CN113230411B - Compound pharmaceutical composition of allisartan isoproxil or salt thereof and calcium channel antagonist - Google Patents
Compound pharmaceutical composition of allisartan isoproxil or salt thereof and calcium channel antagonist Download PDFInfo
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Abstract
The invention provides a compound combination of allisartan isoproxil and/or salt thereof and a calcium channel antagonist (CCB) with pharmaceutical prospect, which realizes the blood pressure reduction synergistic effect by limiting the mass ratio of the allisartan isoproxil and/or salt thereof to the calcium channel antagonist (CCB), and is beneficial to improving the blood pressure reduction effect and reducing the adverse reaction of medicines.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a compound pharmaceutical composition of allisartan isoproxil or salt thereof and a calcium channel antagonist.
Background
Alisartan cilexetil (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 a structural formula of an allisartan isoproxil compound, the allisartan isoproxil has low toxicity, 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 (EXP 3174) through metabolism in vivo so as to play a role in reducing the blood pressure.
However, for people with severe hypertension and/or those with multiple risk factors, target organ damage or clinical disorders, administration of a single antihypertensive drug often fails to achieve optimal therapeutic efficacy, and for such patients, administration of two or more antihypertensive drugs with different antihypertensive mechanisms is often considered.
The prior art does not disclose a compound pharmaceutical composition of allisartan isoproxil or a salt thereof and a calcium channel antagonist (CCB) which can achieve the best synergistic effect. Specifically, chinese patent CN101822837A discloses a pharmaceutical composition of alisartan medoxomil or a salt thereof and a calcium channel antagonist (CCB), discloses that the calcium channel antagonist is a series of products on the market or in the research including levamlodipine, amlodipine, lacidipine, cilnidipine, lercanidipine, nisoldipine, nicardipine, azelnidipine, nitrendipine, felodipine, nifedipine, and the like, and discloses that the use amount of alisartan medoxomil or a salt thereof is 5mg to 800 mg/person/day, and more preferably 5mg to 300 mg/person/day. In the patent examples, the alisartan medoxomil potassium and the amlodipine besylate with the mass ratio of 2.9 to 1 and the alisartan medoxomil potassium and the levamlodipine besylate with the mass ratio of 5.7 to 1 are disclosed, and the patent only mentions that the corresponding composition has an obvious synergistic/enhancement effect, but does not substantially disclose relevant experimental data for embodying compound medication.
Chinese patent CN101822836A discloses pharmaceutical compositions of alisartan ester or salts thereof and a series of calcium channel antagonists (CCB) including levamlodipine, amlodipine, lacidipine, lercanidipine and the like, and discloses recommended daily amounts of alisartan ester or salts thereof and (levamlodipine) besylate, and patent examples disclose alisartan ester and amlodipine besylate in a mass ratio of 14.4.
Chinese patent CN101822667A also discloses a pharmaceutical composition of alisartan medoxomil or salt thereof and a calcium channel antagonist (CCB), and discloses recommended daily amounts of alisartan medoxomil or salt thereof and (levo) amlodipine, but does not disclose experimental data related to the compound administration.
The literature: the alisartan medoxomil and the amlodipine have clinical effects of treating senile hypertension combined with early renal function injury, original fuwei, korean forest and clinical reasonable medicines, 2017,10 (8C) and P12; the literature discloses the clinical efficacy of the combination of alisartan medoxomil and levamlodipine besylate for treating senile hypertension with early renal function impairment, but the combination treatment scheme has the advantages that the alisartan medoxomil is used 240 mg/time, is taken at night and is taken 1 time/d; and the levamlodipine besylate is taken orally at a dose of 2.5 mg/time and 3 times/d, the levamlodipine besylate and the oral administration do not belong to the same administration unit, and the use is not synchronous.
It is known that although the prior art discloses several schemes for combining the alisartan medoxomil or the salt thereof with the calcium channel antagonist (CCB) and using the alisartan medoxomil and the calcium channel antagonist (CCB) with synergistic/enhancing effects, the screening of the compound pharmaceutical composition with optimal ratio is not involved, and the finding of the compound pharmaceutical composition of the angiotensin receptor Antagonist (ARB) alisartan medoxomil or the salt thereof with the calcium channel antagonist (CCB) with pharmaceutical prospect is still a technical problem which is not solved by the prior art.
