CN101229372A - Medicine compounds for treating hypertension - Google Patents
Medicine compounds for treating hypertension Download PDFInfo
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Abstract
The invention provides a medical composite for treating hypertension and a preparation thereof. The medical composite comprises antihypertensive drug, HMGCoA reductase inhibitor and insulin sensitizer. The medical composite of the invention can not only effectively reduce blood pressure, but also has good effect on the treatment and prevention of hypertension complications. The long term survival of patients can be improved obviously.
Description
Affiliated technical field
The present invention is a kind of hypertensive pharmaceutical composition that is used for the treatment of.
Background technology
Hypertensive Population becomes modern metropolitan cities people's a big healthy killer day by day, must cause our attention.Hypertension is mainly damaged human body blood.It can impel the ductus arteriosus wall hardening, the tube chamber stenosis---and it is promptly said at ordinary times that " arteriosclerosis, hypertension worsens the state of an illness rapidly if complication with diabetes then can quicken, increase the weight of blood vessel to be decreased, should active treatment
The medicine of treatment hypertension is a lot of at present, and their common ground is to bring high blood pressure down, and difference is that mechanism of action and link have nothing in common with each other, and is each has something to recommend him on therapeutic effect to the hypertension that different reasons cause.The antihypertensive drug that has has protective effect to target organ, and what have does not then possess organ protection, even can increase the weight of organ injury when bringing high blood pressure down.ACEI (angiotensin converting enzyme inhibitor) can gentle, blood pressure lowering enduringly, simultaneously target organ is had good protective effect, is classified as a line antihypertensive by World Health Organization (WHO) and China's " hypertension therapeutic guide ".Angiotensin ii receptor antagonist (ARB) is the good succedaneum of ACEI class medicine, and untoward reaction is littler, and hypotensive effect is gentle and steadily, effect is more excellent, but also exist onset slow, to problems such as the severe hypertension curative effect are not good enough.Calcium antagonist has the blood vessel selectivity of height, coronary artery dilator, and improve collateral circulation, and the length of holding time, the kind that treatment has to intractable hypertension when using separately causes reflexive tachycardia easily.
The world of medicine prevented and treated cardiovascular disease and stressed in the exploitation of depressor past, had successively invented many effectively depressor.But along with the continuous development of medical science, people recognize cholesterol, fatty equal size is too high is the basic cause of disease that cardiovascular disease takes place, and hyperlipidemia is that coronary heart disease and hypertensive main hazard factor take place.Therefore, people begin the exploitation of blood lipid regulation medicine is grabbed as the emphasis of preventing and treating cardiovascular disease.From late 1980s, blood lipid-lowering medicine is released in a large number, and wherein the HMGCoA reductase inhibitor is subjected to people's favorable comment, and its clinical efficacy good is that other all kinds of blood lipid regulation medicines institute is incomparable.
Nearly 2 years, China doctor treated hypertension in the mode that change to adopt diuresis and blood vessel dilating gradually, and with the Therapeutic Method of cardiovascular and cerebrovascular disease, the mode of releasing with blood fat reducing cures mainly the new thinking of this class disease.2006 the 6th volumes of China's mistaken diagnosis magazine the 17th a phase Liu Qing man of virtue and ability, Yan Shiqin " blood pressure lowering is united accent fat and treated hyperpietic observation of curative effect " uses depressor and simvastatin therapeutic alliance hypertension, has obtained certain effect.But depressor and HMGCoA reductase inhibitor are united and are used for the treatment of hypertension, and the reduction aspect of its antihypertensive effect and side effect also is not very desirable.The HMGCoA reductase inhibitor has lovastatin (lovastatin), simvastatin (simvastain), pravastatin (pravastatin), fluvastatin (fluvastatin), atorvastatin (atorvastatin), rosuvastatin (rosuvastatin), Pitavastatin (pitavastatin) or happiness to cut down his spit of fland (cerivastatin) etc.
Euglycemic agent is the treatment that is used for type 2 diabetes mellitus always, present euglycemic agent mainly is the thiazolidinediones medicine, comprises pyrroles's row ketone (pioglitazone), rosiglitazone (rosiglitazone), ciglitazone (giglitazone), englitazone (englitazonne) etc.
