A compound pharmaceutical composition of allisartan medoxomil or its salt and pitavastatin or its salt

Abstract

The present invention provides a pharmaceutically promising combination of allisartan medoxomil and / or its salt and pitavastatin and / or its salt. The pharmaceutical composition can inhibit myocardial cell apoptosis and reduce the incidence of cardiovascular events.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular, the present invention relates to a compound pharmaceutical composition of allisartan medoxomil and / or its salt and pitavastatin and / or its salt. Background Art

[0002] Alisartan medoxomil (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-[(isopropyloxy)-carbonyloxy]-methyl ester, trade name: Xinlitan, is a novel angiotensin II receptor antagonist. The structural formula of the compound, disclosed in Chinese patent CN200680000397.8, is known to exhibit low toxicity and superior antihypertensive efficacy compared to similar products (such as losartan). This antihypertensive effect is achieved through metabolism in the body to produce an active metabolite (EXP3174).

[0003]

[0004] Pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, reduces mevalonate synthesis, thereby lowering cholesterol synthesis. Pitavastatin primarily acts on the liver, inhibiting hepatic cholesterol synthesis and reducing cholesterol concentrations in hepatocytes. It also promotes concentration-dependent upregulation of low-density lipoprotein (LDL) receptor density and activity, accelerating LDL catabolism. It also reduces very-low-density lipoprotein (VLDL) synthesis, decreasing the conversion of VLDL to LDL, and thus lowering plasma low-density lipoprotein cholesterol (LDL-C). Pitavastatin has a comprehensive effect on the lipid profile. In addition to significantly lowering LDL-C and total cholesterol (TC), it also reduces triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C). It also promotes the regression of coronary atherosclerotic plaques.

[0005] Vascular calcification is a significant risk factor for cardiovascular events. It is prevalent in conditions such as hypertension, atherosclerosis, diabetic vasculopathy, and chronic kidney disease, with an increasing incidence and association with numerous adverse events. Vascular smooth muscle cells (VSMCs) play a crucial role in vascular calcification, primarily by differentiating into osteoblasts and producing matrix vesicles that deposit calcium phosphate in the vessel wall. Reports suggest that Pi-induced apoptosis of human VSMCs plays a crucial role in vascular calcification.

[0006] Chinese patent CN106727580A discloses an allisartan medoxomil / rosuvastatin compound preparation, which is suitable for treating patients with cardiovascular diseases and improving patient compliance.

[0007] Literature: Effects of Alisartan medoxomil combined with pitavastatin calcium on vascular endothelial function, left ventricular hypertrophy and diastolic function in patients with essential hypertension, Xu Jing, Chen Min, He Wanzhen, et al., Chinese Modern Doctor, 2015, 53(9); This literature discloses that Alisartan medoxomil (10-20) mg / d combined with pitavastatin (1-2) mg / d has a definite antihypertensive effect, can significantly improve vascular endothelial function, and has a synergistic effect on reversing left ventricular hypertrophy and improving diastolic function in patients with essential hypertension.

[0008] Xu J, Lü XW, Huang Y, Zhu PL, & Li J. (2009). Simvastatin, losartan, angiotensin, cardiomyocyte, apoptosis. Journal of Pharmacy & Pharmacology, 61(61), 503-510. This paper discloses a study demonstrating that losartan and simvastatin can prevent Ang II-induced apoptosis in neonatal cardiomyocytes. The combination of losartan and simvastatin can significantly reduce Ang II-induced cardiomyocyte apoptosis and increase cell viability.

[0009] Reference: Katsuya I, Yuki I, Bo-Kyung S, et al. Pravastatin and Olmesartan Synergistically Ameliorate Renal Failure-Induced Vascular Calcification[J]. Journal of Atherosclerosis & Thrombosis, 2014, 21(9): 917-929; This reference discloses a study evaluating the direct effects of Olmesartan (100 μM) and Pravastatin (50 μM) alone or in combination on VSMC calcification in an in vitro model. Olmesartan alone partially inhibited Pi-induced apoptosis and subsequent calcification, while the combination had a significant synergistic inhibitory effect.

[0010] Chinese patent CN101822837A discloses a pharmaceutical composition of alisartan medoxomil or its salt and an HMG-CoA reductase inhibitor, and discloses that the HMG-CoA reductase inhibitor can be atorvastatin, rosuvastatin, simvastatin, pitavastatin, fluvastatin, pravastatin, or lovastatin, and discloses that the dosage of alisartan medoxomil and its salt is 5 mg to 800 mg / person / day, more preferably 5 mg to 300 mg / person / day. However, the patent does not disclose the dosage of HMG-CoA reductase inhibitor. Similarly, Chinese patents CN101822836A and CN101822667A also disclose pharmaceutical compositions of allisartan medoxomil or its salts and HMG-CoA reductase inhibitors, and disclose the dosage of allisartan medoxomil and its salts, but similarly do not disclose the dosage of the HMG-CoA reductase inhibitor, as well as the ratio range, optimal ratio and relevant experimental data that can achieve relevant synergistic effects.