Disclosure of Invention
The invention aims to provide a compound combination of angiotensin receptor Antagonist (ARB) allisartan isoproxil or salt thereof and calcium channel antagonist (CCB) with pharmaceutical prospect, which can realize the synergistic effect of blood pressure reduction, is beneficial to improving the blood pressure reduction effect and reducing the adverse reaction of medicines.
The above object of the present invention is achieved by the following technical solutions:
a compound pharmaceutical composition, which consists of alisartan medoxomil and/or a salt thereof and a calcium ion channel antagonist, and is characterized in that the mass ratio of the alisartan medoxomil and/or the salt thereof to the calcium ion channel antagonist is 24.
The alisartan medoxomil and/or the salt thereof refers to a mixture which is obtained by mixing alisartan medoxomil, alisartan medoxomil salt or alisartan medoxomil salt and alisartan medoxomil salt in any proportion in a compound pharmaceutical composition; 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 calcium channel antagonist (CCB) refers to one or a mixture of more than two of amlodipine, levamlodipine or pharmaceutically acceptable salts thereof which are mixed 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.
The mass ratio of the aforementioned alisartan ester and/or salt thereof to the aforementioned calcium channel antagonist (CCB) is 24, 48; specifically, in animal in vivo pharmacodynamic experimental studies, the alisartan medoxomil and the calcium channel antagonist in different dosage ratios have certain difference in synergistic effect, and when the mass ratio of the alisartan medoxomil and/or the salt thereof to the calcium channel antagonist is 24, 48 or 96.
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 is 24; further, the combination of the alisartan medoxomil and the amlodipine besylate is preferably a combination of the alisartan medoxomil and the amlodipine besylate, wherein the mass ratio of the alisartan medoxomil to the amlodipine besylate is 24; specifically, in animal in vivo pharmacodynamic experimental studies, when the mass ratio of the alisartan medoxomil to the amlodipine besylate is 24, 48, or 96: the amlodipine besylate has the maximum synergistic antihypertensive effect when being used together with 24, 48 or 96.
Further, the aforementioned compound pharmaceutical composition may be divided and prepared into administration units of specific specifications according to clinical administration dosage, for example, the aforementioned compound pharmaceutical composition may be divided and prepared into administration units 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 calcium channel antagonist (CCB) is amlodipine besylate, the content of amlodipine besylate in the aforementioned administration units 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.
The invention also aims to provide a preparation method of the compound pharmaceutical composition, which has simple steps and strong operability and can realize industrial production of the compound pharmaceutical composition.
The above object is achieved by the following technical scheme:
a method for preparing the compound pharmaceutical composition, which comprises the step of mixing the allisartan isoproxil and/or the salt thereof with a calcium channel antagonist (CCB).
The alisartan medoxomil and/or the salt thereof is mixed with a calcium channel antagonist (CCB) to directly and physically mix the alisartan medoxomil and/or the salt thereof with the CCB; methods of physical mixing include, but are not limited to, direct mixing and equal-increment; the equipment used for physical mixing can be conventional powder mixing equipment, and a V-shaped mixer is preferred.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. the compound combination of the allisartan isoproxil and/or the salt thereof and the calcium channel antagonist (CCB) with pharmaceutical prospect is provided, and realizes the blood pressure reduction synergistic effect by limiting the mass ratio of the allisartan isoproxil and/or the salt thereof to the calcium channel antagonist (CCB), thereby being beneficial to improving the blood pressure reduction effect and reducing the adverse reaction of medicines;
2. the preparation method of the compound pharmaceutical composition is simple in steps and strong in operability, and industrial production of the compound pharmaceutical composition can be realized.
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-calcium channel antagonist (CCB) Compound pharmaceutical composition
Adding allisartan isoproxil (4.8 kg) into a V-shaped mixing cylinder, adding amlodipine besylate (0.1 kg, calculated by amlodipine), and mixing for 60 minutes to obtain the compound medicinal composition of the allisartan isoproxil-amlodipine besylate, wherein the mass ratio of the allisartan isoproxil to the amlodipine besylate is 48.