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, and otherwise, blood pressure has reduced, and hyperpietic's survival rate can not improve even can reduce patient's survival rate, and this also just makes the blood pressure lowering treatment lose the most basic meaning.We can say, in existing antihypertensive drugs, also do not meet the very good medicine of present hypertension therapeutic theory and come out.
Summary of the invention
The invention provides a kind of hypertensive new pharmaceutical composition for the treatment of, this pharmaceutical composition contains depressor, HMGCoA reductase inhibitor and euglycemic agent.
Wherein depressor is one or more in calcium ion antagonist, angiotensin converting enzyme inhibitor or the angiotensin ii receptor antagonist.Calcium ion antagonist has nifedipine (nifedipine), amlodipine (amlodipine), nicardipine (nicardipine), felodipine (felodipine), lacidipine (lacidipine.), nitrendipine (nitrendipine), nimodipine (nimodipine), Buddhist nun's flordipine (nifedipine) etc.Angiotensin converting enzyme inhibitor has enalapril (enalapril), benazepril (benazepril), fosinopril (fosinopril), cilazapril (cilagapril), perindopril (perindopril), imidapril (imidapril), quinapril (quinapril), captopril (captopril), lisinopril (lisinopril), ramipril (ramipril), benazepril (benazepril), delapril (delapril) etc.Angiotensin ii receptor antagonist has valsartan (valsartan), irbesartan (irbesartan), telmisartan (telmisartan), candesartan Cilexetil (candesartan cilexetil), olmesartan medoxomil (olmesartan medoxomil), losartan (lossartan) etc.
Our Lunan Pharmacy Co. Ltd according to clinical for the latest Progress situation of hypertension therapeutic and hyperpietic's disease progression trend, the creationary euglycemic agent that is used for the treatment of diabetes of in having the blood pressure lowering scheme now, introducing, obtain extraordinary therapeutic effect, especially obtained good synergism and beyond thought effect aspect the caused various cardiovascular and cerebrovascular complications of treatment hypertension.By embodiment 11 and embodiment 12 as can be seen the present invention than existing depressor+HMGCoA reductase inhibitor suitable remarkable advantages is being arranged aspect the blood pressure lowering.In addition, cardiovascular disease is hyperpietic's a disease occurred frequently, and the present invention is the effectively generation of control of cardiovascular disorders then.We in embodiment 12 and embodiment 13 by the exponential mensuration of spontaneous hypertensive rat myocardial hypertrophy having been proved it is in the advantage of preventing and treating aspect the cardiovascular disease.Thereby we have sufficient reason and foundation prediction, after the present invention is used for clinical treatment hypertension in the future, all have low significantly for the death of patients with coronary heart disease, the sudden cardiac arrest of non-lethality incidence rate of myocardial infarction recovery and the incidence rate of deadly and non-lethality apoplexy.
General antihypertensive drugs is that simple pursuit can effectively be fallen, and has ignored hypertensive patient's long-term survival rate, makes hypertension therapeutic has been lost its most basic meaning.
The advantage of the present composition is embodied in following several aspect:
One, ACEI (angiotensin converting enzyme inhibitor) or angiotensin ii receptor antagonist (ARB) or calcium antagonist (CCB) have well collaborative hypotensive effect with HMGCoA reductase inhibitor, euglycemic agent use in conjunction.
Two, side effect of the present invention is very little.Pharmaceutical composition of the present invention has used three kinds of antihypertensive drugs owing to uniting, and has obtained significant synergism aspect blood pressure lowering, and dosage significantly reduces, and makes incidence rate of adverse reaction and untoward reaction degree significantly alleviate.
Three, life-time service compositions of the present invention has wholesome effect to hyperpietic's long-term survival rate, and patient's prognosis is produced active influence, and this also is the clinical treatment problem that has meaning most solved by the invention.General antihypertensive drugs does not all have excellent prevention and therapeutical effect to complication such as the caused apoplexy of hypertension, kidney injury, coronary heart disease.The present invention then at these deficiencies of existing antihypertensive drugs, by drug combination, has not only produced good synergism, but also hypertension complication has been produced beyond thought preventive effect aspect blood pressure lowering.
Four, of the present invention applied widely.The present invention is particularly useful for apoplectic type hyperpietic and hypertension and merges the kidney damage person because its synergism mechanism is applicable to polytype hyperpietic.In addition for hypertensive patients angina pectoris, peripheral vascular disease, senile hypertension, gestation hypertension, intractable hypertension all have good effect.
According to the character of medicine and patient's medication needs easily, we become solid pharmaceutical preparation with preparation of pharmaceutical compositions of the present invention, as tablet, capsule, granule, pill, drop pill etc.Wherein tablet comprises conventional tablet, dispersible tablet, slow releasing tablet etc., and we select slow releasing tablet as first-selected form of administration.
The present invention adopts solid pharmaceutical preparation to have and carries, easy to use, route of administration is simple, the easy advantage of row, is easy to accept into the patient.
We become slow releasing tablet in conjunction with present hyperpietic's demand with preparation of pharmaceutical compositions of the present invention, it can be efficient, safe blood pressure regulation, slowly discharge and keep comparatively stable blood concentration and longer action time, have toxic and side effects and reduce, take convenient advantage.
Slow releasing tablet among the present invention is a sustained-release matrix with cellulose derivative or polyvinyl, and these sustained-release matrixes can be one or more the mixing wherein of methylcellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, carboxyethyl cellulose, microcrystalline Cellulose, starch, polyvinylpyrrolidone, acrylic resin.
Specific embodiment
Now further specify content of the present invention, but range of application of the present invention is not limited to following example by following example.
Embodiment 1 hypertension compound tablet
Simvastatin 20g
Amlodipine 2.5g
Pyrroles's row ketone 20g
All the other pharmaceutic adjuvants are the adjuvant commonly used of preparation tablet.
Preparation technology: according to conventional preparation technology's preparation of tablet.
Embodiment 2 hypertension compound capsules
Atorvastatin 10g
Enalapril 10g
Pyrroles's row ketone 20g
All the other pharmaceutic adjuvants are the adjuvant commonly used of preparation capsule.
Preparation technology: according to capsular conventional preparation technology's preparation.
Embodiment 3 hypertension compound double-layer tablets
Simvastatin 10g
Mannitol 10g
Lactose 40g
Microcrystalline Cellulose 20g
The 95% alcoholic solution 120g of 6%PVP
Magnesium stearate 2g
Preparation technology: simvastatin is crossed 100 mesh sieves, mannitol, lactose, microcrystalline Cellulose are crossed 80 mesh sieves, take by weighing the nicotinic acid of recipe quantity and mannitol, lactose, microcrystalline Cellulose mix homogeneously, 95% alcoholic solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.
Nifedipine 30g
Rosiglitazone 8g
Pregelatinized Starch 50g
Mannitol 50g
The 95% alcoholic solution 100g of 6%PVP
Micropowder silica gel 5g
Preparation technology: nifedipine and rosiglitazone are crossed 100 mesh sieves, pregelatinized Starch, mannitol are crossed 80 mesh sieves, take by weighing nifedipine, rosiglitazone and pregelatinized Starch, the mannitol mix homogeneously of recipe quantity, 95% alcoholic solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.
Adopt the bi-layer tablet press punching press promptly to get double-layer tablet above-mentioned two kinds of components.
Embodiment 4 hypertension compound dispersed tablets
Lovastatin 20g
Captopril 30g
Rosiglitazone 4g
Carboxymethylcellulose calcium 15g
Crospolyvinylpyrrolidone 15g
Microcrystalline Cellulose 140g
10% starch slurry is an amount of
Magnesium stearate 6g
Preparation technology:
Lovastatin, captopril and the rosiglitazone of recipe quantity are crossed 100 mesh sieves, and carboxymethylcellulose calcium, crospolyvinylpyrrolidone, microcrystalline Cellulose are crossed 80 mesh sieves, add an amount of 10% starch slurry behind the mixing and granulate, and tabletting gets final product after the adding magnesium stearate.
Embodiment 5 hypertension compound granular agent
Pravastatin 10g
Amlodipine 5g
Pyrroles's row ketone 20g
All the other pharmaceutic adjuvants are the adjuvant commonly used of preparation granule.
Preparation technology: according to conventional preparation technology's preparation of granule.
