CN113230411A - 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
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.
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 marketed or in-research products including levamlodipine, amlodipine, lacidipine, cilnidipine, lercanidipine, nisoldipine, nicardipine, azelnidipine, nitrendipine, felodipine, nifedipine, and the like, and discloses that the dose 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 2.9:1 and the alisartan medoxomil potassium and the levamlodipine besylate with the mass ratio of 5.7:1 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 its salt and a series of calcium channel antagonists (CCB) including levamlodipine, amlodipine, lacidipine, lercanidipine, etc., and also discloses recommended daily amounts of alisartan ester or its salt and (levamlodipine), patent examples disclose alisartan ester and amlodipine besylate in a mass ratio of 14.4:1 and alisartan ester and levamlodipine besylate in a mass ratio of 28.7:1, and the patent also does not disclose experimental data related to the embodying of compound medication.
Chinese patent CN101822667A also discloses pharmaceutical compositions of alisartan medoxomil or salts thereof and calcium channel antagonists (CCBs), and also discloses recommended daily amounts of alisartan medoxomil or salts thereof and (levo) amlodipine, but does not disclose experimental data related to the combination.
The literature: the alisartan medoxomil and amlodipine are combined to achieve the clinical curative effect of treating senile hypertension combined with early renal function injury, namely original fuwei, Korean lirin and clinical reasonable medication, 2017,10(8C) and P12; the literature discloses the clinical efficacy of combining alisartan medoxomil and levamlodipine besylate to treat senile hypertension with early renal function injury, but the combination treatment scheme has the advantages that alisartan medoxomil is used 240 mg/time, and is taken at night and in a pause mode for 1 time/d; and the levamlodipine besylate is taken orally at a dose of 2.5 mg/time and 3 times/d, and the levamlodipine besylate and the amlodipine besylate are not in the same administration unit and are not used synchronously.
It is known that although the prior art discloses several schemes of combining the alisartan medoxomil or the salt thereof with the calcium channel antagonist (CCB) and combining the alisartan medoxomil and the calcium channel antagonist (CCB) with synergistic/enhancing effects, the screening of the compound pharmaceutical composition with optimal proportion 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:
the compound pharmaceutical composition consists of alisartan medoxomil and/or salt thereof and a calcium ion channel antagonist, and is characterized in that the mass ratio of the alisartan medoxomil and/or salt thereof to the calcium ion channel antagonist is 24:1, 48:1 or 96: 1.
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 above alisartan ester and/or salt thereof to the above calcium channel antagonist (CCB) is 24:1, 48:1 or 96: 1; specifically, in animal in vivo pharmacodynamic experimental studies, the alisartan medoxomil with different dose ratios has a certain difference in synergistic effect after combined administration, and when the mass ratio of the alisartan medoxomil and/or the salt thereof to the calcium channel antagonist is 24:1, 48:1 or 96:1, the drug combination has higher synergistic potential compared with other ratios.
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 can be preferably selected, wherein the mass ratio of the alisartan medoxomil to the amlodipine besylate is 24:1, 48:1 or 96: 1; specifically, in the pharmacodynamic experimental study in animals, when the mass ratio of the alisartan medoxomil to the amlodipine besylate is 24:1, 48:1 or 96:1, the combination has a higher synergistic effect relative to other ratios, so that the alisartan medoxomil in the dosage ratio is as follows: when the amlodipine besylate is 24:1, 48:1 or 96:1, the amlodipine besylate has the maximum synergistic antihypertensive effect after being combined.
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 calcium channel antagonist (CCB) is amlodipine besylate, the content of amlodipine besylate 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.
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, the compound combination 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), is favorable for 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 with the mass ratio of 48: 1.
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 24:1 and 96: 1.
Example 2 preparation of Allisartan medoxomil Potassium-amlodipine besylate Compound pharmaceutical composition
Adding allisartan isoproxil potassium (2.4 kg calculated by allisartan isoproxil) into a V-shaped mixing cylinder, adding amlodipine besylate (0.1 kg calculated by amlodipine), mixing for 30 minutes, then adding allisartan isoproxil potassium (2.4 kg calculated by 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: 1.
The compound medicinal composition of the allisartan isoproxil and the amlodipine besylate with the rest mass ratio, such as the compound medicinal composition of the allisartan isoproxil and the amlodipine besylate with the mass ratio of 48:1 and 96:1, can be prepared by adopting the same method.
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 and 96: 1.
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) 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.
2. Method of producing a composite material
Alisartan ester 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
Table 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 proportion 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) 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.
