan medoxomil.
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 method0～24hAUC 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/indapamide 25mpk/0.039mpk group and the alisartan ester/indapamide 25mpk/0.078mpk group show certain blood pressure reduction effects, but have no significant difference compared with the alisartan ester 25mpk single medicine group; the alisartan ester/indapamide 25mpk/0.156mpk group and the alisartan ester/indapamide 25mpk/0.260mpk group both show obvious blood pressure reducing effects, and have obvious difference compared with a model group and the alisartan ester 25mpk group, and meanwhile, the alisartan ester/indapamide 25mpk/0.156mpk group and the alisartan ester/indapamide 25mpk/0.260mpk group have similar blood pressure reducing effects, which shows that the blood pressure reducing effect in the model is close to a platform, and the high-dose indapamide has clinically obvious adverse reactions (hypokalemia and cardiovascular adverse reactions), and the following experiments adopt the alisartan ester/indapamide 25mpk/0.156mpk combination for further and intensive research.
TABLE 2 results of the experiment
EXAMPLE 5 Effect of different doses of Allisartan cilexetil/Indapamide compositions on the blood pressure of the DOCA-salt hypertension model 5.1, laboratory 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 indapamide is 160:1, a compound pharmaceutical composition; the clinical dose of losartan, hydrochlorothiazide and indapamide on the market is 50mg, 12.5mg and 1.5mg respectively, and the losartan is prepared according to the conversion of daily administration doses of losartan, hydrochlorothiazide and indapamide: the mass ratio of the indapamide is 33.3: 1, losartan: the mass ratio of the hydrochlorothiazide is 4:1, allisartan: the mass ratio of the hydrochlorothiazide is 19.2: 1 of the compound medicine composition.
110 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 allisartan isoproxil administration group (80 individuals), which was administered continuously for 4 weeks by intragastric gavage with allisartan isoproxil 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, 50 animals are screened in total, random grouping is carried out according to 24h MAP, 10 animals are grouped in each group, and the conditions of each group are shown in the following table 3:
table 3: grouping and administration of drugs
Note: all doses were calculated as alisartan medoxomil.
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 method0～24hAUC 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 a model group and an alisartan medoxomil single drug group, the alisartan medoxomil/indapamide group has significant differences (P <0.001, P <0.01), which shows that the combination of the alisartan medoxomil and the indapamide can significantly control a DOCA hypertensive animal model with poor control of alisartan medoxomil single drug treatment; meanwhile, the losartan/indapamide group, the losartan/hydrochlorothiazide group and the allisartan ester/hydrochlorothiazide group also show a certain blood pressure reduction effect, but the blood pressure reduction effect is inferior to that of the allisartan ester/indapamide group.
TABLE 4 results of the experiment
| Group of | Normalized AUC (mmHg x h, mean + -SD) | Inhibition ratio (%) |
| Model set | 1274.7±174.3 | - |
| Allisartan isoproxil 25mpk | 1174.1±135.4 | 7.8 |
| Allisartan isoprox | ||
| 25 mpk/indapamide 0.156mpk | 835.4±185.5 | 34.5％ |
| Losartan 5.2 mpk/indapamide 0.156mpk | 973.4±137.1 | 23.6％ |
| Allisartan cilexetil 25 mpk/hydrochlorothiazide 1.3mpk | 969.4±138.3 | 24.9％ |
| Losartan 5.2 mpk/hydrochlorothiazide 1.3mpk | 1039.4±146.2 | 18.5％ |
Comprehensively, the compound pharmaceutical composition consisting of the alisartan medoxomil and/or the salt thereof and the indapamide can obviously control a DOCA hypertension animal model with poor control of the alisartan medoxomil single-drug therapy, has a blood pressure reducing effect superior to that of the losartan/indapamide group, the losartan/hydrochlorothiazide group and the alisartan medoxomil/hydrochlorothiazide 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) and a diuretic group (alisartan ester tablet (Xin Li Tan) 240mg and indapamide 1.5mg) and continue to be treated 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, 614 people with blood pressure not reaching the standard after 4 weeks of alisartan ester treatment are selected, and 307 people are randomly selected to be grouped into an alisartan ester + indapamide group.
The therapeutic end point is as follows:
the main curative effect indexes are as follows: the standard reaching rate of the sitting blood pressure of the alisartan medoxomil and indapamide group is 62.85% (181/288) at 12 weeks of treatment, and the details are shown in the following table 5.
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: at 8 weeks of treatment, the standard reaching rate of the sitting blood pressure of the alisartan medoxomil and indapamide group is 54.73% (162/296).