[0011] We unexpectedly discovered that the compound pharmaceutical composition of allisartan medoxomil and / or its salts and pitavastatin and / or its salts has a synergistic effect in reducing vascular calcification. This synergistic effect appears to be due to the synergistic inhibition of apoptosis of vascular smooth muscle cells, which led to the completion of the present invention. Summary of the Invention

[0012] The purpose of the present invention is to provide a combination of angiotensin receptor antagonist (ARB) alisartan medoxomil or its salt and pitavastatin and / or its salt with pharmaceutical prospects. This combination can synergistically inhibit the apoptosis of vascular smooth muscle cells, which is beneficial for reducing vascular calcification and reducing the risk of cardiovascular disease.

[0013] The above objectives of the present invention are achieved through the following technical solutions:

[0014] A compound pharmaceutical composition, comprising allisartan medoxomil and / or its salt and pitavastatin and / or its salt, characterized in that the mass ratio of allisartan medoxomil and / or its salt to pitavastatin and / or its salt is 40 to 300:1.

[0015] The aforementioned allisartan medoxomil and / or its salt refers to the compound pharmaceutical composition containing allisartan medoxomil, or containing allisartan medoxomil salt, or containing the mixture of allisartan medoxomil and allisartan medoxomil salt in any proportion; the aforementioned allisartan medoxomil salt refers to the pharmaceutically acceptable salt of allisartan medoxomil, and the pharmaceutically acceptable salt includes but is not limited to sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, aluminum salt, ammonium salt, etc.; unless otherwise specified, the mass of allisartan medoxomil and / or its salt described in the present invention is calculated based on allisartan medoxomil.

[0016] The aforementioned pitavastatin and / or its salt refers to a compound pharmaceutical composition containing pitavastatin, or containing a pitavastatin salt, or containing a mixture of pitavastatin and a pitavastatin salt in any proportion; the aforementioned pitavastatin salt refers to a pharmaceutically acceptable salt of pitavastatin, and the pharmaceutically acceptable salt includes but is not limited to sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, aluminum salt, ammonium salt, etc., preferably calcium salt. Unless otherwise specified, the mass of pitavastatin described in the present invention is calculated as pitavastatin calcium.

[0017] A preferred example of the above technical solution is that the pharmaceutical composition is a combination of allisartan medoxomil and / or its salt and pitavastatin and / or its salt, and the mass ratio thereof is 40 to 300:1; further preferred is a combination of allisartan medoxomil and / or its salt and pitavastatin and / or its salt, and the mass ratio thereof is 60 to 240:1. Specifically, in in vitro pharmacodynamics studies, when the mass ratio of allisartan medoxomil to pitavastatin is within the dose ratio range of 40 to 300:1, the combination has a relatively higher synergistic enhancement potential. It can be seen that when the dose ratio of allisartan medoxomil to pitavastatin is within the range of 40 to 300:1, the combination has the greatest synergistic enhancement antihypertensive effect; more specifically, the mass ratio of allisartan medoxomil and / or its salt to pitavastatin and / or its salt can be 40 to 300:1. ~300:1, such as: 40:1, 50:1, 60:1, 70:1, 80:1, 96:1, 100:1, 120:1, 140:1, 160:1, 200:1, 240:1, 280:1, 300:1, etc.; More preferably, the mass ratio of allisartan medoxomil to pitavastatin is 60:1, 80:1, 96:1, 120:1, 160:1, 200:1, 240:1.

[0018] Furthermore, the aforementioned compound pharmaceutical composition can be packaged according to the clinical dosage and prepared into dosage units of specific specifications. For example, the aforementioned compound pharmaceutical composition can be packaged and prepared into dosage units each containing 240 mg, or 210 mg, or 200 mg, or 180 mg, or 160 mg, or 150 mg, or 120 mg, or 100 mg, or 90 mg, or 80 mg, or 60 mg, or 50 mg, or 30 mg, or 20 mg, or 15 mg, or 10 mg of allisartan medoxomil and / or its salt. More specifically and preferably, when the pitavastatin is pitavastatin calcium, the content of pitavastatin calcium in the dosage unit is 0.5-4 mg, and the specific content can be: 0.5 mg, or 1 mg, or 1.5 mg, or 2 mg, or 2.5 mg, or 3 mg, or 4 mg, etc.

