CN118059105A - Antihypertensive pharmaceutical composition - Google Patents
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- CN118059105A CN118059105A CN202211410319.2A CN202211410319A CN118059105A CN 118059105 A CN118059105 A CN 118059105A CN 202211410319 A CN202211410319 A CN 202211410319A CN 118059105 A CN118059105 A CN 118059105A
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- azilsartan
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 21
- 230000003276 anti-hypertensive effect Effects 0.000 title description 2
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- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 claims abstract description 94
- 239000005485 Azilsartan Substances 0.000 claims abstract description 91
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- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 2
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- 238000012449 Kunming mouse Methods 0.000 description 1
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- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a pharmaceutical composition for reducing blood pressure, which consists of azilsartan, folic acid or derivatives thereof with pharmaceutically effective dose and a carrier acceptable in pharmacy, and belongs to the field of pharmacy.
Description
Technical Field
The invention relates to a pharmaceutical composition for treating hypertension, which consists of azilsartan, folic acid or derivatives thereof with pharmaceutically effective dose and a carrier acceptable in pharmacy, and belongs to the field of pharmacy.
Background
Azilsartan (Azilsartan) is a non-peptide angiotensin receptor II inhibitor (ARB) capable of selectively blocking angiotensin II receptor 1 (AT 1-R), and two forms of metaxartan potassium and azilsartan are currently marketed, wherein metaxartan potassium is a prodrug of azilsartan and is hydrolyzed into the active metabolite azilsartan in the gastrointestinal tract. Losartan potassium was approved by the FDA for marketing in 2011 and azilsartan was marketed in 2012.
Azilsartan has a high affinity for AT 1receptors, 10000 times as high as for AT2 receptors, showing significant therapeutic advantages compared to other ARBs. Azilsartan can smoothly reduce blood pressure and improve blood pressure and blood lipid metabolism, has a protective effect on target organs such as heart, brain, kidney and the like, does not influence bradykinin degradation and prostaglandin synthesis, does not cause dry cough and angioneurotic edema, and is an important medicament for treating cardiovascular diseases.
According to literature reports (development of angiotensin II receptor antagonist azilsartan, meng Lu, etc., new Chinese medicines and clinical impurities, 12 months in 2019, 38 (12), 716-720), the adverse reactions of azilsartan are more common, including hypotension, dizziness, diarrhea, elevated level of phosphocreatine kinase, etc. Among them, diarrhea is the most common adverse reaction in adults, with a incidence of about 2%.
Folic acid is a substance necessary for growth and reproduction of cells of a human body, and has complex functional effects, and changes of folic acid level in blood circulation of the human body directly influence occurrence and development of human health and related diseases. Folic acid is effective in lowering homocysteine levels. The present inventors have been engaged in research and study of folic acid related pharmacological action mechanisms for many years, and especially examined related curative effects and safety under the action of super-physiological dosage of folic acid. In experimental researches of antihypertensive drug intervention, the inventor discovers that the incidence rate of diarrhea of mice is obviously reduced when azilsartan is combined with folic acid, and the application mechanism is not clear, but has a development prospect of a pharmaceutical composition.
Disclosure of Invention
Aiming at the adverse reaction of diarrhea caused by long-term clinical application of azilsartan, the invention provides a pharmaceutical composition for treating hypertension, which has lower risk of side effects.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
A pharmaceutical composition comprises the following components:
(1) A pharmaceutically effective amount of azilsartan or a derivative thereof,
(2) A pharmaceutically effective amount of folic acid or a derivative thereof,
(3) A pharmaceutically acceptable carrier, which is used for the preparation of the medicine,
The mass ratio of the pharmaceutically effective amount of azilsartan or derivative thereof (calculated by azilsartan) to the pharmaceutically effective amount of folic acid or derivative thereof (calculated by folic acid) is 5: 1-400:1, the pharmaceutical composition can reduce the side effect risk of diarrhea caused by azilsartan.
As a preference, the mass ratio of the pharmaceutically effective amount of azilsartan to the pharmaceutically effective amount of folic acid is preferably 100: 1-200:1.
