CN103272236B - Medical composition and its use containing receptor,β blocker and vitamin B group - Google Patents
Medical composition and its use containing receptor,β blocker and vitamin B group Download PDFInfo
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Abstract
The present invention relates to a kind of pharmaceutical composition containing receptor,β blocker (abbreviation beta-blocker) and vitamin B group, be made up of a kind of, one or more and the pharmaceutically acceptable carrier for the treatment of in the vitamin B group of effective dose of the beta-blocker for the treatment of effective dose and active metabolite thereof or salt apoplexy due to endogenous wind; Wherein the content of beta-blocker and active metabolite or salt is 2.5 ~ 200mg, and the content of vitamin B group is 0.1 ~ 50mg.Advantage of the present invention is: this pharmaceutical composition can improve the curative effect of beta-blocker blood pressure lowering; strengthen the target organ protection function of beta-blocker depressor, reduce the incidence rate of the complication such as left ventricular hypertrophy, coronary heart disease, heart failure, apoplexy, nephropathy and renal insufficiency.In addition, this pharmaceutical composition can also make patient consumes convenient, reduces medical expense.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition containing receptor,β blocker (abbreviation beta-blocker) and vitamin B group, the danger that the target organ damage be used for the treatment of hypertension, preventing or delay the factors such as hypertension to cause or reduction cardiocerebrovasculaevents events occur.The invention belongs to pharmaceutical field.
Background technology
Hypertension is one of modal chronic disease, also be the topmost risk factor of cardiovascular and cerebrovascular disease, the disabling of the major complications (target organ damage) such as its apoplexy, myocardial infarction, heart failure and chronic kidney disease, fatality rate are high, serious consumption medical resource, brings heavy burden to family and society.Hypertensive major therapeutic goals reduces the generation of cardiovascular complication and dead overall danger to greatest extent, need to treat all reversibility cardiovascular risk factors, subclinical target organ damage and the various and clinical disease deposited [Chinese hypertension prevention and control guide revision committee. Chinese hypertension prevention and control guide 2010. Chinese Journal of Cardiology, 2011; 39 (7): 579 ~ 616].
The conventional antihypertensive drug of China's hypertension prevention and control Guidelines recommend comprises five large classes, that is: calcium antagonist (CCB), angiotensin converting enzyme inhibitor (ACEI), angiotensin ii receptor antagonist (ARB), diuretic and beta-blocker, or the compound preparation of the fixed dosage be made up of these medicines.Most hyperpietics need two or more antihypertensive drug to reach the target controlling blood pressure, and two kinds of medicines can prescription or be the compound preparation of fixed dosage separately.World clinical trial proves that drug combination has it to need and is worth, and the dosage of often kind of medicine is little, and the therapeutical effect of medicine has concertedness or is at least added, and untoward reaction can be cancelled out each other or at least not overlapping or addition.
Beta-blocker be a class can optionally be combined with receptor,β thus antagonism neurotransmitter to the medicine of beta receptor agonism, can be divided three classes according to action characteristic: the first kind is nonselective, acts on β
1and β
2receptor, common drug is Propranolol (Propranolol); Equations of The Second Kind is optionally, mainly acts on β
1receptor, common drug is bisoprolol (Bisoprolol), metoprolol (Metoprolol), atenolol (Atenolol), betaxolol (Betaxolol); 3rd class is also nonselective, can act on β and α simultaneously
1receptor, has periphery vasodilative effect, and common drug is labetalol (Labetalol), carvedilol (Carvedilol), arotinolol (Arotinolol).Beta-blocker can decreased heart rate, weaken myocardial contraction, thus to reduce blood pressure, be applicable to hypertension in various degree, especially heart rate patient faster, after being also applicable to merge angina pectoris, myocardial infarction, the patient of tachyarrhythmia.
Also some problems is there is in beta-blocker in clinical practice.One, beta-blocker side effect is many, as the retardation of conducting cardiac chamber, on the impact (peripheral angiopathy, diabetics are cautious use of) of glucose-lipid metabolism, have hypertension rebound phenomenon during withdrawal, non-selective beta-blocker can bring out bronchial asthma etc.They are two years old, with other depressor, particularly novel CCB, ACEI class is compared, the target organ protection function of beta-blocker is without clear superiority: within 2005, ESC announces ASCOT result of study [DahlofB, etal.Preventionofcardiovasculareventswithanantihypertens iveregimenofamlodipineaddingperindoprilasrequiredversusa tenololaddingbendroflumeth-iazideasrequired, intheAnglo-ScandinavianCardiacOutcomesTrial-BloodPressur eLoweringArm:amulticentrerandomisedcontrolledtrial.Lance t.2005, 366 (9489): 895-906], this is a multicenter, prospective randomized control study, altogether the selected 19257 example ages 40-79 year, have the hyperpietic of 3 other cardiovascular risk factors at least.Result shows, is all better than the drug combination group based on atenolol based on the drug combination group of amlodipine (CCB class) in multiple endpoints.Amlodipine associating Peridopril in treating scheme makes mean blood pressure level decline the comparatively low 2.7mmHg/1.9mmHg of atenolol associating thiazide diuretic therapeutic scheme, the generation of the former preventing cardiovascular events more, and less induced Diabetic complication.
Research in recent years shows, in blood, homocysteine level rising or folate level reduction raise relevant [SunY with the danger of coronary heart disease, apoplexy, etal.Useofserumhomocysteinetopredictstroke, coronaryheartdiseaseanddeathinEthnicChinese:a12-yearpros pectivecohortstudy.CircJ.2009; 73:1423-1430], Supplement of folic acid or composite B vitamin can reduce homocysteine level, may reduce cardiovascular event and occur.As aforementioned; the main purpose of hypertension treatment reduces the danger of cardiovascular complication to greatest extent; although target control treatment is very crucial, target-organ protection is final goal, needs to treat all reversibility cardiovascular risk factors, subclinical target organ damage and even and the clinical disease deposited.
Summary of the invention
The object of the invention is to overcome beta-blocker above shortcomings, even provide a kind of beta-blocker and toxic and side effects of being better than in efficacy of antihypertensive treatment and target-organ protection not increase the pharmaceutical composition reduced.
