CN103316004B - Pharmaceutical composition used for preventing and controlling metabolic syndrome and application thereof - Google Patents
Pharmaceutical composition used for preventing and controlling metabolic syndrome and application thereof Download PDFInfo
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- 208000001145 Metabolic Syndrome Diseases 0.000 title abstract description 9
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 title abstract description 9
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 claims abstract description 37
- KWWLGXNRLABSMP-UHFFFAOYSA-N phosphoric acid;2,3,5,6-tetramethylpyrazine Chemical compound OP(O)(O)=O.CC1=NC(C)=C(C)N=C1C KWWLGXNRLABSMP-UHFFFAOYSA-N 0.000 claims abstract description 30
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- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical group OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
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- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
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- 241000700157 Rattus norvegicus Species 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 1
- 229940044478 aliskiren 150 mg Drugs 0.000 description 1
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- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a pharmaceutical composition used for preventing and controlling a metabolic syndrome and application thereof. Active components of the pharmaceutical composition comprise: (1) aliskiren or a pharmaceutically acceptable salt thereof; and (2) ligustrazine phosphate. The composition provided by the invention has same effects on reduction of blood pressure, blood fat, blood sugar and body weight as each active component of the composition does; compatible usage of the two active components enables the dosage of each individual component to be greatly reduced, so adverse reaction of aliskiren and drug risk of ligustrazine phosphate are substantially reduced.
Description
Technical field
The invention belongs to medical technical field, in particular to a kind of pharmaceutical composition and application thereof that prevents and treats metabolism syndrome.
Background technology
Overweight or obesity, and with a series of pathological changes such as hypertension, hyperlipidemia, hyperglycemia, atherosclerosis and hyperinsulinemia, this phenomenon is medically being called as metabolism syndrome.Metabolism syndrome is the common physical problems of one that urban population faces, and it not only can increase the initiation potential of diabetes and cardiovascular and cerebrovascular disease, also increases the mortality rate of cardiovascular and cerebrovascular disease simultaneously.Metabolism syndrome be one polygenic, genetic disease, and be subject to the impact of environment.Its clinical characters is that obesity, dyslipidemia, hyperglycemia and hypertension four aspects merge appearance.And often " acting in collusion with each other " of these four kinds of diseases is modern city people " dead quartet ".Therefore, brainstrust appealing, metabolism syndrome must cause medical circle and the public's attention.Metabolism syndrome was in the past actually rare at China's incidence, because living standard is at that time not high, along with improving constantly of living standard, according to incompletely statistics, China is getting more and more of existing adiposis patient 7,000,000 people, particularly Adolescent Obesity now.Hypertensive patient probably has 1.8 hundred million people in China, and diabetic probably has 4～5,000 ten thousand, so the patient of metabolism syndrome is current also very high at the incidence of China.According to another the investigation of diabetes association of Chinese Medical Association, at present at Chinese city in more than 20 years old crowd, the prevalence of metabolism syndrome is 14%～16%.Metabolism syndrome increases along with increasing of age, reaches onset peak at 50 to 70 years old in crowd, and wherein female patient is more than male.At present, for the treatment of metabolism syndrome, significant medicine is also of no curative effect on market.
Aliskiren is the oral direct renin inhibitor of a kind of low molecular mass, high selectivity, can significantly reduce PRA, suppress proangiotensin and be converted into AngI, then the level that reduces AngI, angiotensinⅡ (Ang II), is used to treat essential hypertension clinically.Ligustrazine is a kind of alkaloid monomer of separation and Extraction from Rhizome of Ligusticum Sinense Oliv. Cv. Chuanxiong, for novel agents of calcium ion antagonistic, have the free-radical generating of inhibition, improve endogenous superelevation superoxide dismutase (SOD) activity, remove oxygen-derived free radicals, improve the pharmacologically actives such as blood change, anticoagulant, inhibition fibrosis, regulating lipid metabolism, lipoid peroxidization resistant, main is clinically to be used for the treatment of cerebrovascular disease and ischemia resisting reperfusion injury, cardiovascular disease and respiratory system disease etc.