In the present invention, the pharmaceutically effective amount of azilsartan or a derivative thereof (in terms of azilsartan) is 10 to 150mg, and the pharmaceutically effective amount of folic acid or a derivative thereof is 0.01 to 5mg.
As a preferred, the pharmaceutically effective amount of azilsartan or derivative thereof (calculated as azilsartan) is 20 to 80mg, and the pharmaceutically effective amount of folic acid or derivative thereof is 0.2 to 1.2mg.
Specifically, the azilsartan or a derivative thereof (calculated by azilsartan) in the pharmaceutical composition provided by the invention is 10mg, and folic acid or a derivative thereof (calculated by folic acid) is 0.4mg;
Or 20mg of azilsartan or derivative thereof (calculated as azilsartan), and 0.4mg of folic acid or derivative thereof (calculated as folic acid);
Or 20mg of azilsartan or derivative thereof (calculated as azilsartan), and 0.8mg of folic acid or derivative thereof (calculated as folic acid);
Or azilsartan or derivative thereof (calculated as azilsartan) 40mg and folic acid or derivative thereof (calculated as folic acid) 0.4mg;
or azilsartan or derivative thereof (calculated as azilsartan) 40mg and folic acid or derivative thereof (calculated as folic acid) 0.8mg;
or azilsartan or derivative thereof (calculated as azilsartan) 80mg and folic acid or derivative thereof (calculated as folic acid) 0.4mg;
Or azilsartan or derivative thereof (calculated as azilsartan) 80mg and folic acid or derivative thereof (calculated as folic acid) 0.8mg.
In the present invention, a pharmaceutically effective amount of an active ingredient of a composition means a dosage range in which the active ingredient is combined with other active ingredients in the composition to cause the composition to exert its efficacy. The preferred effective amount is a pharmaceutically effective amount of the active ingredient of the composition, preferably the effective amount is more effective than the pharmaceutically effective amount. Typically, a pharmaceutically effective amount of an active ingredient of a composition includes an optimal effective amount or range of optimal effective amounts that will result in the composition producing maximum efficacy, which optimal effective amount or range of optimal effective amounts will benefit the patient even more.
In the present invention, the folic acid derivative is selected from, but not limited to, synthetic folic acid, 5-methyltetrahydrofolate, leucovorin, folinic acid, or calcium levofolinate. The folic acid derivatives used in the present invention are, for example, 0.416mg of 5-methyltetrahydrofolate, 0.451mg of 5-methyltetrahydrofolate and 0.4mg of folic acid in equimolar amounts, and the amount of 5-methyltetrahydrofolate or 5-methyltetrahydrofolate is 0.4mg in terms of equimolar folic acid mass.
In the present invention, the azilsartan derivative includes crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable precursors, active metabolites or substances which can be converted into azilsartan in vivo. The metaxartan potassium is used as a medicinal precursor of azilsartan and is a manifestation form of protection of the invention.
In the present invention, the hypertensive patient is susceptible to diarrhea when azilsartan or a derivative thereof is taken alone, especially for a long period of time. In experimental researches, the combination of the azilsartan and the folic acid can obviously reduce the probability of diarrhea of animals, namely the composition provided by the invention can obviously reduce the diarrhea risk caused by the independent use of the azilsartan or the derivative thereof and reduce related adverse reactions, so that the combination of the azilsartan or the derivative thereof and the folic acid or the derivative thereof is more suitable for treating hypertension. The present invention is a significant improvement over the prior art.
In experimental researches, the pharmaceutical composition provided by the invention not only reduces the diarrhea risk caused by the single use of azilsartan or derivatives thereof, but also has obvious synergistic effects on treating hypertension and reducing homocysteine level, so that the pharmaceutical composition provided by the invention is a better antihypertensive drug, and is especially suitable for hypertension accompanied by increased homocysteine level.
The invention is further described in connection with the following detailed description, which is not intended to be limiting, but is set forth to cover all equivalent embodiments in the art according to the teachings of the present invention.