For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition, comprises
(1) beta-blocker of pharmaceutical dosage and the one of medicinal precursor, active metabolite or salt apoplexy due to endogenous wind thereof;
(2) one or more of the vitamin B group of pharmaceutical dosage;
(3) acceptable carrier on pharmaceutics.
Above-mentioned " pharmaceutical dosage " refers to the amount of pharmacological action with collaborative, prevention or treatment.Above-mentioned beta-blocker is selected from the one in bisoprolol, metoprolol, atenolol, Propranolol, betaxolol, labetalol, carvedilol, arotinolol, and vitamin B group is selected from vitamin B
6, vitamin B
12with one or more of leaf acid, wherein vitamin B
6comprise pyridoxol, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine., pyridoxamine, pyridoxin phosphate, pyridoxal 5-phosphate, phosphopyridoxamine and above-mentioned substance derivant and can metabolism and/or generate the material of this compounds, vitamin B in vivo
12comprise cobalamine, mecobalamin element, 5 '-deoxyadenosyl cobalamin, hydroxocobalamine, cyanocobalamin and above-mentioned substance derivant and can metabolism and/or generate the material of this compounds in vivo, leaf acid comprises the active metabolite of folic acid, 5-methyltetrahydrofolate, formyl tetrahydrofolic acid, folinic acid, calcium levofolinate, folic acid officinal salt or folic acid officinal salt and can generate the material of folic acid in vivo.
In the present invention, the pharmaceutical dosage scope of beta-blocker is bisoprolol (2.5 ~ 20mg), metoprolol (25 ~ 200mg), atenolol (12.5 ~ 100mg), Propranolol (10 ~ 40mg), betaxolol (5 ~ 30mg), labetalol (50 ~ 300mg), carvedilol (5 ~ 50mg), arotinolol (2.5 ~ 20mg).The better treatment effective dose of these medicines is respectively bisoprolol (2.5 ~ 10mg), metoprolol (50 ~ 200mg), atenolol (12.5 ~ 100mg), Propranolol (10 ~ 20mg), betaxolol (5 ~ 20mg), labetalol (100 ~ 200mg), carvedilol (10 ~ 25mg), arotinolol (5 ~ 20mg).
In the present invention, the pharmaceutical dosage scope of vitamin B group is respectively vitamin B
6(1 ~ 50mg), vitamin B
12(0.05 ~ 2mg), leaf acid (0.1 ~ 5mg).The better treatment effective dose of these medicines is respectively vitamin B
6(5 ~ 50mg), vitamin B
12(0.1 ~ 1mg), leaf acid (0.2 ~ 5mg).
This research finds, vitamin B group is alone slight hypotensive effect, when share with beta-blocker, can strengthen the hypotensive effect of beta-blocker.The alone target organ damage to being caused by hypertension of vitamin B group has slight protective effect, can strengthen with beta-blocker drug combination it to cause target organ damage protective effect to hypertension.
According to the present invention, active component in pharmaceutical composition is the solvent in compositions, one of them active component comes from the one in beta-blocker, another active component is one or more of vitamin B group, the dosage form of this pharmaceutical composition includes but not limited to conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, single chamber controlled release tablet, two rooms controlled release tablet, pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, delayed-release tablet, regularly/position releasing piece, conventional capsule, enteric coated capsule, slow releasing capsule, controlled release capsule, capsule containing micropill or small pieces, pH dependent form capsule containing micropill or small pieces, granule, pill, oral liquid, membrane or patch.
In the present invention, pharmaceutically suitable carrier or excipient can be made into common oral preparation, comprise conventional tablet, conventional capsule, granule etc., when making tablet, described pharmaceutically suitable carrier comprises the excipient and adjuvant that contribute to reactive compound being mixed with pharmaceutical formulation, as microcrystalline Cellulose, inorganic salts, lactose, sodium chloride, citric acid, sodium sulfite, starch, cellulose derivative, pregelatinized Starch, carboxymethyl starch sodium, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl fecula sodium, crospolyvinylpyrrolidone, sucrose, dextrin, Icing Sugar, the compositions of one or more materials of glucose etc., belong to this area general knowledge.
In the present invention, pharmaceutically suitable carrier or excipient can be made into slow releasing preparation, comprise excipient and adjuvant etc.
In the present invention, pharmaceutically suitable carrier or excipient can be made into slow releasing capsule, controlled release capsule, the capsule containing micropill or small pieces, and the pH dependent form capsule containing micropill or small pieces, Bigeminal capsule etc., comprise excipient and adjuvant etc.
Term " pharmaceutical dosage " refers to the object for reaching effectively control or disease therapy, and clinician grants the dosage of medicine to diseased individuals according to diseased individuals coincident with severity degree of condition.Be to be understood that medicine pharmaceutical dosage provided by the invention is not limitation of the present invention, but to preferably of the present invention, under normal circumstances, in this dosage preferable range, this medicine can produce effective therapeutic effect to diseased individuals.Diseased individuals refers to the self-existent life entity suffering from disease, and in the present invention, life entity is the mankind espespecially.Should be appreciated that in prior art, human pharmaceutical use dosage or pharmaceutical dosage scope can with mammal, as rat, mice etc. carry out the pharmaceutical dosage that converts to show that applicable corresponding animal is suitable for or dosage range.
Compound in pharmaceutical composition provided by the invention can grant diseased individuals in identical preparation simultaneously, also in succession grants diseased individuals discriminably.If in succession grant diseased individuals, then the loss of the beneficial effect that the delay that second (or additional) active component is granted should not cause active ingredient combination to bring.If grant diseased individuals simultaneously, the compound in compositions can mix and is present in same pharmaceutical dosage forms, also independently can exist with same dosage form.If independently exist with same dosage form, then pharmaceutical composition can flexible existing with " Combined drug box " form." Combined drug box " is a kind of case type container, the drug regimen of one or more dosage forms built-in and operation instructions thereof, one or more of a kind of and vitamin B group in beta-blocker preferably described in the present invention.