At present, also there is no the drug combination report of aliskiren and ligustrazine both at home and abroad, more there is no the bibliographical information of aliskiren associating ligustrazine metabolism syndrome.
Summary of the invention
In view of the deficiencies in the prior art, the object of the present invention is to provide a kind of novel pharmaceutical composition, be used for the treatment of metabolism syndrome.Through a large amount of animal experiment studies, the present inventor has proposed aliskiren and ligustrazine phosphate to be prepared into pharmaceutical composition, and has filtered out both optimum dose proportions of front and back, demonstrates beyond thought effect in pharmacodynamics test.
The inventor creatively combines aliskiren and ligustrazine phosphate to be prepared into pharmaceutical composition, is used for the treatment of Metabolic Syndrome Patients.Study by a large amount of preclinical tests, the another inventor is beyond thought, and the use in conjunction of aliskiren and ligustrazine phosphate has shown the syndromic synergism of surprising antimetabolic.
The object of the present invention is achieved like this: a kind of pharmaceutical composition of preventing and treating metabolism syndrome, and in this pharmaceutical composition, active component is made up of following component: (1) aliskiren or its officinal salt; (2) ligustrazine phosphate.
Object of the present invention can also realize like this:
The pharmaceutical composition of above-mentioned control metabolism syndrome, in wherein said pharmaceutical composition, aliskiren officinal salt is in aliskiren, and component (1) is 3-30:1 with the weight consumption ratio of component (2).
Preferably, the pharmaceutical composition of above-mentioned control metabolism syndrome, in wherein said pharmaceutical composition, aliskiren officinal salt is in aliskiren, and component (1) is 6-10:1 with the weight consumption ratio of component (2).
Preferably, the pharmaceutical composition of above-mentioned control metabolism syndrome, wherein said aliskiren officinal salt is fumarate, nitrate, sulfate or the Orotate of aliskiren.
Preferably, the pharmaceutical composition of above-mentioned control metabolism syndrome, wherein said pharmaceutical composition is solid orally ingestible.According to the weight ratio of aliskiren and ligustrazine phosphate, by the conventional technology of preparing of solid orally ingestible, said composition can be prepared into tablet, capsule.
Further preferably, the pharmaceutical composition of above-mentioned control metabolism syndrome, in wherein said solid orally ingestible, per unit preparation contains 150-300mg aliskiren, contains 10-50mg ligustrazine phosphate.
Again further preferably, the pharmaceutical composition of above-mentioned control metabolism syndrome, in wherein said solid orally ingestible, per unit preparation contains 150mg aliskiren, contains 20-25mg ligustrazine phosphate.
Study discovery by animal experiment, the compositions that above-mentioned active component is made up of aliskiren and ligustrazine phosphate has the significant curative effect of Synergistic treatment Metabolic Syndrome rat.Therefore, second object of the present invention is to provide a kind of new medical use, i.e. the purposes of above-mentioned composition in the medicine of preparation prevention or treatment metabolism syndrome.
Pharmaceutical composition of the present invention is in treatment when metabolism syndrome, most critical, and ligustrazine phosphate needs low dosage administration as one of active component.Be preferably: when the administration of ligustrazine phosphate low dosage, aliskiren carries out routine dose administration as another active one-tenth.The people who draws compound recipe by test is respectively with oral every daily dose: aliskiren 150mg, ligustrazine phosphate 20-25mg.
By the pharmacodynamic study to compositions of the present invention, in experiment, be surprised to find that, aliskiren used reducing rat body weight with combining of ligustrazine phosphate, reduce blood pressure, and enhancing carbohydrate tolerance aspect existed obvious concertedness effect.In addition, compositions of the present invention, in the time reducing blood pressure, to the significantly reduced while of mean arterial pressure, also has good reducing effect to systolic pressure and pulse pressure difference, has overcome a lot of hyperpietics and has used the pulse pressure after conventional medicament to increase.