Detailed Description
Example 1: effect of the composition of the invention on adverse effects of diarrhea in mice
1. The method comprises the following steps:
SPF-grade Kunming mice, male and female halves, were purchased from the medical laboratory animal center in Guangdong province at 6-7 weeks of age. Free diet, after 1 week of adaptive feeding, mice were randomized, given by gavage, 1 time per day, for 4 weeks. The group of mice and the administration dose are shown in Table 1[ refer to Xu Shuyun professor "pharmacodynamic laboratory methodology (third edition. Ministry of health Press.) for the conversion of mouse and human dose, 3mg/kg of azilsartan I group mice dose corresponds to about 20mg of human dose, 12mg/kg of mesartan potassium group mice dose corresponds to about 80mg of human dose, and the like ], and normal blank group mice are perfused with an equal volume of physiological saline. Mice were placed in a mouse cage with filter paper placed thereon, and the number of animals with loose stool in 8 hours after administration was recorded.
Thin stool diameter: the diameter of each pile of wet feces is counted one by one, and then the diameter of all wet feces is added and divided by the number of loose feces to obtain the diameter of loose feces. Measurement of wet feces diameter: the diameter is measured directly if the stool shape is circular, and the longest and nearly circular diameters are measured if the stool shape is elliptical, added and divided by 2. The results of the stool diameter data are expressed as mean ± standard deviation, and t-test was performed between groups.
Thin stool grade: the average loose stool level was expressed, and the diameter of the loose stool contaminated filter paper was graded into 4 grades: <1.0cm (grade 1), 1.0 to 1.9cm (grade 2), 2.0 to 3.0cm (grade 3), and >3.0cm (grade 4).
And (5) carrying out chi-square test among the rare feces only result groups.
2. Results:
TABLE 1 Effect of the compositions of the invention on diarrhea in mice
Note that: 1) &P<0.05,&& P <0.01 compared to azilsartan group ii; #P<0.05,## P <0.01 compared to azilsartan group i; @P<0.05,@@ P <0.01 compared to the metartan potassium iii group; 2) The dosage of 5-methyltetrahydrofolate is based on equimolar folic acid mass.
One of the adverse effects of azilsartan or metartan potassium is diarrhea, but folic acid (including 5-methyltetrahydrofolate) has no side effects of diarrhea. The azilsartan I group, the azilsartan II group and the metasartan potassium group have diarrhea in 8 mice, 9 mice and 8 mice respectively, and the rare feces level is 3, which indicates that the azilsartan has adverse reaction in diarrhea. Compared with the azilsartan II group, the azilsartan II and folic acid I combined mice have no obvious change in diarrhea number and loose stool progression; compared with azilsartan II, the number of mice suffering from diarrhea in azilsartan II+folic acid II, azilsartan II+5-methyltetrahydrofolate and azilsartan II+folic acid III is 1, 0 and 2 respectively, the number of mice suffering from diarrhea is obviously reduced, the loose stool diameter is also obviously reduced, and the statistical difference is provided (P <0.05 or P < 0.01); the stool number of azilsartan II+5-methyltetrahydrofolate is reduced to 1, which indicates that the dosage of 5-methyltetrahydrofolate (or folic acid) can improve the occurrence of adverse reactions of azilsartan diarrhea.
After azilsartan group I or metartan potassium group is combined with 5-methyltetrahydrofolate, the diarrhea number of mice is obviously reduced, and the loose stool diameter is also obviously reduced.
Experimental results show that the folic acid or the 5-methyltetrahydrofolate can obviously improve the occurrence of adverse reaction of azilsartan diarrhea after being combined with azilsartan (or metaxartan potassium).
Example 2: effects of the composition of the present invention on hypertension and HCY in rats with hypertension and HCY
SPF-class SD rats are adopted in the experiment, male and female rats are half, 8 weeks old and purchased from Beijing Vetong Lihua corporation, 7 days quarantine and adaptive feeding are carried out, the SPF-class SD rats are taken into the experiment, the temperature is controlled between 18 ℃ and 25 ℃, the humidity is controlled between 45% and 75%, the illumination is carried out for 12h/12h alternation, and free drinking is carried out.