Another object of the present invention is to provide the purposes of pharmaceutical composition at preparation treatment hypertension drug of one or more and pharmaceutically suitable carrier of the vitamin B group of a kind of, the pharmaceutical dosage in beta-blocker containing pharmaceutical dosage and active metabolite thereof or its esters, more particularly, be to provide for the preparation for the treatment of hypertension, the purposes of preventing or delaying target organ damage or reducing in the medicine of cardiocerebrovasculaevents events causing danger property, especially in the body injury for the treatment of with high Hcy mass formed by blood stasis induction, have better effect.
The target organ damage that hypertension of the present invention causes comprises left ventricular hypertrophy, heart failure, good/pernicious arteriolar nephrosclerosis, renal insufficiency, Hypertensive Fundus pathological changes, apoplexy etc., and the closely-related disease of hypertension comprises atherosclerosis, coronary heart disease etc.
Advantage of the present invention: the pharmaceutical composition that the invention provides one or more and pharmaceutically suitable carrier of the vitamin B group of a kind of, the pharmaceutical dosage in beta-blocker containing pharmaceutical dosage and active metabolite thereof or its esters.The combined effect of beta-blocker and vitamin B group is not the simple addition of each self-applying of each active substance, but the basis obtaining better control patients' blood is reduced drug side effect, reduces target organ damage or reduce the risk of cardiovascular complication.That is, beta-blocker and vitamin B group drug combination achieve synergistic therapeutic effect, are therefore antihypertensive drug preferably.
Below in conjunction with detailed description of the invention, the present invention will be further described, not limitation of the invention, and the equivalent replacement of all any this areas of carrying out according to content of the present invention, all belongs to protection scope of the present invention.
Detailed description of the invention
Embodiment 1. prepares compound atenolol YESUAN PIAN (1000 amounts)
Preparation method: supplementary material was pulverized 80 mesh sieves, adjuvant drying for standby.Get 25g atenolol, 0.4g folic acid according to equal increments method mix homogeneously, starch, microcrystalline Cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose is added respectively according to recipe quantity, by equal increments method Homogeneous phase mixing, soft material is made with 5% 30 POVIDONE K 30 BP/USP 29/30-95% alcoholic solution, 20 mesh sieves are granulated, 40 DEG C of drying about 2h, 18 mesh sieve granulate, the water content controlling granule is 2-3%, dried granule is mixed homogeneously with magnesium stearate, semi-finished product detect, and measure content, are pressed into 1000 with tablet machine.Note lucifuge in preparation process, the tablet made needs aluminium-plastic bubble plate packing, keeps in Dark Place.In the compound tablet made, every sheet is containing atenolol 25mg, folic acid 0.4mg.
Embodiment 2. prepares compound recipe bisoprolol 5-methyltetrahydrofolate sheet (1000 amounts)
Preparation method: supplementary material was pulverized 80 mesh sieves, adjuvant drying for standby.Get 5g bisoprolol, 0.4g5-methyl tetrahydrofolate according to equal increments method mix homogeneously, starch, microcrystalline Cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose is added respectively according to recipe quantity, by equal increments method Homogeneous phase mixing, soft material is made with 5% 30 POVIDONE K 30 BP/USP 29/30-95% alcoholic solution, 20 mesh sieves are granulated, 40 DEG C of drying about 2h, 18 mesh sieve granulate, the water content controlling granule is 2-3%, dried granule is mixed homogeneously with magnesium stearate, semi-finished product detect, and measure content, are pressed into 1000 with tablet machine.Note lucifuge in preparation process, the tablet made needs aluminium-plastic bubble plate packing, keeps in Dark Place.In the compound tablet made, every sheet is containing bisoprolol 5mg, 5-methyltetrahydrofolate 0.4mg.
Embodiment 3. prepares compound recipe metoprolol folic acid double-layer sustained release tablets (1000 amounts)
Formula:
Preparation method:
(1) metoprolol sustained-release layer: the metoprolol of mistake 80 mesh sieves, hydroxypropyl emthylcellulose and octadecanol are pressed recipe quantity mix homogeneously, add 5% ethyl cellulose alcoholic solution soft material, granulate with 20 mesh sieves, in 60 DEG C of dryings 2 hours, with 18 mesh sieve granulate, then magnesium stearate is added, mix homogeneously, quality inspection.
(2) folic acid layer: get 0.4g folic acid, to mix according to equal increments method with microcrystalline Cellulose and sieve, add starch, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose again, Homogeneous phase mixing, make soft material with 5% 30 POVIDONE K 30 BP/USP 29/30-95% alcoholic solution, 20 mesh sieves are granulated, 40 DEG C of drying about 2h, 20 mesh sieve granulate, the water content controlling granule is 2-3%;
(3) double-layer tablet preparation method: by above-mentioned prepare be respectively charged in feed hopper containing metoprolol and folic acid, be pressed into special-shaped tablets 1000 with double-layer tablet tablet machine.The tablet made needs lucifuge, and uses aluminium-plastic bubble plate packing.In the compound tablet made, every sheet is containing metoprolol 50mg, folic acid 0.4mg.
Embodiment 4. prepares compound recipe betaxolol folic acid capsule (1000 amounts)
Preparation method: supplementary material is pulverized 80 mesh sieves, adjuvant drying for standby.Get 10g betaxolol, 0.8g folic acid according to equal increments method mix homogeneously, add starch, microcrystalline Cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose respectively, according to equal increments method Homogeneous phase mixing, soft material is made with 5% 30 POVIDONE K 30 BP/USP 29/30-95% alcoholic solution, 20 mesh sieves are granulated, 40 DEG C of drying about 2h, 18 mesh sieve granulate, the water content controlling granule is 2-3%, dried granule is mixed homogeneously with magnesium stearate, semi-finished product detect, and measure content, load Capsules and get final product.Note lucifuge in preparation process, the capsule made needs aluminium-plastic bubble plate packing, keeps in Dark Place.In the capsule made, every contains betaxolol 10mg, folic acid 0.8mg.
Embodiment 5. prepares compound recipe labetalol 5-methyltetrahydrofolate double-layer tablet (1000 amounts)
Formula:
Preparation method:
(1) labetalol layer: supplementary material was pulverized 80 mesh sieves, adjuvant drying for standby.Get 50g labetalol, starch, microcrystalline Cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose is added respectively according to equal increments method, Homogeneous phase mixing, soft material is made with 5% polyvidone aqueous solution, 20 mesh sieves are granulated, 40 DEG C of drying about 2h, 20 mesh sieve granulate, the water content controlling granule is 2-3%, obtains granule A;
(2) 5-methyltetrahydrofolate layer: get 0.2g5-methyl tetrahydrofolate, starch, microcrystalline Cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose is added respectively according to equal increments method, Homogeneous phase mixing, sieve, make soft material with 5% 30 POVIDONE K 30 BP/USP 29/30-95% alcoholic solution, 20 mesh sieves are granulated, 40 DEG C of drying about 2h, 20 mesh sieve granulate, the water content controlling granule is 2-3%, obtains granule B;
(3) double-layer tablet preparation method: dried granule A, B are mixed homogeneously with magnesium stearate respectively, semi-finished product detect respectively, after measuring content, is respectively charged in feed hopper, is pressed into 1000 with double-layer tablet tablet machine.Note lucifuge in preparation process, the tablet made needs aluminium-plastic bubble plate packing, keeps in Dark Place.In the compound tablet made, every sheet is containing labetalol 50mg, 5-methyltetrahydrofolate 0.2mg.
Embodiment 6. prepares compound recipe carvedilol 5-methyltetrahydrofolate sheet (1000 amounts)
Preparation method: supplementary material was pulverized 80 mesh sieves, adjuvant drying for standby.Get 12.5g carvedilol, 0.4g5-methyl tetrahydrofolate according to equal increments method mix homogeneously, starch, microcrystalline Cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose is added respectively according to recipe quantity, by equal increments method Homogeneous phase mixing, soft material is made with 5% 30 POVIDONE K 30 BP/USP 29/30-95% alcoholic solution, 20 mesh sieves are granulated, 40 DEG C of drying about 2h, 18 mesh sieve granulate, the water content controlling granule is 2-3%, dried granule is mixed homogeneously with magnesium stearate, semi-finished product detect, and measure content, are pressed into 1000 with tablet machine.Note lucifuge in preparation process, the tablet made needs aluminium-plastic bubble plate packing, keeps in Dark Place.In the compound tablet made, every sheet is containing carvedilol 12.5mg, 5-methyltetrahydrofolate 0.4mg.
Embodiment 7. prepares compound recipe arotinolol vitamin B
6sheet (1000 amounts)
Preparation method: adjuvant is vertical compression adjuvant, drying for standby.Get the vitamin B of recipe quantity
6and 10g microcrystalline Cellulose mix homogeneously, sieve, obtain mixed powder intermediate 1; Take the residue microcrystalline Cellulose of recipe quantity, low-substituted hydroxypropyl cellulose (L-HPC), fully mix by equal increments method with arotinolol, obtain mixed powder intermediate 2; Mixed powder intermediate 1 and mixed powder intermediate 2 are mixed homogeneously with the magnesium stearate of recipe quantity, obtains finally mixed powder intermediate, carry out detecting mixed powder intermediate, be pressed into 1000.Note lucifuge in preparation process, the tablet made needs aluminium-plastic bubble plate packing, keeps in Dark Place.In the compound tablet made, every sheet is containing arotinolol 5mg, vitamin B
610mg.
Embodiment 8. prepares Propranolol vitamin B
12sheet (1000 amounts)
Preparation method: adjuvant is vertical compression adjuvant, drying for standby.Get the vitamin B of recipe quantity
12and 50g microcrystalline Cellulose mix homogeneously, obtain mixed powder intermediate 1; Take the residue microcrystalline Cellulose of recipe quantity, low-substituted hydroxypropyl cellulose (L-HPC), fully mix by equal increments method with Propranolol, obtain mixed powder intermediate 2; Mixed powder intermediate 1 and mixed powder intermediate 2 are mixed homogeneously with the magnesium stearate of recipe quantity, obtains finally mixed powder intermediate, carry out detecting mixed powder intermediate, be pressed into 1000.The tablet made needs aluminium-plastic bubble plate packing, keeps in Dark Place.In the compound tablet made, every sheet is containing Propranolol 10mg, vitamin B
120.2mg.
Embodiment 9. betaxolols+folic acid is to the Synergistic Hypotensive Effects of spontaneous hypertensive rat
One, method
Spontaneous hypertensive rat (SHR) is purchased from Chinese Academy of Sciences's Shanghai Experimental Animal Center, and after 8 week age, rat blood pressure raises, and significantly raises after 10 week age, measures rat blood pressure 1 week (the 1st, 6 day), gets the rat of blood pressure stabilization for experiment.Hypertensive Rats grouping and dosage, in table 1, separately establish Normal group (n=12).Animal gastric infusion, every day 1 time, continuous 2 weeks.Rat blood pressure before measuring administration respectively, after last administration.
Two, result
Folic acid is applied separately spontaneous hypertensive rat without obvious hypotensive effect, betaxolol 1.5mg/kg/d, 2.0mg/kg/d have significant hypotensive effect to spontaneous hypertensive rat, after folic acid (0.08mg/kg/d) and betaxolol (1.5mg/kg/d) share, the hypotensive effect of spontaneous hypertensive rat is strengthened, its effect is close with 2.0mg/kg/d betaxolol, show that betaxolol and folic acid share and has significant Synergistic Hypotensive Effects to spontaneous hypertensive rat, this can reduce the consumption of beta-blocker, thus reduces its side effect.In table 1.
Table 1 betaxolol+folic acid is to the hypotensive effect (x ± s) of spontaneous hypertensive rat
Note: compare with model group
*p < 0.05,
*p < 0.01; Compare with betaxolol 1.5mg/kg group
▲p < 0.05,
Embodiment 10. Propranolol+vitamin B group is to the collaborative blood pressure lowering of SHR rat and target organ protection function
One, method
Spontaneous hypertensive rat (SHR) is purchased from Chinese Academy of Sciences's Shanghai Experimental Animal Center, and after 8 week age, rat blood pressure raises, and significantly raises after 13 week age, measures rat blood pressure 1 week (the 1st, 6 day), gets the rat of blood pressure stabilization for experiment.Hypertensive Rats grouping and dosage are in table 2.Separately establish Normal group (n=12).Gastric infusion, every day 2 times, continuous 13 weeks.Different time rat blood pressure before measuring administration respectively, after administration, measures 24h respectively and urinates α after last administration
1microglobulin.
Two, result
Twenty-four-hour urine α
1microglobulin is the label reflecting early stage injury of renal tubular.Folic acid, vitamin B
6, vitamin B
12independent application to spontaneous hypertensive rat without obvious hypotensive effect and target organ protection function; Propranolol 2.5mg/kg/d has significant hypotensive effect and target organ protection function to spontaneous hypertensive rat, folic acid (0.08mg/kg/d), vitamin B
6(1.0mg/kg/d), vitamin B
12(0.1mg/kg/d) after share with Propranolol; the hypotensive effect of spontaneous hypertensive rat and target organ protection function are significantly strengthened; its effect has exceeded Propranolol group; show that Propranolol and vitamin B group share and have significant collaborative blood pressure lowering and target organ protection function, in table 2 to Hypertensive Rats.
Table 2 Propranolol+vitamin B group is to the collaborative blood pressure lowering of SHR and target organ protection function
Note: compare * P < 0.05, * * P < 0.01 with model group; Compare with Propranolol group,
▲p < 0.05,
▲ ▲p < 0.01
Embodiment 11. carvedilols+vitamin B group is to the collaborative blood pressure lowering of 2K1C Hypertensive Rats and target organ protection function
One, method
With 0.2mm silver brain clip narrow Wistar Rats With Unilateral (left side) renal artery, after 8 ~ 10 weeks, rat blood pressure increases to over more than 150mmHg is antioxidant (2K1C) type hypertension animal model.Hypertensive Rats random packet and administration, in table 3, separately establish Normal group (n=12).Gastric infusion, every day 2 times, continuous 13 weeks.To measure respectively before administration and different time blood pressure after administration.Measure 24h after last administration respectively and urinate α
1microglobulin.
Two, result
Data analysis is in table 3.Twenty-four-hour urine α
1microglobulin is the label reflecting early stage injury of renal tubular.5-methyltetrahydrofolate (5-MTF), vitamin B
6, vitamin B
12independent application to 2K1C Hypertensive Rats without obvious hypotensive effect and target organ protection function; carvedilol (2.0-3.0mg/kg/d) has significant hypotensive effect and target organ protection function to Hypertensive Rats, 5-MTF (0.04mg/kg/d), vitamin B
6(1.0mg/kg/d), vitamin B
12(0.1mg/kg/d) after share with carvedilol (2.0mg/kg/d); the hypotensive effect of 2K1C type Hypertensive Rats and target organ protection function are significantly strengthened; its effect and carvedilol (3.0mg/kg/d) are organized close; show that carvedilol and vitamin B group share and have significant synergistic therapeutic action to 2K1C Hypertensive Rats; the consumption of beta-blocker can be reduced, thus reduce its side effect.
Table 3 carvedilol+vitamin B group is to the collaborative blood pressure lowering of 2K1C rat and target organ protection function (x ± s)
Note: compare with model group
*p < 0.05,
*p < 0.01; Compare with carvedilol 2.0mg/kg group
▲p < 0.05,
▲ ▲p < 0.0l
Embodiment 12. atenolol+folic acid is to the protective effect of Hypertensive Rats blood pressure lowering and target organ damage
One, method
SHR rat, body weight 150 ~ 180g, be equally divided into 4 groups, often organize 20, be respectively model group, atenolol group (2.5mg/kg/d), folic acid group (0.08mg/kg/d), atenolol+folic acid group (2.5+0.08mg/kg/d), separately get 20 normal rats as Normal group, give to wait capacity 0.5%CMC solution.Every day, 2 administrations, weighed weekly once, according to body weight adjustment dose, and successive administration 20 weeks.Testing index comprises (1) blood pressure: to measure respectively before administration and different time Mus tail blood pressure after administration; (2) collect urine, with turbidimetry for Determination urine protein, put and exempt from method mensuration 24h urine α
1microglobulin; Get blood, measure serum creatinine, calculate creatinine clearance rate (Ccr).(3) Myocardial hydroxyproline measures: get left ventricular free wall cardiac muscular tissue, be prepared into the ventricular homogenate of 10%, by hydroxyproline testing cassete description, digestion method measures Myocardial hydroxyproline content, by collagen content=hydroxyproline content × 7.46, be converted into collagen content.(4) cardiac muscular tissue's routine section, Picro-Sirius red-picric acid dyeing, measures myocardial collagen fraction by volume (CVF) and collagen volume fraction (PVCA).CVF is the ratio of area of collagen and the myocardium gross area, and wherein area of collagen does not comprise PVCA, and stochastic analysis 5 visuals field, get its average.PVCA is the ratio that each specimen measures that 4 are arteriolar surrounding area and Lumen Area in cross section wall, gets its average.(5) intrarenal small artery is observed: through abdominal aortic cannulation, after the abundant blood vessel dilating of 0.1mg/ml sodium nitroprusside, formalin with 10% is poured into fixing under 10 ~ 12kPa, be separated left kidney, from the hilus renalis, place cuts kidney, be placed in 4% formaldehyde to fix, conventional dehydration, paraffin embedding, transverse section, HE dyeing.Choose the intrarenal small artery that external diameter is 50 ~ 100 μm under optical microscope, measure intrarenal small artery internal diameter, wall thickness, calculated wall thickness internal diameter ratio.Each specimen measures small artery in 4 cross section walls, gets its meansigma methods.Data statistics process adopts SAS statistical software, compares employing variance analysis between group.
Two, result
(1) on the impact of SHR rat blood pressure: compare with normal rat, SHR rat systolic pressure continues, significantly raise (P < 0.01); Before administration except Normal group, other respectively organize blood pressure level zero difference; After administration, compare with model group, atenolol group each time period systolic pressure declines significantly, shrink during folic acid group 20 weeks and be pressed with slight decline, atenolol+folic acid group each time period systolic pressure declines significantly, and 20 weeks time, comparatively atenolol group is more obvious for hypotensive effect, refers to table 4.