Embodiment 6 hypertension compound tablet
Simvastatin 20g
Nicardipine 60g
Pyrroles's row ketone 10g
All the other pharmaceutic adjuvants are the adjuvant commonly used of preparation tablet.
Preparation technology: according to conventional preparation technology's preparation of tablet.
Embodiment 7 hypertension compound slow-release tablets
Simvastatin 10g
Amlodipine 5g
Pyrroles's row ketone 20g
Hydroxypropyl methylcellulose 3-80g
Polyvinylpyrrolidone 1-100g
Lactose 5-85g
Micropowder silica gel 1-100g
Preparation technology: simvastatin, amlodipine, pyrroles's row ketone and the slow releasing agent mix homogeneously of recipe quantity are added the binding agent granulation, dry under 40 ℃-80 ℃, put in order dried granule, in dried granule, add the lubricant of recipe quantity, mixing, special-shaped stamping gets final product.
Embodiment 8 hypertension compound slow-release tablets
Atorvastatin 5g
Amlodipine 5g
Pyrroles's row ketone 20g
Hydroxyethyl-cellulose 1-100g
Microcrystalline Cellulose 1-80g
Lactose 5-85g
Magnesium stearate 1-50g
Preparation technology: with embodiment 7.
Embodiment 9 hypertension compound slow-release tablets
Atorvastatin 5g
Benazepril 10g
Rosiglitazone 4g
Carboxyethyl cellulose 1-100g
Microcrystalline Cellulose 1-80g
Polyvinylpyrrolidone 1-100g
Magnesium stearate 1-50g
Preparation technology: with embodiment 7.
Embodiment 10 hypertension compound slow-release tablets
Atorvastatin 5g
Valsartan 40g
Rosiglitazone 4g
Carboxyethyl cellulose 1-100g
Microcrystalline Cellulose 1-80g
Lactose 5-85g
Magnesium stearate 1-50g
Preparation technology: with embodiment 7.
Embodiment 11 hypertension compound recipes are to the therapeutic effect animal of essential hypertension apoplectic type rat (SHRsp):
SHRsp, 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 high protein feed.
Method:
With 48 7 the week age SHRsp conventional feed raised for 1 week, weigh and measure with HX-I type toy blood pressure measurement device, by LMS-2B type two road physiology monitor records, conventional tail tremulous pulse method is measured clear-headed animal systolic pressure, be 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 suffering+ammonia group (simvastatin+amlodipine), 4.0mg/ (kg.d) simvastatin+1.0mg/ (kg.d) amlodipine; The 3rd is compound recipe low dose group (simvastatin+amlodipine+pyrroles's row ketone), 1.33mg/ (kg.d) simvastatin+0.33mg/ (kg.d) amlodipine+1.33mg/ (kg.d) pioglitazone; The 4th group is dosage group in the compound recipe, 4.0mg/ (kg.d) suffering+1.0mg/ (kg.d) ammonia+4.0mg/ (kg.d) pyrrole; The 5th group is the compound recipe high dose group, 12.0mg/ (kg.d) suffering+3.0mg/ (kg.d) ammonia+12.0mg/ (kg.d) pyrrole.Each group is gastric infusion.All animals are all drunk 1% 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.
Experimental result
1, the hypertension compound recipe is to the influence of SHRsp blood pressure
The result shows that except that pyrroles's row ketone group, other each group all has significant difference with model group.The high group of group and compound recipe relatively has significant difference with suffering+ammonia group in the compound recipe, illustrate that dosage and high dose have the good antihypertensive effect of working in coordination with for the treatment essential hypertension in simvastatin, amlodipine and the pyrroles's row ketone.
Table 1 hypertension compound recipe to the influence (n=8) of SHRsp blood pressure (kPa)
●Compare p＜0.05 with model group,
Compare p＜0.05. with suffering+ammonia group
2, the 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 2 as seen, 6 groups of rats body weight no significant difference when 8 ages in week.After the grouping administration, the high group of group and compound recipe rat body weight continues to increase in suffering+ammonia group, the compound recipe, with the same period model group relatively there were significant differences (p＜0.05 or p＜0.01); The low body weight in 14 ages in week of organizing of compound recipe is greater than the model group same period (p＜0.05).And along with the outbreak of apoplexy, 3 SHRsp of model group are dead midway, and pyrroles's row ketone group has 1 death, and other each groups take place dead.This fully shown in hypertension the compound recipe group, particularly compound recipe group and the high group of compound recipe for the SHRsp rat lose weight and the apoplexy mortality rate all has good effect.
Table 2 hypertension compound recipe to the influence (n=8) of SHRsp body weight and survival condition (g)
Table 2 (continuing)
Data in () are the quantity of apoplexy survival of rats.
3, the hypertension compound recipe is to the influence of SHRsp cerebral seizure
The result shows that during 14 ages in week, model group has 6 SHRsp that apoplexy takes place, and the low group of suffering+ammonia group and compound recipe respectively has 2 apoplexy takes place, and group is 1 in the compound recipe, and apoplexy does not take place the high group of compound recipe.And after each administration, the apoplexy symptom is obviously alleviated, and shows that organizing the cerebral seizure that the high group of compound recipe particularly causes hypertension in the compound recipe has good preventive and therapeutic effect.
Table 3 hypertension compound recipe is to the influence (n=8) of SHRsp cerebral seizure
4, the mensuration of carotid intimal medial thickness
Animal Anesthesia and fixing after, inject the blue dyestuff (60mg/kg) of Even ' s through femoral artery, be infusion liquid with 0.9% normal saline behind the 30min, adopt careful perfusion, injection pressure 13.3kPa, to effluent limpid after, use 4% paraformaldehyde normal saline perfusion 10min instead, carry out anchored in place (pressure is the same).Get Even ' s blue stain carotid artery section, put into formalin solution further fixing after, three parts are carried out paraffin embedding before, during and after getting, 8～10 layers of discontinuous sections, row HE dyeing, get 3 blood vessel section input Computerized image processing systems at random, carry out computer picture and measure, calculate maximum inner film thickness, media thickness, inner membrance/media thickness ratio.
The result shows that relatively respectively organizing with model group all has significant difference.With the low group of suffering+ammonia group comparison compound recipe significant difference is arranged, the high group of group and compound recipe has utmost point significant difference in the compound recipe.Illustrate that simvastatin, amlodipine and pyrroles's row ketone have good synergism aspect the spontaneous hypertensive rat carotid intimal medial thickness influencing.
Table 4 hypertension compound recipe is to the influence of media thickness in the spontaneous hypertensive rat
●Compare p＜0.05 with model group,
● ●Compare p＜0.01 with model group;
Embodiment 12 hypertension compound recipes are to the therapeutic effect of spontaneous hypertensive rat
Animal and experimental technique
Spontaneous hypertensive rat (300 ± 5g), be divided into 6 groups (n=8) at random, promptly the 1st group is model group, irritates stomach with volume 1% saline; The 2nd group is atropic+shellfish group (atorvastatin+benazepril), 2.5mg/ (kg.d) atorvastatin+2.5mg/ (kg.d) benazepril; The 3rd group is the rosiglitazone group, 1.0mg/ (kg.d) sieve; The 4th group is the low group of compound recipe (atorvastatin+benazepril+rosiglitazone), 0.83mg/ (kg.d) atropic+0.83mg/ (kg.d) shellfish+0.33mg/ (kg.d) sieve; The 5th group is to organize in the compound recipe, 2.5mg/ (kg.d) atropic+2.5mg/ (kg.d) shellfish+1.0mg/ (kg.d) sieve; The 6th group is the high group of compound recipe, 7.5mg/ (kg.d) atropic+7.5mg/ (kg.d) shellfish+3.0mg/ (kg.d) sieve, and each group is gastric infusion.
Experimental result
1, the hypertension compound recipe is to the influence of spontaneous hypertensive rat blood pressure
The result shows that except that the rosiglitazone group, other each group more all has significant difference with model group.Compound recipe group and atropic+shellfish group relatively has significant difference, and the high group of group and compound recipe relatively has utmost point significant difference with atropic+shellfish group in the compound recipe.Illustrate that atorvastatin, benazepril and rosiglitazone compound recipe have good synergism to the antihypertensive effect of spontaneous hypertensive rat.
