CN101632666B - Drug composition used for treating high blood pressure - Google Patents
Drug composition used for treating high blood pressure Download PDFInfo
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- CN101632666B CN101632666B CN2008101445149A CN200810144514A CN101632666B CN 101632666 B CN101632666 B CN 101632666B CN 2008101445149 A CN2008101445149 A CN 2008101445149A CN 200810144514 A CN200810144514 A CN 200810144514A CN 101632666 B CN101632666 B CN 101632666B
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- amlodipine
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- pioglitazone
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Abstract
The invention relates to a drug composition used for treating high blood pressure, comprising amlodipine and thiazolidinediones insulin sensitizer-pioglitazone the weight ratio of which is 1:0.5-6, and can be prepared into tablets, granular formulation, sustained release tablets and capsules. By studying on the pharmacology of the drug composition, ideal primary hypertension treatment effect is discovered, and the drug composition of the invention obtains unexpected effects on the following aspects, such as reducing the systolic pressure, lowering the blood viscosity of hypertensive rats, regulating and controlling the activity of coagulation fibrinolytic system, alleviating the adverse reaction caused by antihypertensive drugs and increasing the survival rate of hypertension patients effectively and the like.
Description
Technical field
The present invention relates to the hypertensive pharmaceutical composition of a kind of treatment, belong to medical technical field.
Background technology
Continuous development along with modern medicine, the theory of hypertension therapeutic is also in continuous development and change, not only be confined in the blood pressure lowering treatment for hypertensive treatment, a series of complication of effectively preventing and treating hypertension to cause are the even more important aspects of hypertension therapeutic.Now to hypertensive treatment, the long-term survival rate that improves the patient is even more important content, otherwise blood pressure has reduced, hyperpietic's survival rate can not improve even can reduce patient's survival rate on the contrary, and this also just makes the blood pressure lowering treatment lose the most basic meaning.
That is to say that the final goal of hypertension therapeutic is an armour, just one of them means bring high blood pressure down.Yet in existing antihypertensive drugs, also there is not the very good medicine that meets present hypertension therapeutic theory to come out.Hypertension becomes modern metropolitan cities people's a big healthy killer day by day, must cause our attention.
Hypertension is mainly damaged human vas, and it can impel the ductus arteriosus wall hardening, and the tube chamber stenosis is narrow---and promptly said at ordinary times " arteriosclerosis ".If the concurrent diabetes of hypertension then can be quickened, increase the weight of vascular lesion, the state of an illness is worsened rapidly, should active prevention and treatment hypertension and complication.
Amlodipine is dihydropyridine type calcium antagonists (calcium ion antagonist or a slow channel blocking agent).The contraction of cardiac muscle and smooth muscle depends on the extracellular Ca2 ion and enters cell by the specificity ion channel.This product selectivity suppresses calcium ion strides film and enters smooth muscle cell and myocardial cell, to the effect of smooth muscle greater than cardiac muscle.It is decided by that with the interaction of calcium channel it and acceptor site combine and dissociated gradual speed, so pharmacological action produces gradually.This product has the blood vessel selectivity of height, coronary artery dilator, and improve collateral circulation, and the length of holding time, treatment causes reflexive tachycardia easily to intractable hypertension when using separately.This product still is the peripheral arterial expander, directly acts on vascular smooth muscle, reduces peripheral vascular resistance, thereby brings high blood pressure down.
Euglycemic agent is used for hypertensive treatment, especially unites to make and be used for treating hypertension, also do not have bibliographical information with amlodipine or Levamlodipine.
Present thiazolidinediones euglycemic agent mainly is to comprise rosiglitazone, pioglitazone, ciglitazone etc.
For hypertensive treatment, single medicine often can not be obtained ideal curative effect now, and hypertension complication also be can not get effectively control and prevention, clinically usually with two or more medication combined use.But which two kinds or which are planted medication combined use, but need carry out study tour carefully! It is exactly water-sodium retention that euglycemic agent has the untoward reaction of a dose dependent, and this may have influence on the antihypertensive effect of other antihypertensive drugs.Whether use can be united, comparatively careful and systematic research should be carried out.