Table 4 atenolol+folic acid is on the impact of SHR rat systolic pressure SBP (mmHg)
Note 1: the number of animals (there is animal dead centre) of numeral each time period in table bracket
Note 2: compare with model group,
*p < 0.05,
*p < 0.01; Compare with atenolol group,
▲p < 0.05;
(2) on the impact of SHR rat heart muscle collagen content, myocardial collagen fraction by volume (CVF) and collagen volume fraction (PVCA): compare with Normal group, SHR rat heart muscle collagen content, Myocardial Interstitial Fibrosis index CVF, myocardial vascular surrounding annulus index PVCA all significantly increase, CVF and PVCA raises almost synchronous, shows that Myocardial Interstitial Fibrosis take part in the pathological process of Hypertensive Rats cardiac remodeling.Compare with model group, atenolol group, atenolol+folic acid group rat heart muscle collagen content, myocardium CVF, PVCA all significantly reduce.Folic acid group has no obvious reducing effect, and the more alone atenolol group of wherein atenolol+folic acid group has significant difference, shows that atenolol and folic acid share, and strengthens, refer to table 5 to hypertrophic myocardium protective effect.
Table 5 atenolol+folic acid is on the impact of SHR rat heart muscle collagen content, CVF and PVCA
Note: compare with normal group,
*p < 0.01; Compare with model group,
▲p < 0.05,
▲ ▲p < 0.01;
Compare with atenolol group,
△p < 0.05.
(3) on impact arteriolar in SHR kidney of rats: the Blood vessel pattern of Hypertensive Rats, main manifestations is the fibrosis of blood vessel wall adventitia, tube wall IMT (being increased caused by smooth muscle cell proliferation, plumpness and intercellular substance); Inner membrance vitreous degeneration, endotheli ocytosis, above-mentioned change makes vessel wall thickness/tube chamber ratio reduce.Compare with normal rat, SHR kidney of rats small artery wall thickness increases, and internal diameter reduces, and wall thickness/internal diameter is than increasing.Compare with model group, atenolol group, atenolol+folic acid group kidney of rats small artery wall thickness reduces, internal diameter increases, wall thickness/internal diameter ratio reduces, folic acid group wall thickness/internal diameter has reduction than also, the reduction of the wall thickness of the more alone atenolol group of atenolol+folic acid group and wall thickness/internal diameter ratio is more remarkable, shows that atenolol and folic acid share to have arteriolosclerosis and prevents or therapeutical effect preferably.In table 6.
Table 6 atenolol+folic acid is on impact arteriolar in SHR kidney of rats
Note: compare with normal group,
*p < 0.05,
*p < 0.01; Compare with model group,
▲p < 0.05,
▲ ▲p < 0.01; Compare with atenolol group,
△p < 0.05.
Embodiment 13. metoprolols+folic acid is to the Synergistic Hypotensive Effects of Hypertensive Rats and target organ protection function
One, method
(1) 2K1C hypertension animal model prepares chloral hydrate (320mg/kg) intraperitoneal injection of anesthesia Wistar rat (male and female half and half, 150 ~ 180g), abdominal cavity is opened along abdomen median line, be separated left renal artery, the narrow rat left renal artery of 0.2mm silver brain clip, gets contractive pressure >=140mmHg person for postoperative 8 ~ 10 weeks for Hypertensive Rats.(2) renal hypertensive rat 98 is got in grouping and administration, divide equally 7 groups, often organize 14, for model control group, metoprolol 6mg/kg/d) group, metoprolol+folic acid (5+0.04mg/kg/d), metoprolol+folic acid (5+0.08mg/kg/d), metoprolol+folic acid (5+0.16mg/kg/d), metoprolol+folic acid (5+0.5mg/kg/d), folic acid (0.08mg/kg/d) group, separately get 14 normal rats as Normal group.Every day gastric infusion 2 times, Normal group, hypertension group such as to give at the capacity distilled water, successive administration 26 weeks.(3) Testing index 1. pressure value: adopt tail cover method, before measuring administration respectively with 179 type non-damage toy blood pressure measuring instrument, administration the 1st, 5,9,13,18,22,26 weeks rat blood pressures, each mensuration 3 times, averages.2. endothelial function: 26 weekends, gets blood by test kit description, measures Plasma Nitric Oxide (NO), Endothelin (ET) level.3. renal function: 26 weekends, collects urine, surveys 24h urine creatine (Scr), urine protein, 24h Urinary α1-microglobulin; Get blood, measure serum creatinine, blood urea nitrogen (BUN), calculate creatinine clearance rate (Ccr).4. hemodynamic index: before last administration, 20% urethane anesthesia, face upward position to fix, be separated right carotid, insert one and be full of heparin-saline conduit to left ventricle, pass through pressure transducer, connect and lead physiological signal collection processing system more, stablize 10min, ig administration, 3 hours left rooms peak pressure meansigma methods (LVSP), maximum the rate of change (± dp/dt in left room before recording last administration respectively, after medicine
max), left room end diastolic pressure (LVEDP).5. pathologic finding: to core, the internal organs such as kidney, spleen, brain, 10% formalin is fixed, paraffin embedding, section, and HE dyes, light microscopy checking.(4) statistical analysis calculates each group of mean and standard deviation respectively, and administration group and matched group carry out t inspection.
Two, result
(1) impact of metoprolol+folic acid on hypertensive rat blood pressure is compared with normal group, and model group rats blood pressure significantly raises, and folic acid group blood pressure slightly reduces, and wherein within the 5th, 9 week, has significant difference.Metoprolol (5mg/kg/d) group, metoprolol (5mg/kg/d)+folic acid (0.04 ~ 0.5mg/kg/d) is organized rat blood pressure and is significantly reduced, and comparing with model group has significant difference.Compare with metoprolol group, metoprolol+folic acid (0.04 ~ 0.5mg/kg/d) is organized blood pressure and is reduced further, and wherein the 9th, 13,18,22,26 week time point compares significant difference.Show that folic acid is alone and have slight hypotensive effect, metoprolol significantly can reduce hypertensive rat blood pressure, and folic acid and metoprolol share for a long time, strengthens further the hypotensive effect of renal hypertensive rat.
