CN118059105A - Antihypertensive pharmaceutical composition - Google Patents
Antihypertensive pharmaceutical composition Download PDFInfo
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- azilsartan
- folic acid
- derivative
- calculated
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 21
- 230000003276 anti-hypertensive effect Effects 0.000 title description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 132
- 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
- 229960002731 azilsartan Drugs 0.000 claims abstract description 91
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims abstract description 66
- 235000019152 folic acid Nutrition 0.000 claims abstract description 66
- 239000011724 folic acid Substances 0.000 claims abstract description 66
- 229960000304 folic acid Drugs 0.000 claims abstract description 66
- 206010012735 Diarrhoea Diseases 0.000 claims description 29
- ZNOVTXRBGFNYRX-ABLWVSNPSA-N levomefolic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-ABLWVSNPSA-N 0.000 claims description 18
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 17
- 235000007635 levomefolic acid Nutrition 0.000 claims description 17
- 239000011578 levomefolic acid Substances 0.000 claims description 17
- 206010020772 Hypertension Diseases 0.000 claims description 15
- 230000000694 effects Effects 0.000 claims description 13
- 239000011591 potassium Substances 0.000 claims description 12
- 229910052700 potassium Inorganic materials 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 7
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 claims description 5
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 claims description 4
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 claims description 4
- 235000008191 folinic acid Nutrition 0.000 claims description 4
- 239000011672 folinic acid Substances 0.000 claims description 4
- 229960001691 leucovorin Drugs 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 150000002224 folic acids Chemical class 0.000 claims description 3
- 239000002207 metabolite Substances 0.000 claims description 3
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 claims description 2
- 150000004105 azilsartan derivatives Chemical class 0.000 claims description 2
- 229960001921 calcium levofolinate Drugs 0.000 claims description 2
- KVUAALJSMIVURS-QNTKWALQSA-L calcium;(2s)-2-[[4-[[(6s)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioate Chemical compound [Ca+2].C([C@@H]1N(C=O)C=2C(=O)N=C(NC=2NC1)N)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-QNTKWALQSA-L 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000001727 in vivo Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000002035 prolonged effect Effects 0.000 claims 1
- 230000036772 blood pressure Effects 0.000 abstract description 19
- 230000001603 reducing effect Effects 0.000 abstract description 3
- 208000033892 Hyperhomocysteinemia Diseases 0.000 description 18
- 230000003225 hyperhomocysteinemia Effects 0.000 description 18
- 241000699670 Mus sp. Species 0.000 description 16
- 241000700159 Rattus Species 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- 206010067484 Adverse reaction Diseases 0.000 description 8
- 230000006838 adverse reaction Effects 0.000 description 8
- 210000003608 fece Anatomy 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000002220 antihypertensive agent Substances 0.000 description 3
- 229940127088 antihypertensive drug Drugs 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 210000002254 renal artery Anatomy 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 108050000824 Angiotensin II receptor Proteins 0.000 description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- DRBBFCLWYRJSJZ-UHFFFAOYSA-N N-phosphocreatine Chemical compound OC(=O)CN(C)C(=N)NP(O)(O)=O DRBBFCLWYRJSJZ-UHFFFAOYSA-N 0.000 description 2
- 238000001467 acupuncture Methods 0.000 description 2
- 230000003044 adaptive effect Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000002301 combined effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 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
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 101150116411 AGTR2 gene Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 102400000967 Bradykinin Human genes 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 208000025047 Non-histaminic angioedema Diseases 0.000 description 1
- 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
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 208000004531 Renal Artery Obstruction Diseases 0.000 description 1
- 206010038378 Renal artery stenosis Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- FCPVYOBCFFNJFS-LQDWTQKMSA-M benzylpenicillin sodium Chemical compound [Na+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 FCPVYOBCFFNJFS-LQDWTQKMSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000000546 chi-square test Methods 0.000 description 1
- 229940126678 chinese medicines Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 208000017574 dry cough Diseases 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000002350 laparotomy Methods 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960000519 losartan potassium Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229950007002 phosphocreatine Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- 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 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211410319.2A CN118059105A (en) | 2022-11-11 | 2022-11-11 | Antihypertensive pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118059105A true CN118059105A (en) | 2024-05-24 |
Family
ID=91097767
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211410319.2A Pending CN118059105A (en) | 2022-11-11 | 2022-11-11 | Antihypertensive pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118059105A (en) |
-
2022
- 2022-11-11 CN CN202211410319.2A patent/CN118059105A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2007135991A (en) | MEDICINAL FORM CONTAINING OXYCODONE AND NALOXONE | |
| CN110801452B (en) | Pharmaceutical composition containing allisartan isoproxil hydrolysate or hydrolysate salt thereof and application thereof | |
| JP2015510908A (en) | Combination therapies for the treatment of proliferative diseases (vemurafenib and MDM2 inhibitors) | |
| KR101891505B1 (en) | Use of anhydroicaritin in preparing medicine for preventing or treating decrease in blood cells | |
| KR20070085470A (en) | S-mirtazapine for the treatment of hot flush | |
| TW200940062A (en) | Combination comprising paclitaxel for treating ovarian cancer | |
| CN113230411B (en) | Compound pharmaceutical composition of allisartan isoproxil or salt thereof and calcium channel antagonist | |
| CN107137417B (en) | Pharmaceutical composition for treating cachexia and application thereof | |
| TWI341728B (en) | Combinations comprising epothilones and anti-metabolites | |
| CN105233288A (en) | Pharmaceutical composition for treatment or prevention of obesity-related hypertension and usage of pharmaceutical composition for treatment or prevention of obesity-related hypertension | |
| CN118059105A (en) | Antihypertensive pharmaceutical composition | |
| CN102512435B (en) | Application of scutellarin methyl ester and medicinal composition as well as preparation thereof | |
| CN113289023A (en) | Medicinal composition of allisartan isoproxil or salt thereof and diuretic | |
| CN102283834B (en) | Orlisat-containing medicinal composition and application thereof | |
| JP3253878B2 (en) | Formulations for iron chelation, methods of preparing the same and methods of treating Mediterranean anemia | |
| KR20120104574A (en) | Tivozanib and temsirolimus in combination | |
| KR20200055117A (en) | Pharmaceutical composition for prevention or treatment of cancer, including PI3 kinase inhibitor and cytotoxic anticancer agent | |
| CN102283832B (en) | Medicinal composition for preventing or treating hypertensive obese patient and application thereof | |
| US20190381034A1 (en) | Pharmaceutical composition and method for acute on chronic liver failure and related liver diseases | |
| CN103638020A (en) | Novel pharmaceutical composition for treating gout | |
| CN113133997B (en) | Pharmaceutical composition containing berberine and application thereof | |
| CN110446505A (en) | For treating dermopathic conjoint therapy | |
| CN116617313B (en) | A Chinese medicinal composition with antidepressant, anxiolytic and antifatigue effects, and its preparation method | |
| CN112641765B (en) | Anti-fatigue pharmaceutical application of propofol | |
| JP7357386B2 (en) | Application of the compound or its pharmaceutically acceptable salt, dimer or trimer in the preparation of drugs for cancer treatment |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination |