CN101879168A - Antihypertensive drug compound preparation - Google Patents
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- CN101879168A CN101879168A CN 201010164677 CN201010164677A CN101879168A CN 101879168 A CN101879168 A CN 101879168A CN 201010164677 CN201010164677 CN 201010164677 CN 201010164677 A CN201010164677 A CN 201010164677A CN 101879168 A CN101879168 A CN 101879168A
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Abstract
The invention discloses an antihypertensive drug compound preparation, which mainly contains the following components in parts by weight: mixture of 20-400 parts of piperazine ferulate and 2-40 parts of benazepril as pharmaceuitical components. The invention provides a compound antihypertensive preparation of the piperazine ferulate and an RAS inhibitor, which is convenient to take and safe to use and emphasizes omni-directional systolic pressure control, and the reduction of the diastolic pressure is brought. The antihypertensive drug compound preparation not only can relieve the vasoconstrictor effect of ET, but also can relieve the vasoconstrictor effect of AngII, and simultaneously relieves the pathological vascular multiplication effect of the ET and the AngII. Aiming at the present known hypertensive mainly caused by the factor of pathological neurohumor, the antihypertensive drug compound preparation has the effect of reducing the systolic pressure furthest, and simultaneously brings the effect of reducing the diastolic pressure.
Description
Technical field
The present invention relates to a kind of Antihypertension drug compound preparation.
Background technology
Since nineteen ninety-five Stern proposes " common soil " theory, people have had more deep understanding to the pathogenic factor of diseases such as hypertension, coronary heart disease, obesity, type 2 diabetes mellitus, blood fat disorder, in essence, these diseases all are to become longer different performance on the common pathologic basis.In treatment, these diseases have common treatment measure and medicine.At present, except hypertension (essential hypertension), need the sickness rate of the disease of controlling blood pressure to increase, as type 2 diabetes mellitus, chronic nephropathy, coronary heart disease, apoplexy etc., wherein cardiovascular and cerebrovascular disease has become the primary cause of death.Controlling blood pressure is significant for these treatment of diseases, is common treatment measure.
At present, treat hypertensive medicine and mainly contain following a few class:
1, suppresses vasoconstriction: renin-angiotensin system (RAS) inhibitor (comprising ACEI and ARB), calcium antagonist, vasodilation
2, suppress myocardial contraction: beta-blocker.
3, reduce blood volume: diuretic.
Wherein most widely used is the RAS inhibitor, because of the effect with blocking-up Angiotensin II (AngII) produces vasodilation, reaches the blood pressure lowering purpose, especially systolic pressure is had bigger antihypertensive effect.Reduce systolic pressure and have bigger meaning than reducing diastolic pressure for preventing myocardial infarction and cerebral hemorrhage.But be not that all height contraction die mould hypertension can reach therapeutic purposes by the use of RAS inhibitor, because cause not only AngII of vasoconstrictive factor, Endothelin has the stronger high hypertensive ability of die mould of shrinking that causes.
Endothelin (ET) is the most powerful up to now a kind of vaso-excitor material of just finding in 1988, and its vascular effect that contracts is 10 times of AngII, is the important neuro humor cause of disease of hypertension.
Piperazine ferulate is as a class endothelin-receptor antagonists, has the vasoconstriction effect and blood pressure lowering, antihypertensive effect is embodied in and reduces on the systolic pressure, simultaneously, the piperazine ferulate oral formulations is national medical insurance Class B medicine, as the new non-peptide-like endothelin receptor antagonist of a class, be widely used in auxiliary treatment and the leukocyte and the thrombocytopenia of vascular conditions such as arteriosclerosis, coronary heart disease, cerebrovascular, renal glomerular disease, pulmonary hypertension, diabetic angiopathy change, vasculitis, also can be used for the treatment of migraine, vascular headache.
Summary of the invention
Technical problem to be solved by this invention provides a kind of Antihypertension drug compound preparation.
The present invention addresses the above problem the technical scheme that is adopted: a kind of Antihypertension drug compound preparation is that medicinal component constitutes by 20～400 parts of mixture with 2～40 parts of benazeprils of piperazine ferulate mainly by weight.
Further, described compound preparation also comprises 10～120 parts of inert solids as pharmaceutical carrier, and the admixture that inert solid and medicinal component form constitutes compound preparation.
Described inert solid is a kind of or above-mentioned multiple mixture that constitutes with arbitrary proportion in excipient, disintegrating agent, lubricant, cosolvent, correctives, the binding agent.Excipient, disintegrating agent, lubricant, cosolvent, correctives, binding agent have comprised lactose, starch, dextrin, microcrystalline Cellulose, polyvidone, gelatin, micropowder silica gel, Polyethylene Glycol etc.
Described compound preparation also comprises 160～1000 parts of inert fluids as pharmaceutical carrier, and the admixture that inert fluid and medicinal component form constitutes compound preparation.
Described inert fluid is a kind of or above-mentioned two kinds of mixture that constitute with arbitrary proportion in diluent, wetting agent, the additive.
Antihypertensive compound preparation of the present invention can be according to industrial known method preparation, promptly gets by piperazine ferulate and RAS inhibitor are admixed with suitable inert solid or liquid medicine carrier.Can make suitable oral compound preparation, the dosage form that is fit to oral compound preparation can be tablet, granule, capsule, suspensoid, syrup.Wherein tablet, granule, capsule can contain carrier and/or adjuvant commonly used in the pharmaceuticals industry.For example Icing Sugar, starch, absorbent (for example dextrin), disintegrating agent (for example tween 80), lubricant (for example 50% ethanol), magnesium stearate etc.Wherein suspensoid, syrup also can contain industrial carrier commonly used of system and/or adjuvant.For example diluent (for example water, distilled water, ethanol, Polyethylene Glycol, glycerol etc.), commonly used additive (for example suspending liquid, antiseptic, correctives etc.).Tablet, granule can be by dry method or wet granulation technology preparations.Capsule can be inserted soft or hard gelatine capsule kind with the suitable mixture of chemical compound and make.Suspensoid and syrup can add the suitable mixture of chemical compound in the diluent that is mixed with suspending agent, antiseptic etc. makes aqueous solution, described diluent is preferably distilled water, suspending agent is preferably the tragakanta, antiseptic is preferably nipalgin second, third fat, preferably add correctives in the syrup, correctives is a sucrose.
The pharmacology of piperazine ferulate:
This product is non-peptide-like endothelin receptor antagonist, but the vasoconstriction that the antagonism Endothelin causes, boosts and vascular smooth muscle cell proliferation; Increase the synthetic of NO, lax vascular smooth muscle; Anticoagulant, anticoagulation, improve the hemorheology feature.This product also can suppress the synthetic of cholesterol, and blood fat reducing is removed free radical, the control lipid peroxidation injury; Influence complement, the enhance immunity function, and have certain analgesia, spasmolysis.
The toxicity of piperazine ferulate:
Acute toxicity testing is the result show: the oral LD50 of one-level Kunming mouse is: 3580.1 ± 251.7mg/kg crediblely is limited to 95%.The long term toxicity result of study shows: the long term toxicity test result of quiet notes piperazine ferulate 300mg (continuous 30 times) proves that piperazine ferulate toxicity is less by to the healthy adult male dog next day, can be for clinical use.Genotoxicity studies show that: through Wistar kind rat is not seen tangible embryotoxic effect and teratogenic effect with lumbar injection and two kinds of approach experiments of filling stomach, show that this medicine is being safe and reliable basically aspect the teratogenesis tire.The carcinogenecity result of study shows: by to the mutagenesis of piperazine ferulate to Salmonella typhimurium TA98, TA100, piperazine ferulate bone marrow micronucleus test and piperazine ferulate show this product non-carcinogenesis to the distored influence test of mouse marrow cell chromosome.
The pharmacokinetics of piperazine ferulate: this product oral absorption blood peak time of drug is 29 minutes, and the distribution phase half-life, (t1/2 α) was 27 minutes, and eliminating the phase half-life (t1/2 β) is 5.5 hours.This product is distributed more widely in vivo, in liver, kidney blood, distribute more, it is also more to distribute in stomach, small intestinal fat, this product is discharged mainly and is discharged from urine, feces.Can see through placental barrier.
The oral median lethal dose(LD 50) of mice (LD50) is 3.2g/kg.Rat oral gavage administration 600mg/kg, once a day, successive administration 3 months, hematology and blood biochemical are learned the index testing result and are all belonged to normally, and main organs histopathologic examination does not find drug-induced pathological change.
Benazepril is a kind of high ACEI1 that organizes affinity.Pharmacology (1) blood pressure lowering: this product is hydrolyzed to benazeprilat in liver, become a kind of emulative angiotensin converting enzyme inhibitor, the prevention angiotensin i-converting is an Angiotensin II, and vascular resistance is reduced, the aldosterone secretion reduces, and plasma renin activity increases.Benazeprilat also suppresses the degraded of Kallidin I, and vascular resistance is reduced, and produces hypotensive effect.(2) lower cardiac load: this product expansion artery and vein, reduce peripheral vascular resistance or cardiac afterload, reduce pulmonary capillary embedding pressure or cardiac preload, also reduce pulmonary vascular resistance, thereby improve cardiac output, make exercise tolerance and time lengthening.2. toxicity rat and mice continue oral benazepril 2 years, and dosage is 150mg/kg every day, does not find that this product has carcinogenecity.(this dosage is pressed mg/kg and is calculated, and is 110 times of the maximum consumption of the mankind; Press mg/m
2Calculate, be 18 times and 9 times of the maximum consumption of the mankind).No matter in bacteria test, still in the mammalian cell test of In vitro culture, do not find that all this product has mutagenicity.The oral benazepril of female, great and mighty or powerful Mus, dosage is 50-150mg/kg every day, does not find that this product influences reproductive performance.(this dosage is pressed mg/kg and is calculated, and is 37～375 times of the maximum consumption of the mankind; Press mg/m
2Calculate, be 6～60 times of the maximum consumption of the mankind).
Because the blood vessel function that contracts of RAS inhibitor Angiotensin II capable of blocking (AngII), but can not block the blood vessel function that contracts of ET; The blood pressure effect that rises of piperazine ferulate ET capable of blocking and blood pressure lowering, but therefore the vascular effect that contracts that can not antagonism AngII needs drug combination controlling blood pressure better, especially systolic pressure.But do not see the compound preparation that piperazine ferulate and other depressor are arranged so far.
In sum, the invention has the beneficial effects as follows: the invention provides a kind of taking convenience, piperazine ferulate safe in utilization and the compound antihypertensive preparation of RAS inhibitor, it focuses on comprehensive control systolic pressure, must bring the decline of diastolic pressure certainly.It can remove the vascular effect that contracts of ET, also can remove the vascular effect that contracts of AngII, also removed simultaneously the pathologic vessels multiplication effect of the two, at mainly known at present causing hypertensive pathologic neuro humor factor, have and reduce the systolic pressure effect to greatest extent, bring the effect that reduces diastolic pressure simultaneously.
The specific embodiment
The present invention is described in further detail below in conjunction with embodiment, but embodiments of the present invention are not limited thereto.
The compound oral administration preparation of present embodiment adopts with the preparation of pharmaceuticals industry known method, and the concrete consumption of each component sees table:
| Component | Consumption | Effect |
| Piperazine ferulate | ?1200g | Principal agent |
| Benazepril | ?120g | Principal agent |
| Starch | ?150g | Filling, disintegrate |
| Icing Sugar | ?90g | Flavoring, bonding |
| Dextrin | ?60g | Increase hardness, absorption |
| Tween 80 | ?10g | Disintegrate |
| 50% ethanol | In right amount | Bonding, moistening |
| Component | Consumption | Effect |
| Magnesium stearate | ?10g | Lubricated |
| Make | 0.54g/ sheet * 3000 slice |
Adopt two kinds of oral drugs of piperazine ferulate and benazepril to mix simultaneously to take the therapeutic effect that carries out and show, use the effect of piperazine ferulate and benazepril all to be better than single a kind of medicine of using, thereby be that the compound preparation of developing two kinds of reasonable 5 usefulness of medicine is laid a good foundation.
The therapeutic effect checking of hypertensive rat model:
Purpose: the compound preparation of the different proportionings of observation piperazine ferulate associating benazepril is to the influence of DOCA (desoxycorticosterone acetate (DOCA)) hypertensive rat blood pressure (BP), to inquire into the hypotensive effect under the various dose collocation in the compound recipe.
Method: 96 of SD rats, ♂, body weight 180～190g.After aseptic condition was excised the right side kidney down, secondary only gave DOCA 5mg/ weekly, sc, and raise with 1% sodium chloride solution; Be divided into 12 groups at random, 8 every group, specifically divide into groups and disposal situation such as table one.