(2) impact of metoprolol+folic acid on Hypertensive Rats blood plasma NO, ET level is compared with normal rats, and hypertension group rat plasma NO level significantly reduces, and ET level significantly raises.Compare with hypertension model group, folic acid group, metoprolol group rat plasma NO rising, ET reduce.Metoprolol+folic acid (0.04 ~ 0.5mg/kg/d) is organized rat plasma NO and is raised further; ET reduces further; show that renal hypertensive rat has occurred that inner skin cell function damages; metoprolol, folic acid on rats inner skin cell function have protective effect; both share and this protective effect are strengthened, in table 7.
Table 7 metoprolol+folic acid is on the impact (X ± SD) of Hypertensive Rats blood plasma NO, ET level
Compare with normal group,
*p < 0.01; Compare with model group,
▲p < 0.05,
▲ ▲p < 0.01; Compare with metoprolol group,
★p < 0.05
(3) impact of metoprolol+folic acid on Hypertensive Rats renal function is compared with normal rat, Hypertensive Rats urine 24h α
1-microglobulin, urine protein significantly raise, and Ccr obviously reduces.Metoprolol group rat urine 24h α
1-microglobulin, urine protein reduce, and Ccr raises, and folic acid is alone to be had no significant effect renal hypertensive rat renal function.Metoprolol+various dose folic acid group rat urine 24h α
1-microglobulin, urine protein reduce further; Ccr raises further; compare with metoprolol group that there were significant differences; show that renal hypertensive rat occurs that Renal function in early period damages; the renal function injury of metoprolol to Hypertensive Rats has protective effect; folic acid and Metoprolol In Combination, significantly strengthen the protecting renal function effect of renal hypertensive rat.In table 8 ~ 10.
Table 8 metoprolol+folic acid administration 26 weeks presses rat urine α to height
1the impact (X ± SD) of-microglobulin
compare with normal group,
*p < 0.01; Compare with model group,
▲ ▲p < 0.01; Compare with metoprolol group,
★p < 0.05,
★ ★p < 0.01
The table 9 metoprolol+impact of folic acid successive administration 26 weeks on renal hypertensive rat urinaryalbumin (X ± SD)
Compare with normal group, * * P < 0.01; Compare with model group,
▲p < 0.05,
▲ ▲p < 0.01; Compare with metoprolol group,
★p < 0.05,
★ ★p < 0.05
The table 10 metoprolol+impact of folic acid administration 26 weeks on renal hypertensive rat Scr, BUN, Ccr (X ± SD)
Compare with normal group, * * P < 0.01; Compare with model group,
▲ ▲p < 0.01; Compare with metoprolol group,
★p < 0.05
(4) metoprolol+folic acid compares with normal rats the hemodynamic impact of renal hypertensive rat, and hypertension group rat LVSP, LVEDP significantly raise, and ± dp/dtmax declines.Metoprolol group rat LVSP, LVEDP significantly reduce, and ± dp/dtmax raises; Folic acid is alone to be had no significant effect renal hypertensive rat hemodynamics.Metoprolol+various dose folic acid group rat LVSP, LVEDP reduces further, and ± dp/dtmax raises further, and comparing with metoprolol group has significant difference.Show that renal hypertensive rat cardiac preload, afterload increase; heart contraction, diastolic dysfunction, the cardiac function of metoprolol to renal hypertensive rat has protective effect, folic acid and Metoprolol In Combination; the cardiac function protective effect of renal hypertensive rat is significantly strengthened, in table 11.
Table 11 metoprolol+folic acid is on the hemodynamic impact of Hypertensive Rats (X ± SD, n=8 ~ 11)
Compare with normal group,
*p < 0.01; Compare with model group,
▲ ▲p < 0.01; Compare with metoprolol group,
★p < 0.05,
★ ★p < 0.01
(5) the histopathological examination normal rats heart, kidney, brain, spleen are showed no obvious change.Model group rats cardiac myocyte hypertrophy, thicker, elongated, core is engrain greatly, and part myocardial cell has cellular edema (showing as cloudy swelling or hydropic degeneration), minority animal coronary atherosclerosis; The kidney major part glomerule fibrosis of being pressed from both sides, vitreous degeneration or blood capillary ball are lobulated, sacculus parietal layer epithelial proliferation, and corresponding renal tubules atrophy, even disappears; Part glomerule compensatory hypertrophy, tubular ectasia; Arteriole and arteriolosclerosis, interstitial fibers hamartoplasia, lymphocytic infiltration; Opposite side nephropathy is not obvious, and glomerule is slightly loose; Spleen central artery vitreous degeneration; The brain arteriolosclerosis of Some Animals, minority is shown in capillary proliferation.The above-mentioned pathological changes of administration group rat all has and alleviates in various degree: the target organ damage of alone folic acid to renal hypertensive rat has slight protective effect; the target organ damage of metoprolol to Hypertensive Rats has significant protective effect, and folic acid and the target organ protection function of Metoprolol In Combination to renal hypertensive rat strengthen further.
Embodiment 14. bisoprolols+5-methyltetrahydrofolate (5-MTF) is to the protective effect of apoplexy susceptible type SHR
One, method
Male apoplexy susceptible type SHR (SHR-SP) rat totally 100 about 8 week age, in conjunction with blood pressure values, be divided into model group, bisoprolol (0.5mg/kg/d) group, 5-methyltetrahydrofolate (5-MTF) group (0.08mg/kg/d), bisoprolol+5-MTF group (0.5+0.08mg/kg/d) at random.Rearing conditions is: room temperature 22 ± 2 DEG C, relative humidity 50%, and solid feed and bedding and padding provide by Chinese Academy of Medical Sciences's laboratory animal breeding field, and drinking water is pure water.Separately establish blood pressure Normal group 20.Administration group gastric infusion, every day 1 time, weighs weekly once, according to body weight adjustment dose, and continuous 8 weeks.
