CN1857726A - Medicine composition for treating hypertension complicated with hyperlipemia and cardiac and cerebral vascular diseases - Google Patents

Abstract

The medicine composition for treating hypertension complicated with hyperlipemia and cardiac and cerebral vascular diseases belongs to the field of medicine technology, and aims at raising the comprehensive curative effect. Technologically, the medicine composition consists of levoamlodipine and its medicinal salt, HMG-COA reductase inhibitor and its medicinal salt and medicine carrier, with the content being levoamlodipine 1.25-20 mg and HMG-COA reductase inhibitor 2.5-100 mg. Owing to the adding or synergistic effect of the medicines, the present invention has obviously raised medicinal effect, reduced dosage and obviously lowered side effect.

Description

A kind of pharmaceutical composition for the treatment of the hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease

Technical field

The present invention relates to a kind of pharmaceutical composition for the treatment of the hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease, belong to medical technical field.

Background technology

Cardiovascular and cerebrovascular disease is the No.1 killer who threatens human health always, shows that according to relevant investigation report the people that China dies from cardiovascular and cerebrovascular disease every year has more than 300 ten thousand, account for 50% of the annual total death toll of China, and this disease also more is the age downward trend.Therefore, developing the medicine for the treatment of cardiovascular and cerebrovascular disease is one of focus of Pharmaceutical research field.

Hypertension and hyperlipidemia not only all are the risk factors that causes cardiovascular and cerebrovascular disease, and in close relations between the two relevant.Many hypertensive patients are with lipid metabolic disorder, and the normal high 3-4 of blood pressure person that suffers from hyperlipidemia simultaneously doubly.On the other hand, the also normal complicated hypertension of many hyperlipemias, both are cause effect relation mutually.Therefore, can for providing the medicine of treatment, two kinds of diseases will bigger market potential be arranged simultaneously clinical well received.

In hypertension therapeutic, what clinical practice at present was more is the Norvasc of Pfizer, i.e. Amlodipine Besylate Tablet.It is the calcium ion antagonist of a new generation, is regarded as Altace Ramipril safely and effectively by U.S. FDA.

On the other hand, HMG-COA (hydroxy-methyl-glutaryl coenzyme A) reductase inhibitor is a fat regulation medicine commonly used both at home and abroad at present.In the cholesterol building-up process, from HMG-COA to the mevalonate rate-limiting step, this step is by the catalysis of HMG-CoA reductase.The HMG-COA reductase inhibitor suppresses this transition process of HMG-COA reductase catalysis, makes the synthetic minimizing of cholesterol.Therefore, the HMG-COA reductase inhibitor is the lipid lowerers that has potentiality.

At present the patent documentation relevant with this theme mainly contains the publication number that Pfizer has and is 268053, is called " comprising atorvastatin and antihypertensive conjoint therapy "; Publication number be 1352640, name is called several pieces of documents such as " the common precursor medicines of amlodipine and atorvastatin ".This several patents discloses the pharmaceutical composition of calcium ion antagonist amlodipine and HMG-CoA reductase inhibitor, and they are used for the treatment of the purposes of atherosclerosis, angina pectoris, hypertension complicated with hyperlipemia, prevention of cardiac etc., but Levamlodipine and the therapeutic combination that contains left-handed ammonia chlorine ground are not mentioned.

Summary of the invention

Problem to be solved by this invention is that to overcome the defective of prior art and provide a kind of be that principal agent and pharmaceutically acceptable carrier are formed with Levamlodipine and officinal salt, HMG-COA reductase inhibitor and officinal salt thereof, can effectively treat the pharmaceutical composition of hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease.

The alleged problem of the present invention realizes with following technical proposals:

A kind of pharmaceutical composition for the treatment of the hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease, it is main component, is equipped with pharmaceutically suitable carrier and forms with Levamlodipine and officinal salt, HMG-COA reductase inhibitor and officinal salt thereof, wherein, described Levamlodipine officinal salt is selected from pharmaceutically acceptable salts such as maleate, benzene sulfonate, hydrochlorate, formates, acetate, hydrobromate, aspartic acid, mesylate, sulphuric acid or tartaric acid; Described HMG-COA reductase inhibitor is selected from atorvastatin, lovastatin, pravastatin, simvastatin, Buddhist nun and cuts down his spit of fland, fluvastatin, Pitavastatin, Rosuvastatin or rosuvastatin and officinal salt thereof, and each component content unit is by weight counted:

Maleic acid levo amido chloro diping 1.25-20,

The atorvastatin calcium content is 2.5-100.

The pharmaceutical composition of above-mentioned treatment hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease, preferred maleate of described Levamlodipine officinal salt or benzene sulfonate, its content unit is by weight counted: 2.5-10.