The final purpose of hypertension therapeutic is protection patient's an important vital organ, rather than with the reduction of blood pressure as final objective, the particular importance so the organ protection of antihypertensive drugs just seems!
Summary of the invention
By studying for a long period of time to amlodipine and thiazolidinediones euglycemic agent, and to the close attention of insulin resistant hypertension, we are with amlodipine and thiazolidinediones euglycemic agent---after pioglitazone makes up, through it is carried out pharmaceutical research, the effect of finding the essential hypertension that it treats insulin resistant is ideal, at synergitic reduction systolic pressure; Alleviate the untoward reaction that antihypertensive drugs causes; Effectively increase hyperpietic's aspects such as survival rate, obtained beyond thought effect.Therefore, the combination antihypertensive that contains euglycemic agent provided by the present invention, antihypertensive therapy mistaken ideas have clinically been broken through for a long time, the promptly simple blood pressure lowering target of pursuing, ignored the hypertensive patient and can not obtain long-term survival rate, made hypertension therapeutic has been lost its most basic meaning owing to the existence of some complication.
By amlodipine respectively with thiazolidinediones euglycemic agent rosiglitazone, pyrroles's row ketone, the combination of ciglitazone, and by its pharmacodynamics test, the combined effect that draws amlodipine and pyrroles's row ketone is the most desirable, so the side effect minimum is first-selected these two kinds of drug regimens.The weight ratio of amlodipine and pyrroles's row ketone is 1: 0.5～6.
The advantage of the present composition is embodied in following several aspect:
One, calcium antagonist amlodipine or Levamlodipine and euglycemic agent have well collaborative hypotensive effect.This synergistic generation, mechanism be very clear not also, with the insulin-sensitizing effect of pioglitazone etc. direct relation not.Because under the situation that amlodipine or Levamlodipine exist, the hypotensive effect of euglycemic agent is not to have good linear relationship with their dosage.
Two, compositions of the present invention is compared with traditional antihypertensive drug, can reduce the blood viscosity of Hypertensive Rats preferably, the activity of regulation and control hemostatic system reduces thrombosis and the concurrent probability of other cardiovascular and cerebrovascular disease, and the mechanism of action also needs further research.
Three, life-time service compositions of the present invention, the secular apopiecticus insultus of SHR rat has been produced positive effect, this is indicating that the long-term survival rate to the hyperpietic will produce wholesome effect, prognosis to the patient produces active influence, and this also is the clinical treatment problem that has meaning most solved by the invention.
In a word, the antihypertensive composition that the present invention contains euglycemic agent has revolutionary meaning for hypertensive treatment, and the obtained long term clinical results of compositions of the present invention is unprecedented on the hypertension therapeutic history.
Result of study shows that each group all has significant difference with model group.3 groups of 2 groups of compound recipes and compound recipes and amlodipine group relatively have significant difference, illustrate that amlodipine and pioglitazone compound recipe group have well collaborative antihypertensive effect to the SHR rat.
The result shows that SHRsp takes place the appetite minimizing often to occur before the apoplexy, loses weight.By table 2 as seen, 6 groups of rats body weight no significant difference when 8 ages in week.After the grouping administration, amlodipine group, 2 groups of compound recipes and 3 groups of rat body weights of compound recipe continue to increase, and there were significant differences with the model group comparison same period, and there were significant differences for the body weight in age 1 group of 14 week of compound recipe and the model group comparison same period.And along with the outbreak of apoplexy, 3 SHR of model group are dead midway, and the amlodipine group has 1 death, and the pioglitazone group has 2 death, and other each groups take place dead.This has fully shown hypertension compound recipe group, particularly 3 groups of 2 groups of compound recipes and compound recipes for the SHR rat lose weight and the apoplexy mortality rate all has good effect.