Safety endpoint:
blood routine: the number and the proportion of subjects with abnormal conventional indexes of the blood of the alxosartan medadamide group at 12 weeks of treatment are as follows: 6 cases of white blood cells (16.67%), 20 cases of red blood cells (5%), 12 cases of neutrophil percentage (8.33%), 13 cases of lymphocyte percentage (7.69%), 19 cases of platelets (15.79%), 23 cases of hemoglobin (17.39%), and 39 cases of packed cell volume (10.26%).
The routine of urine: the number and the proportion of the subjects with abnormal conventional indexes of the alrestartrate indapamide sustained-release tablet set at 12 weeks of treatment are as follows: 31 cases of urine leucocyte (22.58%), 36 cases of urine erythrocyte (19.44%), 38 cases of urine protein (31.58%), 16 cases of urine glucose (50%), 48 cases of urine albumin/creatinine (54.17%).
Blood biochemistry: the number and the proportion of the subjects with abnormal blood biochemical indexes of the alisartan medadapalene sustained-release tablet set at 12 weeks of treatment are as follows: 25 alanine aminotransferases (40%), 29 aspartate aminotransferases (37.93%), 27 total bilirubin (7.41%), 26 blood urea nitrogen (11.54%), 11 blood creatinine (36.36%), 122 uric acid (63.11%), 15 eGFR (40%), 71 total cholesterol (61.97%), 145 triglyceride (60%), 96 high density lipoprotein cholesterol (25%), 102 low density lipoprotein cholesterol (54.9%), 91 fasting plasma glucose (59.34%).
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.
Claims (7)
1. The new application of the compound pharmaceutical composition of the alisartan medoxomil and/or the salt thereof and the indapamide 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 indapamide in preparing a medicine for treating a hypertension patient with poor single-drug control over a renin-angiotensin-aldosterone system inhibitor, and the renin-angiotensin-aldosterone system inhibitor is alisartan medoxomil.
2. The new application of the compound pharmaceutical composition of the allisartan isoproxil and/or the salt thereof and the indapamide according to claim 1, characterized in that the allisartan isoproxil and/or the salt thereof in the compound pharmaceutical composition is a mixture containing the allisartan isoproxil, or containing the mixture of the allisartan isoproxil and the allisartan isoproxil in any proportion in the compound pharmaceutical composition.
3. The new application of the compound pharmaceutical composition of the allisartan isoproxil and/or the salt thereof and the indapamide according to claim 2, 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 and ammonium salt.
4. The novel application of the compound pharmaceutical composition of the alisartan ester and/or the salt thereof and the indapamide according to any one of claims 1 to 3 is characterized in that the mass ratio of the alisartan ester and/or the salt thereof to the indapamide in the compound pharmaceutical composition is 1: 3-300: 1, specifically 1:3, 1:1, 1.6:1, 3.2:1, 3.3:1, 4.8:1, 9.6:1, 10:1, 16:1, 30:1, 32:1, 33:1, 48:1, 60:1, 64:1, 72:1, 80:1, 84:1, 88:1, 96:1, 100:1, 160:1, 192:1, 300: 1.
5. The novel use of the compound pharmaceutical composition of alisartan ester and/or a salt thereof and indapamide according to any one of claims 1 to 4, characterized in that the compound pharmaceutical composition is divided into clinical administration doses and prepared into specific-sized administration units, and the administration units can contain alisartan ester and/or a 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 amount of indapamide used is 7.5mg, or 5mg, or 2.5mg, or 1.5mg, or 1.25mg, or 1mg, or 0.75mg, or 0.625mg, or 0.5 mg.
6. The new application of the compound pharmaceutical composition of the alisartan medoxomil and/or the salt thereof and the indapamide according to claim 5, is characterized in that the compound pharmaceutical composition is subpackaged according to clinical administration dosage and prepared into a specific specification of administration unit, and when the use amount (calculated as alisartan medoxomil) of the alisartan medoxomil and/or the salt thereof is 80mg, 90mg, 120mg, 160mg, 180mg, 210mg and 240mg, the use amount of the indapamide is 2.5mg, or 1.5mg, or 1.25 mg.
7. New use of a combination pharmaceutical composition of allisartan isoproxil and/or its salts with indapamide according to any of claims 1 to 6, characterised in that the allisartan isoproxil and/or its salts is allisartan isoproxil.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211512353.0A CN115737638A (en) | 2020-11-13 | 2021-11-11 | New application of compound medicinal composition of allisartan isoproxil and indapamide |
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| CN202211512353.0A Division CN115737638A (en) | 2020-11-13 | 2021-11-11 | New application of compound medicinal composition of allisartan isoproxil and indapamide |
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| CN202111334633.2A Pending CN113876766A (en) | 2020-11-13 | 2021-11-11 | New application of compound medicinal composition of allisartan isoproxil and indapamide |
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| CN109833481A (en) * | 2017-11-24 | 2019-06-04 | 深圳信立泰药业股份有限公司 | A kind of pharmaceutical composition of A Lishatan ester or its salt and diuretics |
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