The pharmaceutical composition of above-mentioned treatment hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease, described HMG-COA reductase inhibitor is selected from atorvastatin or simvastatin and officinal salt thereof, and its content unit is by weight counted: 5-80.

The pharmaceutical composition of above-mentioned treatment hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease, described dosage form is tablet, capsule, granule (comprising powder), slow releasing agent or injection dosage form, or the medicine box compositions of maleic acid levo amido chloro diping single preparations of ephedrine and Atorvastatin calcium single preparations of ephedrine composition.

The pharmaceutical composition of above-mentioned treatment hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease, described dosage form are tablet, and 1000 middle each component content are counted by gram:

Levamlodipine 2.5～10;

HMG-COA reductase inhibitor 2.5-100;

Beta-schardinger dextrin-20～50;

Water 40～100;

Microcrystalline Cellulose 10～40;

Amylum pregelatinisatum 20～40;

Magnesium stearate 1

Described Levamlodipine is maleic acid levo amido chloro diping or Levamlodipine besylate, and described HMG-COA reductase inhibitor is simvastatin or Atorvastatin calcium.

The pharmaceutical composition of above-mentioned treatment hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease, described dosage form are capsule, and the each component content in 1000 capsules is as follows by gram:

Levamlodipine 2.5～10;

HMG-COA reductase inhibitor 10～20;

Beta-schardinger dextrin-20;

Water 40;

Starch 240;

Magnesium stearate 2.

Described Levamlodipine is maleic acid levo amido chloro diping or Levamlodipine besylate, and described HMG-COA reductase inhibitor is simvastatin or Atorvastatin calcium.

The pharmaceutical composition of above-mentioned treatment hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease, described dosage form are the sterile solution compositions, and each component content is as follows by gram:

Levamlodipine 2.5～5;

HMG-COA reductase inhibitor 10～20

Sodium chloride 0.9;

Water for injection adds to 100 milliliters;

Described Levamlodipine is maleic acid levo amido chloro diping or Levamlodipine besylate, and described HMG-COA reductase inhibitor is simvastatin or Atorvastatin calcium.

In concrete pharmaceutical composition provided by the present invention, maleic acid levo amido chloro diping is the maleate of the levo form of amlodipine, and its calcium ion antagonistic activity approximately is 1000 times of d-isomer, 2 times of raceme.The pharmacodynamic study of maleic acid levo amido chloro diping also shows, maleic acid levo amido chloro diping is compared with the equal antihypertensive effect of Amlodipine Besylate Tablet, can reduce half consumption of medicine, the untoward reaction that simultaneously can eliminate or alleviate original raceme, as side effect such as acro-edema, headache, dizzinesses, patient's medication compliance is better.And Atorvastatin calcium is selectivity, the competitive inhibitor of HMG-COA reductase, cholesterol biosynthesis rate-limiting enzyme HMG-CoA reductase there is special competitive inhibition, make the synthetic minimizing of cholesterol, liver plasma membrane density lipoprotein acceptor quantity increases, very low density lipoprotein (VLDL) in the circulation and low density lipoprotein, LDL are removed and are increased, thus the cholesterol reducing level.Atorvastatin calcium can not only blood lipid regulation, but also can improve arterial elasticity, reduces the generation of oxygen-derived free radicals, and blood vessel is had protective effect.Above two kinds of medicines are put together, make pharmaceutical composition, because the addition or the synergism of medicine can obviously improve therapeutic effect, and owing to reduced cancelling out each other of amount of drug and detrimental effect separately, side effects of pharmaceutical drugs are obviously reduced.

As compositions of the present invention can be concrete dosage form such as tablet, capsule, granule (comprising powder), sustained-release preparation, injection, can use various suitable suitable additive or substrate according to its dosage form, is prepared according to a conventional method according to each dosage form.

Pharmaceutical composition of the present invention can give the various compositions of compositions simultaneously when clinical administration, perhaps the interval certain hour gives the various compositions of compositions respectively.

Above-mentioned " simultaneously " administration, so long as can get final product at the administering mode of much at one time administration, there is no particular limitation, preferably as single compositions administration.

In addition, above-mentioned " certain hour is respectively at interval " administration, so long as can get final product in the mode of the different time difference administration of determining, there is no particular limitation.

The specific embodiment

The invention will be further described below in conjunction with embodiment.

One, embodiment 1-5: tablet composition

Component	Embodiment 1	2	3	4	5
						Maleic acid levo amido chloro diping Levamlodipine besylate Atorvastatin calcium Simvastatin beta-schardinger dextrin-water microcrystalline cellulose amylum pregelatinisatum dolomol	2.5 10 20 40 40 40 1	5 10 40 80 25 40 1	5 20 40 80 20 30 1	10 5 30 60 20 40 1	2.5 80 50 100 10 20 1

Above-mentioned prescription is 1000 a content, and unit is gram.

Preparation method: with the efficient grinding fast of levo-amlodipine salt, beta-schardinger dextrin-and water 1 hour, 40 ℃ of dryings of vacuum were pulverized then, cross 100 mesh sieves, add leftover materials again, and mixer mixed 10 minutes, and tabletting is chemically examined qualified back and packed.

Two, embodiment 6-8: capsule composition

Component	Embodiment 6	Embodiment 7	Embodiment 8
				Maleic acid levo amido chloro diping Levamlodipine besylate Atorvastatin calcium Simvastatin beta-schardinger dextrin-water-starch dolomol	2.5 10 20 40 240 2	10 10 20 40 240 2	5 20 20 40 240 2

Above-mentioned prescription is 1000 a content, and unit is gram.

Preparation method: with the efficient grinding fast of levo-amlodipine salt, beta-schardinger dextrin-and water 1 hour, 40 ℃ of dryings of vacuum were pulverized then, cross 100 mesh sieves, add leftover materials again, and mixer mixed 10 minutes, and the fill capsule is chemically examined qualified back and packed.

Three, embodiment 9-11: sterile solution compositions

Component	Embodiment 9	Embodiment 10	Embodiment 11
				Maleic acid levo amido chloro diping Levamlodipine besylate simvastatin Atorvastatin calcium chloride injection water	2.5g 10g 0.9g adds to 100 milliliters	0.9g to 100 milliliter of 5g 10g	0.9g to 100 milliliter of 5g 20g

Preparation method: sodium chloride is dissolved in the water for injection, add people's levo-amlodipine salt, statins, the dissolving back further adds water for injection, and adjusted volume is to desired concn, then solution is carried out aseptic filtration, under aseptic condition, pack into ampoule or the oral liquid bottle.

Medicine of the present invention has been carried out zoopery, and effect is as follows:

Subjects: Beagle Canis familiaris L.

Test group: maleic acid levo amido chloro diping 2.5mg and Atorvastatin calcium 20mg compound tablet

Matched group 1: Amlodipine Besylate Tablet 5mg and Atorvastatin calcium 20mg compound tablet

Matched group 2: Atorvastatin calcium 20mg folk prescription tablet

Testing program: before administration, got blood 20ml by cephalic vein respectively in 4 days, 8 days, 12 days after 1 week, 2 weeks and the administration, it is jejunitas to get preceding 18 hours of blood, with the blood collecting that obtains in test tube, room temperature was placed 30 minutes-1 hour, centrifugalize (3000rpm, 10 minutes), with the serum that obtains, adopt CEH-COD-POD method, GK-GPO-POD method, SUR method to measure the content of T-CHOL, triglyceride and low density lipoprotein, LDL in the blood respectively.

Result of the test: the meansigma methods with T-CHOL, triglyceride and low density lipoprotein, LDL amount in the blood before 1 week, 2 weeks before the administration is 100, converts and obtains the amount of T-CHOL, triglyceride and low density lipoprotein, LDL in the administration bleeding from anus.Each numerical value is 1 group 5 meansigma methods.

Test situation	T-CHOL			Triglyceride			Low density lipoprotein, LDL
										4 days	8 days	12 days	4 days	8 days	12 days	4 days	8 days	12 days
	Test group	94.5	85.6	72.2	95.6	87.3	77.5	93.5	83.6										69.5
Matched group 1										94.3	85.8	72.6	94.9	87.8	77.6	93.3	83.3	70.2
	Matched group 2	96.5	90.6	82.6	97.2	91.5	84.6	95.5	89.4										80.4

Conclusion: by this result of the test as can be seen, present composition medicine has good effect for reducing blood fat, compares with tester 1 compound medicine, and consumption is little, and is evident in efficacy; Compare with tester 2 folk prescription medicines, its lipid-lowering effect is considerably beyond the folk prescription medicine.

The zoopery result of efficacy of antihypertensive treatment is:

Subjects: renal hypertension dog;

Test group: maleic acid levo amido chloro diping 2.5mg and Atorvastatin calcium 20mg compound tablet;

Matched group 1: Amlodipine Besylate Tablet 5mg and Atorvastatin calcium 20mg compound tablet;

Matched group 2: maleic acid levo amido chloro diping 2.5mg folk prescription tablet;

Testing program: renal hypertension dog is divided into 3 groups at random, every group 5, give investigational agent and contrast 1, contrast 2 medicines respectively, the successive administration fortnight, and before administration, after (0 day) and the administration 1,4,7,11,14 day the time, adopt and press the arteries and veins auscultation to measure systolic pressure and diastolic pressure respectively.