The result shows that each group all has significant difference with model group.Compound recipe group and amlodipine group, pioglitazone group relatively have significant difference, illustrate that amlodipine and pioglitazone compound recipe group have excellent control effect to the blood viscosity level of essential hypertension SHR rat, and can effectively regulate and control the hemostatic system activity.
The specific embodiment
Now by following example of formulations and the present invention of experimental example more detailed description, but do not limit the present invention in any form.
Example of formulations 1
Prepare composite sheet according to methods known in the art, every contains following compositions;
The hypertension compound tablet
Amlodipine Besylate Tablet 2.5g
Pyrrolidine hydrochloride row ketone 22.5g
All the other pharmaceutic adjuvants are the adjuvant commonly used of preparation tablets.
Annotate: used Amlodipine Besylate Tablet, pyrrolidine hydrochloride row ketone weight are calculated with amlodipine, pyrroles's row ketone respectively.
Preparation technology: according to conventional preparation technology's preparation of tablet.
Example of formulations 2
The hypertension compound tablet
Amlodipine maleate 5g
Pyrrolidine hydrochloride row ketone 2.5g
All the other pharmaceutic adjuvants are the adjuvant commonly used of preparation tablets.
Annotate: used amlodipine maleate, pyrrolidine hydrochloride row ketone weight are calculated with amlodipine, pyrroles's row ketone respectively.
Preparation technology: according to conventional preparation technology's preparation of tablet.
Example of formulations 3
The agent of hypertension compound granular
Amlodipine 5g
Pyrroles's row ketone 30g
All the other pharmaceutic adjuvants are the adjuvant commonly used of granule preparation.
Preparation technology: according to conventional preparation technology's preparation of granule.
Example of formulations 4
The hypertension compound tablet
Amlodipine maleate 10g
Pyrrolidine hydrochloride row ketone 15g
All the other pharmaceutic adjuvants are the adjuvant commonly used of preparation tablets.
Annotate: used amlodipine maleate, pyrrolidine hydrochloride row ketone weight are calculated with amlodipine, pyrroles's row ketone respectively.
Preparation technology: according to conventional preparation technology's preparation of tablet.
Example of formulations 5
The hypertension compound slow-release tablet
Amlodipine 5g
Pioglitazone 20g
Hydroxypropyl methylcellulose 50g
Polyvinylpyrrolidone 10-20g
Lactose 5-85g
Micropowder silica gel 1-10g
80% alcoholic solution is an amount of
Preparation technology: amlodipine, pioglitazone and the slow releasing agent mix homogeneously of recipe quantity are added the granulation of 80% alcoholic solution, dry about 60 ℃, whole dried granule, the lubricant of adding recipe quantity in dried granule, mixing, special-shaped stamping gets final product.
Example of formulations 6
The hypertension compound slow-release tablet
Amlodipine 5g
Pioglitazone 25g
Hydroxyethyl-cellulose 10-50g
Microcrystalline Cellulose 1-80g
Lactose 5-85g
Magnesium stearate 1-50g
80% alcoholic solution is an amount of
Preparation technology: with embodiment 4.
If needed, tablet can be used hydroxypropyl emthylcellulose, and Pulvis Talci and coloring agent etc. carries out film coating.
Example of formulations 7
The hypertension compound capsule
Amlodipine 5g
Pioglitazone 20g
Preparation technology: according to capsular conventional preparation technology's preparation.
Example of formulations 8
The hypertension compound sustained release capsules
Amlodipine 5g
Pioglitazone 35g
Hydroxyethyl-cellulose 20-100g
Microcrystalline Cellulose 5-40g
Lactose 5-85g
80% alcoholic solution is an amount of
Preparation technology: according to conventional preparation technology's preparation of slow releasing capsule.