The compound medicinal composition of the allisartan isoproxil-amlodipine besylate with the rest mass ratio can be prepared by adopting the same method, such as the compound medicinal composition of the allisartan isoproxil-amlodipine besylate with the mass ratio of 24 to 96.
Example 2 preparation of compound pharmaceutical composition of alisartan medoxomil potassium and amlodipine besylate
Adding allisartan isoproxil potassium (2.4 kg, calculated as allisartan isoproxil) into a V-shaped mixing cylinder, adding amlodipine besylate (0.1 kg, calculated as amlodipine), mixing for 30 minutes, then adding allisartan isoproxil potassium (2.4 kg, calculated as allisartan isoproxil), and further mixing for 30 minutes to obtain the compound pharmaceutical composition of the allisartan isoproxil-amlodipine besylate with the mass ratio of 24.
The compound medicinal composition of the allisartan isoproxil and the amlodipine besylate with the rest mass ratio can be prepared by adopting the same method, such as the compound medicinal composition of the allisartan isoproxil and the amlodipine besylate with the mass ratio of 48.
Example 3 preparation of Compound pharmaceutical composition of other Allisartan medoxomil salts
The compound pharmaceutical composition of the other salts of alisartan medoxomil and the other salts of amlodipine can be prepared by the same method as in example 1 or 2, such as a compound pharmaceutical composition of the other salts of alisartan medoxomil and the other salts of amlodipine with the mass ratio of 24, 48.
EXAMPLE 4 pharmacodynamic Experimental study
Experiment one: effect of Allisartan isoproxil (Ali) in combination with amlodipine besylate (Aml) on blood pressure of SHR rats
1. Laboratory animal and instrument
SHR (spontaneous hypertension) rat, 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, genetian technology Limited.
2. Method of producing a composite material
The allisartan cilexetil was prepared according to the method of example 1 or 2 respectively: the amlodipine besylate is a compound pharmaceutical composition with the mass ratio.
200 SHR rats were taken and the experiment was started after one week of acclimatization. The animals were randomly divided into 25 groups of 8 animals each by body weight. Each group of rats was anesthetized by intraperitoneal injection of pentobarbital sodium at 40mg/kg and fixed on the rat plates in a supine position. A self-made arterial catheter is inserted into the lower abdominal aorta through the left femoral artery for measuring blood pressure, and then a gastrostomy cannula is performed. The stomach tube and the artery catheter are led out from the back subcutaneous to the neck incision. The animal is placed in a constant-temperature constant-humidity animal room with automatic brightness switching after the operation and is recovered for 20 to 30 hours. The recovered animal is connected into a conscious freely-moving rat blood pressure monitoring device and is stabilized for 3-4 hours, and the arterial catheter is connected with the pressure transducer through a perfusion three-way pipe. The systolic pressure, diastolic pressure and cardiac interval are recorded by the computer in real time. Blood pressure was recorded over 1 hour as the pre-dose baseline. The test drugs were administered through the gastric fistula and continuously recorded for 6 hours, and the area under the blood pressure-time curve (mmHg · h) was calculated, and at the same time, the area inhibition rate under the curve for 6 hours after administration was calculated for each animal in comparison with the model group, and the data of each group was expressed as Mean ± SD, and the analysis of variance LSD test was performed using SPSS 19.0.
The combination of the clinical dose of the alisartan medoxomil and the amlodipine besylate is grouped and tested according to the following grouping table (table 1-1):
TABLE 1-1 grouping table of animal experiments
Tables 1-2 area under blood pressure-time curve (mmHg. H, mean. + -. SD, n = 8)
P <0.05, P <0.01, compared to model group
From the experimental data in tables 1-2, it can be seen that different doses of alisartan medoxomil and amlodipine can reduce the blood pressure of SHR rats in a dose-dependent manner on average, and different dose-ratio combinations can also significantly reduce the blood pressure of SHR rats (P <0.05, P < -0.01).
Dose-effect relationship curve drawing is respectively carried out on data of the alisartan medoxomil and the amlodipine single drug, the area inhibition rate under a blood pressure time curve of an SHR rat is compared with the theoretical inhibition rate through experimental research, the optimal dose ratio after the two drugs are combined is discussed, and the results are shown in the following tables 1-3 and 1-4.