2. Method of 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)
P <0.05, P <0.01, compared to model group
From the experimental data in table 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 ratios of the combination can also reduce the blood pressure of SHR rats significantly (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 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, in the experimental study dosage range, the compound composition with the mass ratio of the alisartan medoxomil to the amlodipine besylate of 24:1, 48:1 and 96:1 is obviously higher than the synergistic effect of other groups; more specifically, the compound composition with the mass ratio of the alisartan medoxomil to the amlodipine besylate being 24:1, 48:1 and 96:1 has the synergistic potential increased by more than 11 percent, which is far higher than that of other experimental groups by 0.1 to 8.6 percent; further experiments also prove that the allisartan cilexetil has the mass ratio: pharmacodynamic jumps exist at the sites of 24:1, 48:1 and 96:1 of the amlodipine besylate, so that the synergistic effect reaches the optimal values at the sites of 24:1, 48:1 and 96: 1.
The results of the second experiment show that: the compound composition with the mass ratio of the alisartan medoxomil to the amlodipine besylate being 14.4:1 and 2.9:1 and the mass ratio of the alisartan medoxomil to the levoamlodipine besylate being 28.7:1 and 5.7:1 has less than 5 percent of synergistic effect, and the synergistic effect is poor.
It can be seen that the dosage ratio of the allisartan isoproxil: when the amlodipine besylate is combined at 24:1, 48:1 and 96:1, the maximum synergistic antihypertensive effect is achieved.
In subsequent repeated animal experiments for 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 24:1, 48:1 and 96:1, the medicinal composition shows the synergistic effect consistent with that of the compound medicinal composition of the allisartan isoproxil-amlodipine besylate.
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 better in-vivo blood pressure reduction synergistic effect when the dosage ratio is 24:1, 48:1 and 96:1, 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 (10)
1. The compound pharmaceutical composition is composed of alisartan medoxomil and/or salts thereof and a calcium ion channel antagonist, and is characterized in that the mass ratio of the alisartan medoxomil and/or the salts thereof to the calcium ion channel antagonist is 24:1, 48:1 or 96:1, and the alisartan medoxomil and/or the salts thereof are a mixture obtained by mixing alisartan medoxomil, alisartan medoxomil salt or alisartan medoxomil salt and alisartan medoxomil salt in any proportion in the compound pharmaceutical composition.
2. The compound pharmaceutical composition according to claim 1, wherein the allisartan isoproxil salt refers to an allisartan isoproxil pharmaceutically acceptable salt, i.e. a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a zinc salt, an aluminum salt, an ammonium salt.
3. The compound pharmaceutical composition according to any one of claims 1-2, wherein the calcium channel antagonist refers to one or more of amlodipine, levamlodipine or pharmaceutically acceptable salts thereof, which are mixed in any proportion; 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.
4. The combination pharmaceutical composition according to any one of claims 1 to 3, wherein the combination pharmaceutical composition is divided into clinical administration doses and prepared into specific dosage units, and the dosage units can contain alisartan medoxomil and/or salts thereof 240mg, or 210mg, or 180mg, or 160mg, or 120mg, or 90mg, or 80mg, or 60mg, or 50mg, or 30mg, or 15mg, or 10 mg.
5. The combination pharmaceutical composition according to any one of claims 1-4, wherein when the calcium channel antagonist is amlodipine besylate, the content of amlodipine besylate in the administration unit is 0.02-10 mg.
6. The compound pharmaceutical composition according to claim 5, wherein the specific content of amlodipine besylate in the administration unit is as follows: 10mg, or 8mg, or 5mg, or 2.5mg, or 1.25mg, or 1mg, or 0.5 mg.
7. The combination pharmaceutical composition according to any one of claims 1 to 6, wherein when the content of the amlodipine besylate and/or the salt thereof in the administration unit is 240mg, or 210mg, or 180mg, or 160mg, or 120mg, or 90mg, or 80mg, the content of the amlodipine besylate is as follows: 10mg, or 5mg, or 2.5 mg.
8. A process for the preparation of a combination pharmaceutical composition according to any one of claims 1 to 7 comprising the step of mixing alisartan ester and/or a salt thereof with a calcium channel antagonist.
9. The preparation method of the combination pharmaceutical composition according to claim 8, wherein the alisartan ester and/or the salt thereof and the calcium channel antagonist are mixed by directly and physically mixing the alisartan ester and/or the salt thereof and the calcium channel antagonist; the physical mixing method is a direct mixing method or an equivalent incremental method.
10. The process for preparing the combination pharmaceutical composition according to claim 9, wherein the physical mixing equipment is a V-shaped mixer.
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| CN113876768B (en) * | 2020-11-13 | 2023-05-02 | 深圳信立泰药业股份有限公司 | New application of aliskirilowii and amlodipine compound pharmaceutical composition |
| CN114224859B (en) * | 2020-12-29 | 2023-05-26 | 深圳信立泰药业股份有限公司 | Compound antihypertensive pharmaceutical composition and preparation method thereof |
| CN116157119A (en) * | 2021-08-26 | 2023-05-23 | 深圳信立泰药业股份有限公司 | Pharmaceutical composition of ARNi and calcium ion antagonist and application thereof |
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| CN109865139A (en) | 2019-06-11 |
| CN109865139B (en) | 2021-07-20 |
| CN113230411B (en) | 2023-04-11 |
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