Result of the test: each numerical value is 1 group 5 meansigma methods

Test situation	Systolic pressure (mmHg)						Diastolic pressure (mmHg)
													0 day	1 day	4 days	7 days	11 days	14 days	0 day	1 day	4 days	7 days	11 days	14 days
	Test group	189	174	154	149	145	142	128	113	100	92	89													90
Matched group 1													190	177	156	150	147	141	126	113	102	95	92	92
	Matched group 2	190	181	170	165	158	150	122	115	108	105	100													100

Conclusion: by this result of the test as can be seen, present composition medicine has good hypotensive activity, compares with tester 1 compound medicine, and consumption is little, and is evident in efficacy; Compare with tester 2 folk prescription medicines, its blood pressure lowering effect is considerably beyond the folk prescription medicine.

Medicine of the present invention has carried out the drug effect checking, and is respond well, and its typical case history is a female patient, and this patient's merging suffers from hypertension, hyperlipemia, once takes other related drugs in the past, confirms that curative effect is not satisfactory.Before taking this medicine, blood pressure 100/160, T-CHOL 6.03mmol/L, triglyceride 3.98mmol/L, low density lipoprotein, LDL 5.93mmol/L, oral administration maleic acid levo amido chloro diping (2.5mg) and simvastatin (10mg) treatment once a day, blood pressure 80/130 during 7 backs enters range of normal value; T-CHOL 5.53mmol/L, triglyceride 1.98mmol/L, low density lipoprotein, LDL 3.10mmol/L, except that triglyceride a little more than the normal range 0.23-1.22mmol/L, all the other indexs all change over to normally, detect once more after one week, all index is normal, used 3 months continuously, blood pressure, blood lipids index normally do not rebound, and health is good.

Claims (7)

1, a kind of pharmaceutical composition for the treatment of the hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease, it is characterized in that, it is main component, is equipped with pharmaceutically suitable carrier and forms with Levamlodipine and officinal salt, HMG-COA reductase inhibitor and officinal salt thereof, wherein, described Levamlodipine officinal salt is selected from pharmaceutically acceptable salts such as maleate, benzene sulfonate, hydrochlorate, formates, acetate, hydrobromate, aspartic acid, mesylate, sulphuric acid or tartaric acid; Described HMG-COA reductase inhibitor is selected from atorvastatin, lovastatin, pravastatin, simvastatin, Buddhist nun and cuts down his spit of fland, fluvastatin, Pitavastatin, Rosuvastatin or rosuvastatin and officinal salt thereof, and each component content unit is by weight counted:

Levamlodipine 1.25-20,

HMG-COA reductase inhibitor 2.5-100.

2, the pharmaceutical composition of treatment hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease according to claim 1 is characterized in that, preferred maleate of described Levamlodipine officinal salt or benzene sulfonate, and its content unit is by weight counted: 2.5-10.

3, the pharmaceutical composition of treatment hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease according to claim 1 and 2, it is characterized in that, described HMG-COA reductase inhibitor is atorvastatin or simvastatin and officinal salt thereof, and its content unit is by weight counted: 5-80.

4, the pharmaceutical composition of treatment hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease according to claim 3, it is characterized in that, described dosage form is tablet, capsule, granule, powder, slow releasing agent or injection dosage form, or the medicine box compositions of maleic acid levo amido chloro diping single preparations of ephedrine and Atorvastatin calcium single preparations of ephedrine composition.

5, the pharmaceutical composition of treatment hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease according to claim 4 is characterized in that, described dosage form is a tablet, and 1000 middle each component content are counted by gram:

Levamlodipine 2.5～10;

HMG-COA reductase inhibitor 2.5-100;

Beta-schardinger dextrin-20～50;

Water 40～100;

Microcrystalline Cellulose 10～40;

Amylum pregelatinisatum 20～40;

Magnesium stearate 1

Described Levamlodipine is maleic acid levo amido chloro diping or Levamlodipine besylate, and described HMG-COA reductase inhibitor is simvastatin or Atorvastatin calcium.

6, the pharmaceutical composition of treatment hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease according to claim 4 is characterized in that, described dosage form is a capsule, and the each component content in 1000 capsules is as follows by gram:

Levamlodipine 2.5～10;

HMG-COA reductase inhibitor 10～20;

Beta-schardinger dextrin-20;

Water 40;

Starch 240;

Magnesium stearate 2.

Described Levamlodipine is maleic acid levo amido chloro diping or Levamlodipine besylate, and described HMG-COA reductase inhibitor is simvastatin or Atorvastatin calcium.

7, the pharmaceutical composition of treatment hypertension complicated with hyperlipemia cardiovascular and cerebrovascular disease according to claim 4 is characterized in that, described dosage form is the sterile solution compositions, and each component content is as follows by gram:

Levamlodipine 2.5～5;

HMG-COA reductase inhibitor 10～20

Sodium chloride 0.9;

Water for injection adds to 100 milliliters;

Described Levamlodipine is maleic acid levo amido chloro diping or Levamlodipine besylate, and described HMG-COA reductase inhibitor is simvastatin or Atorvastatin calcium.