Observation index: (1) every day observes animal diet followed, survival condition and behavioral activity, recorded each treated animal apoplexy a situation arises in 8 weeks.(2) function of nervous system's classification is with reference to function of nervous system's grade scale of Bederson, is divided into 5 grades of (as described below), observes weekly once.(3) pathological observation: all surviving animals and the dead rear desirable rat obtaining pathological tissue all get cerebral tissue, and section, HE dyeing, observe cerebral hemorrhage, cerebral infarction or Mixed Cerebrovascular disiase, calculate each group of rat brain stroke incidence.
[attached] Bederson function of nervous system grade scale:
0 grade (normally): impassivity functional impairment symptom.
1 grade (slightly): forelimb is rolled up or flexing, mainly persistence wrist flexing or shoulder adduction companion ancon stretch.
2 grades (moderate): forelimb persistence is rolled up or flexing, the whole flexing of visible wrist, elbow, shoulder adduction or inward turning.
3 grades (seriously): persistence limbs are rolled up or flexing, the side anti-persistence of limbs thrust body weakens, and does not accompany limbs to draw circle behavior during autonomic activities.
4 grades (very heavy): both limbs persistence is rolled up or flexing, the side anti-persistence of limbs thrust body weakens, and occurs that limbs draw circle behavior during autonomic activities.
Two, result
In this experimentation, there is obvious lethargy in model group rats Post stroke, drowsiness, hair is fluffy, withered or come off, matt, weight loss, active movement obviously reduces, be slow in action, limbs in paralysing in various degree, partial rat morbidity simultaneously with symptoms such as tics, diarrhoea, urinary incontinence, eyeball are hemorrhage, the interior death of the person's of being in a bad way a few hours.Comparatively model group is slight for most of animal nerve functional impairment for the treatment of group, and the mental status is obviously better than model group, and autonomic activities increases, and initiatively look for food, drink water, weight loss is not obvious, and hair is also smooth compared with model group glossy.
16 generation apoplexy are had, apoplexy stove and around all visible small artery hyaline degeneration or fibrinoid necrosis, tube wall thickening, luminal stenosis, visible microthrombusis in some tube chambers, all oozings of blood of pipe in model group 20 rats.Bisoprolol group 20 rats have 14 apoplexy occurs, and 14 animals have apoplexy pathological manifestations, compare have no significant difference with model group.5-MTF group 20 rats have 13 apoplexy occurs, and 12 only have apoplexy pathological manifestations, compare incidence of stroke decrease with model group.Bisoprolol+5-MTF organizes in 20 rats has 9 apoplexy occurs, and 9 only have apoplexy pathological manifestations, and its incidence of stroke obviously reduces.Compare with model group or compare with bisoprolol group and 5-MTF group, bisoprolol+5-MTF group all shows more excellent stroke prevention curative effect, refers to table 12.
The impact on SHR-SP rat brain apoplexy in 8 weeks of table 12 bisoprolol+5-MTF successive administration
Note: compare with normal group,
*p < 0.01; Compare with model group,
▲p < 0.05; Compare with bisoprolol group,
△p < 0.05
Relatively 4 weeks and the classification of 8 Zhou Shigezu rats with stroke function of nervous system.On the whole, the classification of model group animal apoplexy, apparently higher than Normal group, meets the requirement of SHR-SP animal; Compare with model group, the function of nervous system of 5-MTF group improves not obvious, bisoprolol group, bisoprolol+5-MTF group then shows comparatively significantly improving (P < 0.05) of each classification of animal nerve function, especially organize with bisoprolol+5-MTF more remarkable, refer to following table 13 and 14.
Table 13 bisoprolol+5-MTF successive administration 4 weeks to SHR-SP apoplexy function of nervous system size scale comparatively (only)
Note: compare with normal group,
*p < 0.01; Compare with model group,
▲p < 0.05; Compare with bisoprolol group,
△p < 0.05
Table 14 bisoprolol+5-MTF successive administration 8 weeks to SHR-SP apoplexy function of nervous system size scale comparatively (only)
Note: compare with normal group,
*p < 0.01; Compare with model group,
▲p < 0.05; Compare with bisoprolol group,
△p < 0.05.
Claims (5)
1. a pharmaceutical composition, constituent is:
(1) the receptor,β blocker of pharmaceutical dosage or the one of its salt;
(2) the leaf acid of pharmaceutical dosage;
(3) acceptable carrier on pharmaceutics.
Wherein, leaf acid is selected from folic acid, 5-methyltetrahydrofolate, formyl tetrahydrofolic acid, folinic acid, calcium levofolinate, folic acid officinal salt, and content is 0.1 ~ 5mg; Receptor,β blocker is selected from atenolol, metoprolol, bisoprolol, betaxolol, arotinolol, carvedilol, labetalol, Propranolol, and atenolol content is 12.5 ~ 100mg, metoprolol content is 50 ~ 200mg, bisoprolol content is 2.5 ~ 10mg, betaxolol content is 5 ~ 20mg, arotinolol content is 5 ~ 20mg, carvedilol content is 10 ~ 25mg, labetalol content is 100 ~ 200mg, Propranolol content is 10 ~ 20mg.
2. pharmaceutical composition according to claim 1, is characterized in that the pharmaceutical dosage form of this pharmaceutical composition is oral formulations, is selected from tablet, capsule or granule.
3. pharmaceutical composition according to claim 1 for the preparation for the treatment of hypertensive medicine in purposes.
4. pharmaceutical composition according to claim 1 for the preparation of prevention, treat or delay purposes in the medicine of the target organ damage that hypertension causes, described target organ damage comprises left ventricular hypertrophy, benign arteriolar nephrosclerosis disease, pernicious arteriolar nephrosclerosis, renal failure, retinal arteriosclerosis, Hypertensive Fundus pathological changes, apoplexy.
5. the purposes of pharmaceutical composition according to claim 1 in the medicine of the cardiocerebrovasculaevents events danger caused for the preparation of reduction hypertension, the cardiocerebrovasculaevents events danger that described reduction hypertension causes refers to the incidence rate reducing angina pectoris, myocardial infarction, heart failure, apoplexy.
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