Table 5 hypertension compound recipe to the influence (n=8) of spontaneous hypertensive rat blood pressure (kPa)
●Compare p＜0.05 with model group,
● ●Compare p＜0.01 with model group;
2, cardiac weight, left ventricular mass, body weight and left ventricular hypertrophy index (left ventricular mass/body weight) are measured: after 10% potassium chloride (2mmol/L, 1ml/ are only) is put to death rat, survey body weight, take out heart, remove the outer connective tissue of trunk and heart, rinse well, filter paper is inhaled in back weighing cardiac weight; Remove the atrium again and claim left ventricular mass, calculate left ventricular mass and body weight ratio.
The result shows that except that the rosiglitazone group, other each group more all has significant difference with model group.Compound recipe group and atropic+shellfish group relatively has significant difference, and the high group of group and compound recipe relatively has utmost point significant difference with atropic+shellfish group in the compound recipe.Illustrate that atorvastatin, benazepril and rosiglitazone compound recipe have good synergism for the treatment of spontaneous hypertensive rat myocardial hypertrophy.
Table 6 hypertension compound recipe to the influence (n=8) of spontaneous hypertensive rat myocardial hypertrophy (g)
●Compare p＜0.05 with model group,
● ●Compare p＜0.01. with model group
3, the mensuration of microalbumin in the urine:
Reagent: 1, the glacial acetic acid solution of 10% (v/v) (PH2.8).
2,0.303mol/L glycine-glacial acetic acid buffer (PH3.0): take by weighing the 22.72g glycine, be diluted to 1000ml, add NaN with 10% glacial acetic acid solution
3100mg, the room temperature sealing can be stablized 1 year.
3, bromophenol blue (1.924mmol/L) stock solution: accurately take by weighing 257,36mgBPB, molten to 200ml with dehydrated alcohol, 4 ℃ of refrigerators can be stablized 1 year.
4, bromophenol blue (0.231mmol/L) developer: get the 60mlBPB stock solution, add 2.5mlTriton X-100,
Be diluted to 500ml with glycine-glacial acetic acid buffer, the room temperature sealing can be preserved 1 year.
The collection of specimen and detection: in the 4th, 8,12 and 16 weeks rat is put in the metabolic cage respectively and raises, collect 12 hours overnight urine, accurate recording urine amount.Get 4ml, after sodium azide was handled, centrifugal (2000r/min) 10min got supernatant and puts-20 ℃ of refrigerators and preserves urinaryalbumin to be measured.Measure the rat urine 2ml of storage, respectively add developer 1ml, mixing (preventing to produce bubble) is measured absorbance A with ultraviolet spectrophotometer down in 600nm.
The result shows that each group more all has significant difference with model group.The high group of group and compound recipe and atropic+Bei Zuyou utmost point significant difference in the compound recipe.Illustrate that atorvastatin, benazepril and rosiglitazone compound recipe have good synergism aspect the spontaneous hypertensive rat microdose urine protein influencing.
Table 7 hypertension compound recipe is to the influence of spontaneous hypertensive rat microdose urine protein
●Compare p＜0.05 with model group,
● ●Compare p＜0.01. with model group
Compare p＜0.05 with atropic+shellfish group,
Compare p＜0.01. with atropic+shellfish group
4, the mensuration of carotid intimal medial thickness
Experimental technique is with embodiment 11
The result shows that relatively respectively organizing with model group all has significant difference.Comparing the low group of compound recipe with atropic+shellfish group has significant difference, and high group of group and compound recipe has utmost point significant difference in the compound recipe.Illustrate that atorvastatin, benazepril and rosiglitazone have good synergism aspect the spontaneous hypertensive rat carotid intimal medial thickness influencing.
Table 8 hypertension compound recipe is to the influence (n=8) of media thickness in the spontaneous hypertensive rat
●Compare p＜0.05 with model group,
● ●Compare p＜0.01 with model group;
Embodiment 13
Spontaneous hypertensive rat (300 ± 5g), be divided into 6 groups (n=8) at random, promptly the 1st group is model group, irritates stomach with volume 1% saline; The 2nd group is Luo Su+figured silk fabrics group (rosuvastatin+valsartan), 1.0mg/ (kg.d) rosuvastatin+15mg/ (kg.d) valsartan; The 3rd group is the rosiglitazone group, 1.0mg/ (kg.d) sieve; The 4th group is the low group of compound recipe (rosuvastatin+valsartan+rosiglitazone), 0.33mg/ (kg.d) Luo Su+5mg/ (kg.d) figured silk fabrics+0.33mg/ (kg.d) sieve; The 5th group is to organize in the compound recipe, 1.0mg/ (kg.d) Luo Su+15mg/ (kg.d) figured silk fabrics+1.0mg/ (kg.d) sieve; The 6th group is the high group of compound recipe, 3.0mg/ (kg.d) Luo Su+45mg/ (kg.d) figured silk fabrics+3.0mg/ (kg.d) sieve, and each group is gastric infusion.