Embodiment 9 hypertension compound recipes are to the therapeutic effect of SHR Mus
1, laboratory animal
The SHR rat, age in male and female half and half, 7 week, 150～200g, test temperature (20 ± 1) ℃, humidity 40%～70%, entire test are drunk 0.9% saline and feed conventional feed.
2, experimental technique
With 40 7 age in week SHR rat conventional feed raised for 1 week, weigh and measure with BP2006A type toy survey meter of blood pressure, conventional tail tremulous pulse method is measured the animal systolic pressure of regaining consciousness, and is divided into 6 groups at random by blood pressure level, 8 every group.The 1st group is model group, irritates stomach with volume 0.9% saline; The 2nd group is the Levamlodipine group, 0.5mg/ (kg.d) Levamlodipine; The 3rd group is the pioglitazone group, 1.0mg/ (kg.d); The 4th group is 1 group of compound recipe (Levamlodipine+pioglitazone), 0.5mg/ (kg.d) Levamlodipine+1.0mg/ (kg.d) pioglitazone; The 5th group is 2 groups of compound recipes (amlodipine+pioglitazone), 1.0mg/ (kg.d) amlodipine+0.5mg/ (kg.d) pioglitazone; The 6th group is 3 groups of compound recipes (Levamlodipine+pioglitazone).0.5mg/ (kg.d) Levamlodipine+3.0mg/ (kg.d) pioglitazone.Each group is gastric infusion.All animals are all drunk 0.9% saline.In the experimentation, observe animal diet followed, survival condition and behavioral activity every day, measure body weight every day, adjust drug dose according to body weight; Per 2 weeks are carried out an arteria caudalis blood pressure determination.Carrying out blood viscosity and hemostatic system activity index at last measures.Measure blood viscosity with LG-R-80F type blood viscometer; Measure the blood clotting index with MC-4000, MC-2000 measures the D-dimer.
3, experimental result
1, the hypertension compound recipe is to the influence of spontaneous hypertensive rat (SHR) blood pressure
The result shows, amlodipine and pioglitazone are united use has well collaborative antihypertensive effect for the blood pressure of SHR rat.
Table 1 hypertension compound recipe to the influence (n=8) of SHR rat blood pressure (kPa)
●Compare with model group, p＜0.05,
● ●Compare p＜0.01 with model group;
■Compare p＜0.05 with the pioglitazone group,
■ ■Compare p＜0.01 with the pioglitazone group.
2. the hypertension compound recipe is to the influence of SHR blood viscosity
The result shows, the blood viscosity level of the effectively collaborative reduction SHR Hypertensive Rats of amlodipine and pioglitazone compound recipe group energy, and the mechanism of action it be unclear that, and also needs further research.
Table 2 hypertension compound recipe is to the influence (n=8) of SHR blood viscosity
●Compare p＜0.05 with model group,
● ●Compare p＜0.01. with model group
3. the hypertension compound recipe is to the active influence of blood coagulation system
The result shows, behind amlodipine and the pioglitazone drug combination, the height that has effectively improved the SHR rat blood coagulates and high fibrinolytic state, illustrate that amlodipine and pioglitazone drug combination have excellent control effect for the hemostatic system activity level of hypertension SHR rat, the mechanism of action also needs further research.
Table 3 hypertension compound recipe is to the active influence of blood coagulation system (n=8)
●Compare p＜0.05 with model group
● ●Compare p＜0.01 with model group
Embodiment 10 hypertension compound recipes are to the therapeutic effect of SHRsp rat
1, laboratory animal
The SHRsp rat, age in male and female half and half, 7 week, 150～200g, test temperature (20 ± 1) ℃, humidity 40%～70%, entire test are drunk 0.9% saline and feed conventional feed.