[0019] Another object of the present invention is to provide a pharmaceutical composition for preventing cardiovascular events or reducing the risk of cardiovascular events, wherein the pharmaceutical composition contains allisartan medoxomil and / or its salt, pitavastatin or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients.

[0020] Another object of the present invention is to provide a method for preparing the aforementioned compound pharmaceutical composition, which has simple steps and strong operability, and can realize industrial production of the aforementioned compound pharmaceutical composition.

[0021] A method for preparing the aforementioned compound pharmaceutical composition comprises the step of mixing allisartan medoxomil and / or its salt with pitavastatin and / or its salt.

[0022] The mixing of allisartan medoxomil and / or its salt with pitavastatin and / or its salt is direct physical mixing of the two; the physical mixing method includes but is not limited to direct mixing and equal incremental mixing; the equipment used for the physical mixing can be conventional powder mixing equipment, preferably a V-type mixer.

[0023] The present invention has the following advantages and beneficial effects compared to the prior art:

[0024] 1. Provide a promising pharmaceutical combination of allisartan medoxomil and / or its salts and pitavastatin and / or its salts, which can synergistically inhibit apoptosis of vascular smooth muscle cells, thereby reducing vascular calcification and the risk of cardiovascular disease.

[0025] 2. Provide a method for preparing the aforementioned compound pharmaceutical composition, which has simple steps and strong operability, and can realize industrial production of the aforementioned compound pharmaceutical composition. DETAILED DESCRIPTION

[0026] The present invention will be further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0027] Example 1 Study on the Protective Effect of Alisartan Medoxomil and Pitavastatin Calcium Compound Pharmaceutical Composition on Smooth Muscle Cell Calcification

[0028] Experimental drugs: Alisartan medoxomil, pitavastatin calcium, losartan potassium, and olmesartan medoxomil were all from Shenzhen Xinlitai Pharmaceutical Co., Ltd.; simvastatin was purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.; and pravastatin was purchased from CNS Pharmaceuticals.

[0029] Experimental instruments and reagents: FLUOstar Omega microplate reader, ML204 electronic balance, CKX41SF inverted microscope, Cell Counting Kit-8 cell counting reagent (CCK-8, purchased from Shanghai Liji Biotechnology Co., Ltd.), dimethyl sulfoxide (DMSO, purchased from Guangzhou Chemical Reagent Factory), smooth muscle cell culture medium (SMCM, brand Sciencell), smooth muscle cell growth factor (SMCCGS, brand Sciencell).

[0030] Experimental groups:

[0031]

[0032] Note: All dosages are calculated as allisartan medoxomil and pitavastatin calcium as pitavastatin calcium.

[0033] Complete culture medium preparation: SMCM + 2% fetal bovine serum (FBS) + 1% penicillin and streptomycin + 1% SMCCGS factor.

[0034] Incomplete culture medium preparation: SMCM + 1% penicillin and streptomycin + 1% SMCCGS factor.

[0035] Preparation of inorganic phosphate solution (Pi): 0.2 M disodium hydrogen phosphate: 0.2 M sodium dihydrogen phosphate = 4.2:1, and adjust to pH = 7.4.

[0036] Preparation of drug solution:

[0037] a) Dissolve the grouped test compounds in DMSO and store at -20°C;

[0038] b) Preparation of drug solution:

[0039] Alisartan medoxomil single drug dilution: Take 1 μl of 3.318 mg / ml Alisartan medoxomil and add it to 1 ml of incomplete culture medium containing 20 mM inorganic phosphate solution to dilute to 6 μM.

[0040] Dilution of pitavastatin calcium alone: ​​Take 10 μl of pitavastatin calcium with a concentration of 7.465 mg / ml and add 440 μl of DMSO to dilute it to 165.9 μg / ml pitavastatin calcium. 200 μM pitavastatin calcium is diluted with DMSO by 1.5, 2, 3, 4, 6, 12, 15, 20, and 24 times in sequence. After dilution, a series of drugs containing DMSO are diluted 1000 times with incomplete culture medium.

[0041] Drug dilution of the combination group of allisartan medoxomil and pitavastatin calcium: take 1 μl of 3.318 mg / ml allisartan medoxomil + 1 μl of a series of DMSO-diluted pitavastatin calcium + 980 μl incomplete culture medium.

[0042] Dilution of the losartan potassium and simvastatin combination group: take 1 μl of 3.318 mg / ml losartan potassium + 1 μl of 1.327 mg / ml simvastatin + 980 μl of incomplete culture medium.