A rat model of renal hypertension with Hyperhomocysteinemia (HCY) is prepared by adopting a two-kidney one-clamp method (2 k1 c), and the specific operation method is as follows: the qualified SD rats after quarantine are subjected to intraperitoneal injection anesthesia by 3% pentobarbital sodium (the animal administration dose is 30 mg/kg), the dorsal position is fixed, the abdominal midline is sheared, conventional sterilization and laparotomy are carried out, the left renal artery is separated, an acupuncture needle (0.3 mm) is used for being parallel to the left renal artery, the acupuncture needle is extracted after being ligated by a No. 0 wire, a model of left renal artery stenosis is caused, a muscle layer and a skin layer are sutured gradually, 10 ten thousand units/unit of penicillin sodium are injected every day for 1 time, and 3 days continuously, and conventional feeding is carried out. The 2k1c model rats began to drink 0.5% methionine water from week 3 post-surgery to create the high Hcy model. After 6 weeks, the blood pressure of the 2k1c model rats rises above 140mmHg to be a model animal of hypertension. 10 rats were also randomly selected, and only the renal arteries were picked during surgery and not ligated as a sham group.
Rats with elevated blood pressure and systolic blood pressure above 140mmHg and HCY levels above 20% were selected for grouping as rats with successful modeling of hypertension with high HCY, and for grouping, stratified random grouping was performed according to blood pressure and HCY levels while compromising body weight uniformity (see table 2). The dosing was performed according to the following table [ reference Xu Shuyun professor "pharmacological Experimental methodology (third edition. Minn health Press) conversion of rat and human dose, 8mg/kg for the rat dose of losartan potassium group of Table 2, 80mg for human dose, and so on ], and blood pressure and HCY levels were measured 4 weeks after dosing.
Interactions between the components in the composition were calculated by the golden average Q method: the positive average Q value method calculates the composition interactions using the following formula q=e A+B/(EA+EB-EA×EB where the numerator represents the "measured combined effect", the denominator represents the "expected combined effect", and Q is the ratio of the two. The combination of the two drugs is considered antagonistic when the Q value is <0.85, additive when the Q value is <0.85 and synergistic when the Q value is > 1.15. In order to meet the analysis of pharmacological action relation, the measured value is converted into an effect which can intuitively embody the pharmacological action intensity, and the calculation formula is as follows: e i＝(1-Pi/P Model group )×100％,Pi is the actual measurement of each group, and P Model group is the actual measurement of the model group. The results are shown in the following table:
table 2. Effects of the invention on blood pressure and HCY levels in rats with the combination of hypertension and hypertension in the HCY model (n=9-10)
Note that: 1) *P<0.05,** P <0.01 compared to model control; 2) The dosage of 5-methyltetrahydrofolate is based on equimolar folic acid mass.
The blood pressure and HCY levels were significantly elevated in the rats of the model group compared to the sham group. Compared with the rats in the model group, the blood pressure level of the azilsartan II group and the blood pressure level of the metartan potassium group are obviously reduced, and the blood pressure level of the azilsartan II group and the blood pressure level of the metartan potassium group have statistical differences (P <0.05 or P < 0.01), which indicate that the azilsartan or the metartan potassium has obvious blood pressure reducing effect; azilsartan or metartan potassium has no obvious effect on HCY. Compared with the model rat, the blood pressure level of the folic acid II group and the 5-methyltetrahydrofolate group has no obvious change, and the HCY level is obviously reduced. Compared with azilsartan II and folic acid II with corresponding doses, the azilsartan II and folic acid II compound has the advantages that the blood pressure level or HCY level is further obviously reduced, and the calculated Q values of the composition are respectively 1.77 and 1.17 and are both more than 1.15 on the blood pressure reduction level and HCY level relative to the two single medicines. The blood pressure level or HCY level of the mesartan potassium + 5-methyltetrahydrofolate composition is further reduced compared to the corresponding dose of mesartan potassium or 5-methyltetrahydrofolate; the composition had calculated Q values of 1.24 and 1.25, respectively, and greater than 1.15 for both drug units at reduced pressure and HCY levels. It is shown that azilsartan or metaxartan potassium can further improve blood pressure and HCY level by combining folic acid or 5-methyltetrahydrofolate, and has synergistic effect.