TABLE 1-3 comparison of the inhibition (%) of the area under the blood pressure-time curve with the theoretical inhibition (%)
Table 1-4 results of synergy of alisartan medoxomil with amlodipine besylate at different dose ratios (experimental value-theoretical value)
Experiment two: effect of Alisartan medoxomil (Ali) in combination with amlodipine besylate (Aml) and levoamlodipine besylate (L-Aml) on blood pressure of SHR rats
1. Laboratory animal and instrument
SHR (spontaneous hypertension) rat, 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, genetian technology Limited.
2. Method for producing a composite material
88 SHR rats were taken and the experiment was started after one week of acclimatization. The animals were randomly divided into 11 groups of 8 animals each by body weight. The specific method is the same as the experiment I.
Combining the clinical dosage conditions of the alisartan medoxomil, the amlodipine besylate and the levoamlodipine besylate, grouping and testing are carried out according to the following grouping table (table 2-1):
TABLE 2-1 grouping table of animal experiments
Table 2-2 area under blood pressure-time curve (mmHg · h, mean ± SD, n = 8)
Comparison with model group, P <0.05, P <0.01
From the experimental data in tables 2-2, it can be seen that different doses of alisartan medoxomil, amlodipine besylate and levoamlodipine besylate can reduce the blood pressure of SHR rats in a dose-dependent manner on average, and different dose-ratio combinations can also reduce the blood pressure of SHR rats significantly (P < 0.05.
Dose-effect relationship curve drawing is respectively carried out on data of the alisartan medoxomil and the amlodipine single drug, the area inhibition rate under the blood pressure time curve of the SHR rat is compared with the theoretical inhibition rate through experimental research, and the results are shown in the following tables 2-3 and 2-4.
TABLE 2-3 comparison of the area inhibition (%) under the blood pressure-time curve with the theoretical inhibition
TABLE 2-4 synergistic results (Experimental-theoretical) after different dose ratios
From the results of the first experiment and the second experiment, the alisartan medoxomil and the amlodipine besylate can generate a certain synergistic blood pressure reducing effect after being used in a combined mode, but the advantages and the disadvantages of different groups are different; specifically, within the dosage range of experimental study, the mass ratio of the alisartan medoxomil to the amlodipine besylate is 24, 48, 1 and 96, and the compound composition is obviously higher than the synergistic effect of other groups; more specifically, the mass ratio of the alisartan ester to the amlodipine besylate is 24, 48, 1 and 96, the compound composition has a synergistic potential increased by more than 11%, which is far higher than that of other experimental groups by 0.1-8.6%; further experiments also prove that the allisartan cilexetil has the mass ratio: amlodipine besylate is present at 24, 48, 1 and 96, with pharmacodynamic jumps that give the synergistic effect to an optimum at 24.
The results of the second experiment show that: the mass ratio of the alisartan medoxomil to the amlodipine besylate is 14.4, 1 and 2.9, and the mass ratio of the alisartan medoxomil to the levamlodipine besylate is 28.7, wherein the compound composition has less than 5 percent of synergistic effect.
It can be seen that the dosage ratio of the allisartan isoproxil: the amlodipine besylate has the maximum synergistic antihypertensive effect after being combined with 24.
In subsequent repeated animal experiments on the administration of the compound medicinal composition of the allisartan isoproxil-amlodipine besylate, when the dose ratio of the allisartan isoproxil to the amlodipine besylate is 24, 48.
Comprehensively, the compound pharmaceutical composition consisting of the alisartan medoxomil and/or the salt thereof and the calcium channel antagonist (amlodipine and/or the salt thereof) shows a better in-vivo blood pressure reduction synergistic effect when the dosage ratio is 24, 1, 48 and 1, and is more favorable for improving the blood pressure reduction effect, can reduce the incidence rate of adverse drug reactions, and has a considerable patent medicine 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 (9)
1. A compound pharmaceutical composition comprises alisartan medoxomil potassium salt and amlodipine besylate, and is characterized in that the mass ratio of the alisartan medoxomil potassium salt to the amlodipine besylate is 24.