The hypertension compound recipe is to the influence of spontaneous hypertensive rat (SHR) myocardial hypertrophy
Experimental technique is with embodiment 12.
The result shows that except that the rosiglitazone group, other each group more all has significant difference with model group.Compound recipe group and Luo Su+figured silk fabrics group relatively has significant difference, and the high group of group and compound recipe relatively has utmost point significant difference with Luo Su+figured silk fabrics group in the compound recipe.Illustrate that rosuvastatin, valsartan and rosiglitazone compound recipe have good synergism for the treatment of spontaneous hypertensive rat myocardial hypertrophy.
Table 9 hypertension compound recipe to the influence (n=8) of spontaneous hypertensive rat myocardial hypertrophy (g)
●Compare p＜0.05 with model group,
● ●Compare p＜0.01. with model group
Compare p＜0.05 with Luo Su+figured silk fabrics group,
Compare p＜0.01. with Luo Su+figured silk fabrics group
In addition, blood pressure, microdose urine protein and the carotid intimal medial thickness aspect for spontaneous hypertensive rat can obtain good synergy equally.
In embodiment 11,12 and 13 simvastatin, atorvastatin, rosuvastatin all can by other statinses as: lovastatin, pravastatin, fluvastatin, Pitavastatin or happiness are cut down his spit of fland and are substituted.Pyrroles's row ketone and rosiglitazone all can be by other thiazolidinediones antidiabetic drugs: ciglitazone, englitazone etc. replace.Amlodipine, benazepril, valsartan can be by other depressor calcium ion antagonists: nifedipine, nicardipine, felodipine, lacidipine, nitrendipine, nimodipine, Buddhist nun's flordipine etc.; Angiotensin converting enzyme inhibitor: enalapril, fosinopril, cilazapril, perindopril, imidapril, quinapril, captopril, lisinopril, ramipril, benazepril, delapril; Angiotensin ii receptor antagonist: irbesartan, telmisartan, candesartan Cilexetil, olmesartan medoxomil, losartan etc. substitute.More than substitute all scientific and reasonablely, and detect with the every index in embodiment 11,12 and 13 and all to have obtained same good synergy.
Claims (13)
1. one kind is used for the treatment of hypertensive pharmaceutical composition, it is characterized in that it contains Altace Ramipril, HMGCoA reductase inhibitor and euglycemic agent.
2. pharmaceutical composition as claimed in claim 1 is characterized in that described depressor is one or more in calcium ion antagonist, angiotensin converting enzyme inhibitor or the angiotensin ii receptor antagonist.
3. pharmaceutical composition as claimed in claim 2 is characterized in that described calcium ion antagonist is nifedipine, amlodipine, nicardipine, felodipine, lacidipine, nitrendipine, nimodipine, Buddhist nun's flordipine.
4. pharmaceutical composition as claimed in claim 2 is characterized in that described angiotensin converting enzyme inhibitor is enalapril, benazepril, fosinopril, cilazapril, perindopril, imidapril, quinapril, captopril, lisinopril, ramipril, benazepril, delapril.
5. pharmaceutical composition as claimed in claim 2 is characterized in that described angiotensin ii receptor antagonist is valsartan, irbesartan, telmisartan, candesartan Cilexetil, olmesartan medoxomil, losartan.
6. pharmaceutical composition as claimed in claim 1 is characterized in that described HMGCoA reductase inhibitor is that one or more in his spit of fland are cut down in lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, Pitavastatin or happiness.
7. pharmaceutical composition as claimed in claim 1 is characterized in that described HMGCoA reductase inhibitor is one or more in simvastatin, atorvastatin or the rosuvastatin.