The research results show that the combination of the azilsartan or the prodrug (or derivative) thereof and folic acid substances has the functions of synergism and adverse reaction reduction, and is a better antihypertensive drug selection.
Claims (10)
1. A pharmaceutical composition comprises the following components:
(1) A pharmaceutically effective amount of azilsartan or a derivative thereof,
(2) A pharmaceutically effective amount of folic acid or a derivative thereof,
(3) A pharmaceutically acceptable carrier, which is used for the preparation of the medicine,
Wherein the mass ratio of the pharmaceutically effective amount of azilsartan or derivative thereof (calculated by azilsartan) to the pharmaceutically effective amount of folic acid or derivative thereof (calculated by folic acid) is 5: 1-400:1, the pharmaceutical composition can reduce the side effect risk of diarrhea caused by azilsartan.
2. The pharmaceutical composition according to claim 1, characterized in that the mass ratio of azilsartan to folic acid of the pharmaceutically effective amount is preferably 100: 1-200:1.
3. Pharmaceutical composition according to claim 1, characterized in that the pharmaceutically effective amount of azilsartan or derivative thereof (in terms of azilsartan) is between 10 and 150mg, preferably between 20 and 80mg; the pharmaceutically effective amount of folic acid or its derivatives is 0.01-5 mg, preferably 0.2-1.2 mg.
4. A pharmaceutical composition according to claim 3, characterized in that the azilsartan or derivative thereof (in terms of azilsartan) is 10mg and the folic acid or derivative thereof (in terms of folic acid) is 0.4mg;
Or 20mg of azilsartan or derivative thereof (calculated as azilsartan), and 0.4mg of folic acid or derivative thereof (calculated as folic acid);
Or 20mg of azilsartan or derivative thereof (calculated as azilsartan), and 0.8mg of folic acid or derivative thereof (calculated as folic acid);
Or azilsartan or derivative thereof (calculated as azilsartan) 40mg and folic acid or derivative thereof (calculated as folic acid) 0.4mg;
or azilsartan or derivative thereof (calculated as azilsartan) 40mg and folic acid or derivative thereof (calculated as folic acid) 0.8mg;
or azilsartan or derivative thereof (calculated as azilsartan) 80mg and folic acid or derivative thereof (calculated as folic acid) 0.4mg;
Or azilsartan or derivative thereof (calculated as azilsartan) 80mg and folic acid or derivative thereof (calculated as folic acid) 0.8mg.
5. The pharmaceutical composition according to claim 1, wherein the folic acid derivative is selected from, but not limited to, synthetic folic acid, 5-methyltetrahydrofolate, leucovorin, folinic acid or calcium levofolinate.
6. The pharmaceutical composition according to claim 1, wherein the azilsartan derivative comprises a crystalline form, a pharmaceutically acceptable salt, a pharmaceutically acceptable precursor, an active metabolite or a substance convertible in vivo into azilsartan.
7. The pharmaceutical composition according to claim 6, wherein the azilsartan pharmaceutical precursor is metartan potassium.
8. Use of a pharmaceutical composition according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of hypertension.
9. The use according to claim 8, wherein the hypertension is hypertension accompanied by elevated homocysteine.
10. The use according to claim 8, wherein the pharmaceutical composition reduces the risk of diarrhea caused by prolonged administration of azilsartan.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211410319.2A CN118059105A (en) | 2022-11-11 | 2022-11-11 | Antihypertensive pharmaceutical composition |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211410319.2A CN118059105A (en) | 2022-11-11 | 2022-11-11 | Antihypertensive pharmaceutical composition |
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| CN202211410319.2A Pending CN118059105A (en) | 2022-11-11 | 2022-11-11 | Antihypertensive pharmaceutical composition |
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