[0043] Dilution of the Olmesartan Medoxomil and Pravastatin combination group: take 1 μl of 3.318 mg / ml Olmesartan Medoxomil + 1 μl of 1.659 mg / ml Pravastatin + 980 μl of incomplete culture medium.

[0044] Experimental steps:

[0045] Seed 8,500 cells / well in 100 μl of complete medium / well and allow cells to adhere. After overnight attachment, add incomplete medium containing 20 mM inorganic phosphate solution and various drugs. Positive wells are then incubated with incomplete medium without inorganic phosphate solution at a volume of 100 μl / well. Incubate in an incubator for 24 hours. Remove the medium and add phosphate-buffered saline (PBS) containing 10% CCK-8. Incubate at 37°C for 30-60 minutes. Read the plate at 450 nm and read the OD.

[0046] Protection rate % = (OD of the drug-dosing hole 450nm -OD of the model hole 450nm ) / OD of the model hole 450nm *100

[0047] Model group: high phosphorus cell wells without drug treatment

[0048] The protection rate of each group of drugs on apoptosis of smooth muscle cells:

[0049]

[0050]

[0051] Note: The dosage of losartan potassium is calculated as losartan potassium, and the dosage of olmesartan medoxomil is calculated as olmesartan medoxomil.

[0052] From the results in the above table, it can be seen that the combination of allisartan medoxomil and pitavastatin calcium in the mass ratio range of 40 to 300:1 can produce a synergistic effect. Within the experimental dosage range, the four drug dosage ratios of allisartan medoxomil and pitavastatin calcium, namely 60:1, 80:1, 120:1, and 240:1, have an apoptosis protection rate of more than 20%, which is significantly higher than the synergistic effect of other groups and can significantly inhibit Pi-induced smooth muscle cell apoptosis. It can be seen that the combination of allisartan medoxomil and pitavastatin calcium in the dosage ratio range of 60 to 240:1 has the greatest synergistic effect.

[0053] In subsequent repeated in vitro experiments on the combination of alisartan medoxomil potassium and pitavastatin calcium, when the mass ratio of alisartan medoxomil potassium to pitavastatin calcium was in the range of 40 to 300:1, the pharmaceutical composition exhibited a synergistic effect similar to the aforementioned alisartan medoxomil-pitavastatin calcium pharmaceutical composition.

[0054] In summary, for the compound pharmaceutical composition consisting of allisartan medoxomil and / or its salt and pitavastatin, when the mass ratio of allisartan medoxomil and / or its salt to pitavastatin calcium is 40 to 300:1, the drug combination has a relatively high synergistic enhancement potential, can significantly inhibit Pi-induced smooth muscle cell apoptosis, and is better than the inhibitory effect of the losartan potassium / simvastatin group and the olmesartan medoxomil / pravastatin group, and has considerable drug development prospects.

[0055] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A pharmaceutical composition comprising allisartan medoxomil and pitavastatin calcium, characterized in that The mass ratio of allisartan medoxomil to pitavastatin calcium is 40 to 300:

1.

2. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of allisartan medoxomil to pitavastatin calcium is 60 to 240:

1.

3. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of allisartan medoxomil to pitavastatin calcium can be 40:1, 50:1, 60:1, 80:1, 96:1, 100:1, 120:1, 140:1, 160:1, 200:1, 240:1, 280:1, or 300:

1.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutical composition is packaged according to the clinical dosage and prepared into dosage units of specific specifications, and the dosage unit contains 240 mg, or 210 mg, or 200 mg, or 180 mg, or 160 mg, or 150 mg, or 120 mg, or 100 mg, or 90 mg, or 80 mg, or 60 mg, or 50 mg, or 30 mg, or 20 mg, or 15 mg, or 10 mg of allisartan medoxomil.

5. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The content of pitavastatin calcium in the dosage unit is 0.5-4 mg.

6. The pharmaceutical composition according to claim 5, characterized in that The specific content of pitavastatin calcium in the dosage unit is 1 mg, or 1.5 mg, or 2 mg, or 2.5 mg, or 3 mg, or 4 mg.

7. A method for preparing the pharmaceutical composition according to any one of claims 1 to 6, characterized in that The preparation method of the pharmaceutical composition comprises the step of mixing allisartan medoxomil and pitavastatin calcium.

8. The method for preparing the pharmaceutical composition according to claim 7, characterized in that The mixing of olisartan medoxomil and pitavastatin calcium is performed by directly physically mixing the two; the method of the physical mixing is selected from a direct mixing method and an equal amount incremental method; and the equipment used for the physical mixing is a V-type mixer.

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