8. pharmaceutical composition as claimed in claim 1 is characterized in that described euglycemic agent is any one or a few in pyrroles's row ketone, rosiglitazone, ciglitazone, the englitazone.
9. pharmaceutical composition as claimed in claim 1 is characterized in that described euglycemic agent is pyrroles's row ketone and ciglitazone.
10. pharmaceutical composition as claimed in claim 1 is characterized in that it is tablet, capsule, granule, pill or drop pill.
11. pharmaceutical composition as claimed in claim 5 is characterized in that described tablet is conventional tablet, dispersible tablet or slow releasing tablet.
12. pharmaceutical composition as claimed in claim 6 is characterized in that containing in the described slow releasing tablet cellulose derivative or polyvinyl.
13. pharmaceutical composition as claimed in claim 1 is characterized in that it also contains in methylcellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, carboxyethyl cellulose, little product cellulose, starch, polyvinylpyrrolidone, the acrylic resin one or more.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100025437A CN101229372B (en) | 2007-01-26 | 2007-01-26 | Medicine compounds for treating hypertension |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100025437A CN101229372B (en) | 2007-01-26 | 2007-01-26 | Medicine compounds for treating hypertension |
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| Publication Number | Publication Date |
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| CN101229372A true CN101229372A (en) | 2008-07-30 |
| CN101229372B CN101229372B (en) | 2010-09-01 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2007100025437A Active CN101229372B (en) | 2007-01-26 | 2007-01-26 | Medicine compounds for treating hypertension |
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| CN (1) | CN101229372B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010009618A1 (en) * | 2008-07-24 | 2010-01-28 | 鲁南制药集团股份有限公司 | Pharmaceutical composition for treating hypertension and metabolic syndrome and use thereof |
| WO2010009619A1 (en) * | 2008-07-24 | 2010-01-28 | 鲁南制药集团股份有限公司 | Pharmaceutical composition for treating hypertension and metabolic syndrome and use thereof |
| CN101926798A (en) * | 2009-06-26 | 2010-12-29 | 北京德众万全药物技术开发有限公司 | Dispersible tablet containing amlodipine and valsartan |
| CN105395551A (en) * | 2015-11-19 | 2016-03-16 | 哈尔滨圣吉药业股份有限公司 | Olmesartan medoxomil/rosuvastatin compound preparation and preparation method thereof |
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2007
- 2007-01-26 CN CN2007100025437A patent/CN101229372B/en active Active
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010009618A1 (en) * | 2008-07-24 | 2010-01-28 | 鲁南制药集团股份有限公司 | Pharmaceutical composition for treating hypertension and metabolic syndrome and use thereof |
| WO2010009619A1 (en) * | 2008-07-24 | 2010-01-28 | 鲁南制药集团股份有限公司 | Pharmaceutical composition for treating hypertension and metabolic syndrome and use thereof |
| EP2322175A4 (en) * | 2008-07-24 | 2011-11-23 | Lunan Pharm Group Corp | Pharmaceutical composition for treating hypertension and metabolic syndrome and use thereof |
| JP2011528670A (en) * | 2008-07-24 | 2011-11-24 | ルナン ファーマシューティカル グループ コーポレーション | Pharmaceutical composition used for the treatment of hypertension and metabolic syndrome and use thereof |
| US8722697B2 (en) | 2008-07-24 | 2014-05-13 | Lunan Pharmaceutical Group Corporation | Pharmaceutical composition for treating hypertension and metabolic syndrome and use thereof |
| US8815286B2 (en) | 2008-07-24 | 2014-08-26 | Lunan Pharmaceutical Group Corporation | Pharmaceutical composition for treating hypertension and metabolic syndrome and use thereof |
| CN101926798A (en) * | 2009-06-26 | 2010-12-29 | 北京德众万全药物技术开发有限公司 | Dispersible tablet containing amlodipine and valsartan |
| CN101926798B (en) * | 2009-06-26 | 2013-09-18 | 北京德众万全药物技术开发有限公司 | Dispersible tablet containing amlodipine and valsartan |
| CN105395551A (en) * | 2015-11-19 | 2016-03-16 | 哈尔滨圣吉药业股份有限公司 | Olmesartan medoxomil/rosuvastatin compound preparation and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN101229372B (en) | 2010-09-01 |
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