2. The combination pharmaceutical composition according to claim 1, wherein the combination pharmaceutical composition is divided into dosage units according to clinical administration dosage and prepared into specific dosage units, and the dosage units contain alisartan medoxomil potassium salt 240mg, or 210mg, or 180mg, or 160mg, or 120mg, or 90mg, or 80mg, or 60mg, or 50mg, or 30mg, or 15mg, or 10mg, calculated on alisartan medoxomil.
3. The compound pharmaceutical composition according to any one of claims 1-2, wherein the content of amlodipine besylate in the administration unit is 0.02 to 10mg in terms of amlodipine.
4. The compound pharmaceutical composition according to claim 3, wherein the specific content of amlodipine besylate in the administration unit is as follows in terms of amlodipine: 10mg, or 8mg, or 5mg, or 2.5mg, or 1.25mg, or 1mg, or 0.5 mg.
5. The combination pharmaceutical composition according to any one of claims 1-2, 4, wherein the specific content of amlodipine besylate in the administration unit is 240mg, or 210mg, or 180mg, or 160mg, or 120mg, or 90mg, or 80mg, based on amlodipine: 10mg, or 5mg, or 2.5mg.
6. The combination pharmaceutical composition according to claim 3, wherein when the content of the potassium salt of amlodipine besylate in the administration unit is 240mg, or 210mg, or 180mg, or 160mg, or 120mg, or 90mg, or 80mg, calculated as amlodipine, the content of amlodipine besylate is as follows: 10mg, or 5mg, or 2.5mg.
7. A process for the preparation of a combination pharmaceutical composition according to any one of claims 1-6 comprising the step of mixing the potassium salt of alisartan medoxomil with amlodipine besylate.
8. The method for preparing the compound pharmaceutical composition according to claim 7, wherein the alisartan medoxomil potassium salt and the amlodipine besylate are mixed by directly and physically mixing the alisartan medoxomil potassium salt and the amlodipine besylate; the physical mixing method is a direct mixing method or an equivalent incremental method.
9. The process for preparing the combination pharmaceutical composition according to claim 8, wherein the physical mixing equipment is a V-shaped mixer.
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| CN105963296A (en) * | 2015-03-12 | 2016-09-28 | 深圳信立泰药业股份有限公司 | A pharmaceutical composition containing allisartan isoproxil or a salt thereof or a hydrolysate thereof or a salt of the hydrolysate thereof and uses of the composition |
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| CN101822837A (en) * | 2010-02-02 | 2010-09-08 | 王丽燕 | Medicine composition containing allisartan isoproxil salts |
| CN101822667A (en) * | 2010-02-02 | 2010-09-08 | 王丽燕 | Medicine composition containing imidazole-5-carboxylic acid derivatives |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105963296A (en) * | 2015-03-12 | 2016-09-28 | 深圳信立泰药业股份有限公司 | A pharmaceutical composition containing allisartan isoproxil or a salt thereof or a hydrolysate thereof or a salt of the hydrolysate thereof and uses of the composition |
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| Publication number | Publication date |
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| CN113230411A (en) | 2021-08-10 |
| CN109865139B (en) | 2021-07-20 |
| CN109865139A (en) | 2019-06-11 |
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Address after: Area A, 4th Floor, Digital Peninsula, No. 2, Hongliu Road, Fubao Community, Fubao Street, Futian District, Shenzhen, Guangdong, 518017 Applicant after: SHENZHEN SALUBRIS PHARMACEUTICALS Co.,Ltd. Applicant after: HUIZHOU XINLITAI PHARMACEUTICAL Co.,Ltd. Applicant after: SHANDONG SALUBRIS PHARMACEUTICALS Co.,Ltd. Address before: 518040 37th floor, chegongmiao Lvjing Plaza, 6009 Shennan Avenue, Futian District, Shenzhen City, Guangdong Province Applicant before: SHENZHEN SALUBRIS PHARMACEUTICALS Co.,Ltd. Applicant before: HUIZHOU XINLITAI PHARMACEUTICAL Co.,Ltd. Applicant before: SHANDONG SALUBRIS PHARMACEUTICALS Co.,Ltd. |
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