2, experimental technique
With 40 7 age in week SHRsp rat conventional feed raised for 1 week, weigh and measure with BP2006A type toy survey meter of blood pressure, conventional tail tremulous pulse method is measured the animal systolic pressure of regaining consciousness, and is divided into 6 groups at random by blood pressure level, 8 every group.The 1st group is model group, irritates stomach with volume 0.9% saline; The 2nd group is the amlodipine group, 0.5mg/ (kg.d) amlodipine; The 3rd group is the pioglitazone group, 1.0mg/ (kg.d); The 4th group is 1 group of compound recipe (amlodipine+pioglitazone), 0.5mg/ (kg.d) amlodipine+1.0mg/ (kg.d) pioglitazone; The 5th group is 2 groups of compound recipes (amlodipine+pioglitazone), 1.0mg/ (kg.d) ammonia+0.5mg/ (kg.d) pyrrole; The 6th group is 3 groups of compound recipes (amlodipine+pioglitazone).0.5mg/ (kg.d) ammonia+3.0mg/ (kg.d) pyrrole.Each group is gastric infusion.All animals are all drunk 0.9% saline.In the experimentation, observe animal diet followed, survival condition and behavioral activity every day, measure body weight every day, adjust drug dose according to body weight; Per 2 weeks are carried out an arteria caudalis blood pressure determination.Each treated animal cerebral seizure number of times reaches duration of seizure first in the record 6 week test.
3, experimental result hypertension compound recipe is to the influence of SHRsp body weight and survival condition
The result shows that SHRsp takes place the appetite minimizing often to occur before the apoplexy, loses weight.By table 4 as seen, 6 groups of rats body weight no significant difference when 8 ages in week.After the grouping administration, amlodipine group, 2 groups of compound recipes and 3 groups of rat body weights of compound recipe continue to increase, and there were significant differences with the model group comparison same period, and there were significant differences for the body weight in age 1 group of 14 week of compound recipe and the model group comparison same period.And along with the outbreak of apoplexy, 3 SHRsp of model group are dead midway, and the amlodipine group has 2 death, and the pioglitazone group has 4 death, and each group of drug combination takes place dead.This fully shown hypertension compound recipe group for the SHRsp rat lose weight and the apoplexy mortality rate all has good effect.
Table 4 hypertension compound recipe to the influence (n=8) of SHRsp body weight and survival condition (g)
Table 4 (continuing)
●Compare p＜0.05 with model group;
● ●Compare p＜0.01 with model group;
★Compare p＜0.05 with the amlodipine group.
Claims (5)
1. treat hypertensive pharmaceutical composition for one kind, it is characterized in that its active component is grouped into by following one-tenth:
(1) amlodipine or available salt of its medicinal forms or Levamlodipine; With
(2) pioglitazone or the available salt of its medicinal forms.
2. compositions as claimed in claim 1, the weight ratio that it is characterized in that amlodipine or Levamlodipine and pioglitazone is 1: 0.5～6.
3. compositions as claimed in claim 1 is characterized in that the available salt of amlodipine medicinal forms is maleate, benzene sulfonate or its mixture.
4. compositions as claimed in claim 1 is characterized in that the available salt of pyrroles's row ketone medicinal forms is hydrochlorate.
5. compositions as claimed in claim 1 is characterized in that it is tablet, granule, capsule or slow releasing preparation.
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| CN101632666B true CN101632666B (en) | 2011-02-23 |
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- 2008-07-24 CN CN2008101445149A patent/CN101632666B/en active Active
Non-Patent Citations (3)
| Title |
|---|
| 亓翠玲.罗格列酮并硝苯地平控释片治疗2型糖尿病并稳定型心绞痛的效果.《齐鲁医学杂志》.2007,第22卷(第5期),451-452. * |
| 刘敏.替米沙坦降压治疗对原发性高血压患者胰岛素抵抗的影响.《江汉大学学报(自然科学版)》.2008,第36卷(第4期),60-61,摘要. * |
| 谢成刚.吡格列酮对新发高血压伴单纯性肥胖患者血压、血脂、胰岛素水平的影响.《中国实用医药》.2007,第2卷(第23期),47-48，讨论. * |
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