Compositions of the present invention is by the research work of pharmacology aspect, show when by compositions of the present invention, especially while adopting preferred proportioning, compared with during with the aliskiren of independent application effective dose or ligustrazine phosphate, compositions of the present invention provides astonishing synergy, toxicity does not increase simultaneously, in the situation that reaching identical blood pressure lowering, blood fat reducing, blood sugar lowering, falling body weight effect, two class drug combinations greatly reduce the using dosage of every kind of medicine, and this has just significantly reduced the untoward reaction of aliskiren and the drug risk of ligustrazine phosphate.
The specific embodiment
By the form of animal experiment example, foregoing of the present invention is described in further detail again below, but this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following example, all technology realizing based on foregoing of the present invention all belong to scope of the present invention.
The impact of embodiment 1 aliskiren/ligustrazine phosphate on metabolic syndrome rat model
Male Wistar rat, body weight 180～220g, first animal is screened, and while stimulation to give first foot shock and noise, animal performance is escaped rapidly, screams, erects tail, is panted and be difficult for being adapted to standard, elects as originally and zoologizes.Animal is raised in cages separately in stimulating cage, raises with high lipid food.Before starting to stimulate, first normally raise one week, then starting stimulates, and stimulates stimulus intensity every day 2 times: each 2h of upper and lower noon, continued stimulus approximately 8 weeks.After finishing, modeling does carbohydrate tolerance test test.Oral glucose tolerance test (OGTV): after rat fasting 12h, with 2.5g/kg dosage gavage 50% glucose solution, tail venous blood sampling detects the blood glucose value of 2h, eliminate the rat of blood glucose lower than 6.20mmol/L, eliminate body weight lower than the rat of 350g (with reference to " China Medicine University's journal " 2006,37 (I): 67-7 foundation of metabolic syndrome rat model " stress add high caloric diet cause ", Su Changhai, Fu Jihua etc.), then grouping administration.
Modeling success rat is divided into as each in following table 1 group at random according to body weight:
The grouping of table 1 laboratory animal and administration
| Grouping | Sample size (only) | Dosage |
| Model group | 12 | The purified water of same volume |
| Aliskiren group | 12 | 15mg·kg -1·d -1Aliskiren |
| Ligustrazine phosphate group | 12 | 2.5 mg·kg -1·d -1Ligustrazine phosphate |
| Drug combination group | 12 | 15mg·kg -1·d -1Aliskiren+2.5mgkg -1·d -1Ligustrazine phosphate |
Every group 12, during administration, still raise with high lipid food, every day gastric infusion once, successive administration 3 months.
After finishing, claim rat body weight after administration, measure systolic pressure (SBP), diastolic pressure (DBP), serum total cholesterol (TC), HDL-C (HDL-C), triglyceride (TG).In addition, after administration finishes, water 8h is can't help in rat fasting, cuts tail and gets blood, by micro-blood glucose meter mensuration fasting glucose.After having surveyed, the Glucose Liquid gavage (determining the amount of glucose by body weight, i.e. 2.5g/kg) with 25%, again cuts tail and gets blood after 2h, measures post-prandial glycemia by micro-blood glucose meter, and calculates the difference of post-prandial glycemia and fasting glucose.Specific experiment the results are shown in Table 2-4.
Result by table 2 can find out, body weight, systolic pressure and the diastolic pressure of drug combination group all decrease, and wherein, compared with model group or each single medicine group, the body weight of drug combination group and the level of systolic pressure significantly reduce, have significant difference (
p< 0.05) or utmost point significant difference (
p< 0.01), this shows that aliskiren associating ligustrazine phosphate has well collaborative Weight-lossing antihypertensive effect to rats with metabolic syndrome model.
The impact of each group of table 2 on rat body weight and blood pressure
| Group | Body weight (g) | SBP（mmHg） | DBP（mmHg） |
| Model group | 439±42 | 171.5±18.2 | 93.2±11.9 |
| Aliskiren group | 426±35 | 137.6±14.3 | 97.2±13.2 |
| Ligustrazine phosphate group | 442±39 | 168.9±16.7 | 98.3±13.5 |
| Drug combination group | 363±36 ★★●▼▼ | 133.6±15.0 ★★▼▼ | 92.9±12.4 |
★with model group comparison, P < 0.05;
★ ★with model group comparison, P < 0.01;
●with aliskiren group, P < 0.05;
● ●with the comparison of aliskiren group, P < 0.01;
▼with the comparison of ligustrazine phosphate group, P < 0.05;
▼ ▼with the comparison of ligustrazine phosphate group, P < 0.01.
In addition, no matter fasting glucose or post-prandial glycemia, compound recipe group have compared with model group or each single medicine group significant difference (
p< 0.05) or utmost point significant difference (
p< 0.01), this shows that compound recipe respectively organizes treatment metabolism of rat syndrome and all have good blood sugar reducing function.In addition, can find out by the difference of respectively organizing post-prandial glycemia and fasting glucose, the carbohydrate tolerance of compound recipe group has the enhancing of significance, and this shows aliskiren and ligustrazine phosphate drug combination, has good synergism for the carbohydrate tolerance aspect that strengthens rats with metabolic syndrome.Experimental result refers to table 3.
The impact of each group of table 3 on rat carbohydrate tolerance
| Group | Fasting glucose | Post-prandial glycemia | Difference |
| Model group | 6.10±0.52 | 8.59±0.41 | 2.49±0.34 |
| Aliskiren group | 5.74±0.32 ★ | 8.16±0.38 | 2.42±0.39 |
| Ligustrazine phosphate group | 6.12±0.39 | 8.68±0.46 | 2.56±0.51 |
| Drug combination group | 5.27±0.32 ★★●▼▼ | 7.10±0.40 ★★●●▼▼ | 1.83±0.32 ★★●▼▼ |
★with model group comparison, P < 0.05;
★ ★with model group comparison, P < 0.01;
●with aliskiren group, P < 0.05;
● ●with the comparison of aliskiren group, P < 0.01;
▼with the comparison of ligustrazine phosphate group, P < 0.05;
▼ ▼with the comparison of ligustrazine phosphate group, P < 0.01.
After administration finishes, detect serum total cholesterol (TC), HDL-C (HDL-C), triglyceride (TG).Result shows, the level of the T-CHOL of each administration group, triglyceride, HDL-C decreases compared with model group, regulates the synergism of rats with metabolic syndrome lipid aspects but compound recipe group does not demonstrate aliskiren and ligustrazine phosphate.Experimental result refers to table 4.
The impact of each group of table 4 on rat fat
| Group | TC | TG | HDL-C |
| Model group | 3.50±0.48 | 1.35±0.20 | 0.79±0.29 |
| Aliskiren group | 3.19±0.46 | 1.16±0.18 | 0.85±0.33 |
| Ligustrazine phosphate group | 3.08±0.51 | 1.04±0.23 ★ | 0.82±0.30 |
| Drug combination group | 2.93±0.40 ★ | 1.10±0.14 ★ | 0.93±0.27 |
★with model group comparison, P < 0.05;
★ ★with model group comparison, P < 0.01.
Claims (3)
1. a pharmaceutical composition of preventing and treating metabolism syndrome, is characterized in that: in described pharmaceutical composition, active component is made up of following component: (1) aliskiren; (2) ligustrazine phosphate; Wherein, component (1) is 6:1 with the weight consumption ratio of component (2).
2. the pharmaceutical composition of preventing and treating according to claim 1 metabolism syndrome, is characterized in that: described pharmaceutical composition is solid orally ingestible.
3. the pharmaceutical composition of preventing and treating according to claim 2 metabolism syndrome, is characterized in that: in described solid orally ingestible, per unit preparation contains 150mg aliskiren, contains 25mg ligustrazine phosphate.
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| 张峰等.天然生物碱川芎嗪通过阻断PDGF-β受体介导的ERK和/或p38信号通路抑制高糖高胰岛素和过氧化氢诱导的肝星状细胞的活化.《中华中医药杂志》.2013,第28卷(第5期),1174-1182. |
| 张雅娉等.肾素抑制剂阿利吉仑.《中国临床药理学杂志》.2012,第28卷(第3期),221-224. |
| 肾素抑制剂阿利吉仑;张雅娉等;《中国临床药理学杂志》;20120331;第28卷(第3期);221-224 * |
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