Grouping of table one animal and pharmaceutical formulation, medication
| Model group | Normal saline |
| The piperazine ferulate group | 400 milligrams of piperazine ferulates |
| The high group of benazepril | 40 milligrams of benazeprils |
| One group of compound recipe | 20 milligrams of piperazine ferulates, 2 milligrams of benazeprils |
| Two groups of compound recipes | 20 milligrams of piperazine ferulates, 20 milligrams of benazeprils |
| Three groups of compound recipes | 20 milligrams of piperazine ferulates, 40 milligrams of benazeprils |
| Four groups of compound recipes | 200 milligrams of piperazine ferulates, 2 milligrams of benazeprils |
| Five groups of compound recipes | 200 milligrams of piperazine ferulates, 20 milligrams of benazeprils |
| Six groups of compound recipes | 200 milligrams of piperazine ferulates, 40 milligrams of benazeprils |
| Seven groups of compound recipes | 400 milligrams of piperazine ferulates, 2 milligrams of benazeprils |
| Eight groups of compound recipes | 400 milligrams of piperazine ferulates, 20 milligrams of benazeprils |
| Nine groups of compound recipes | 400 milligrams of piperazine ferulates, 40 milligrams of benazeprils |
Medication: compound recipe group medicine is diluted with water to scattered paste shape, every day gastric infusion, po, qd (oral, once a day); Continuous 5 weeks
The result: after 5 weeks, measure the blood pressure of each treated animal, each treated animal mediodespidine average and statistical result see Table two, table three, get P＜0.05 for there were significant differences; Get P＜0.01 for utmost point significant difference is arranged.
The meansigma methods and the statistical result of each treated animal systolic pressure of table two
| Group | Systolic pressure (mmHg) |
| Model group | ??167.4 |
| The piperazine ferulate group | ??130.5 A |
| The benazepril group | ??128.7 A |
| One group of compound recipe | ??158.4 aJK |
| Two groups of compound recipes | ??144.6 AbJK |
| Three groups of compound recipes | ??126.5 ABC |
| Four groups of compound recipes | ??146.2 AbDJK |
| Five groups of compound recipes | ??122.8 ABCEjk |
| Six groups of compound recipes | ??113.7 ABCdEJK |
| Seven groups of compound recipes | ??132.8 ABcefG |
| Eight groups of compound recipes | ??116.7 ABbCdEfHJk |
| Nine groups of compound recipes | ??110.9 ABCDEFGHiJK |
The meansigma methods and the statistical result of each treated animal diastolic pressure of table three
| Group | Diastolic pressure (mmHg) |
| Model group | ??135.8 |
| The piperazine ferulate group | ??117.6 A |
| The benazepril group | ??100.2 AJ |
| One group of compound recipe | ??133.2 JK |
| Two groups of compound recipes | ??126.5 abjK |
| Group | Diastolic pressure (mmHg) |
| Three groups of compound recipes | ??98.7 ABcCj |
| Four groups of compound recipes | ??124.8 AbDK |
| Five groups of compound recipes | ??87.3 ABCdEJK |
| Six groups of compound recipes | ??73.3 ABCDEFJK |
| Seven groups of compound recipes | ??115.4 ABceFGk |
| Eight groups of compound recipes | ??102.4 ABCEFGhJ |
| Nine groups of compound recipes | ??67.6 ABCDEFgHIJK |
Annotate: with model group relatively,
aP＜0.05;
AP＜0.01
With the piperazine ferulate group relatively,
jP＜0.05;
JP＜0.01
With the benazepril group relatively,
kP＜0.05;
KP＜0.01
Compare for one group with compound recipe,
bP＜0.05;
BP＜0.01
Compare for two groups with compound recipe,
cP＜0.05;
CP＜0.01
Compare for three groups with compound recipe,
dP＜0.05;
DP＜0.01
Compare for four groups with compound recipe,
eP＜0.05;
EP＜0.01
Compare for five groups with compound recipe,
fP＜0.05;
FP＜0.01
Compare for six groups with compound recipe,
gP＜0.05;
GP＜0.01
Compare for seven groups with compound recipe,
hP＜0.05;
HP＜0.01
Compare for eight groups with compound recipe,
iP＜0.05;
IP＜0.01
In table two and the table three, there are A or a to indicate after each data, indicate the statistic analysis result that this group experimental data is compared with the model group experimental data, A shows this group experimental data P＜0.01 of comparing with the model group experimental data, and a shows this group experimental data P＜0.05 of comparing with the model group experimental data; The meaning that B～K, b～k indicates by that analogy.
According to the result of table two and table three as seen:
1, when piperazine ferulate in the compound recipe or one of them dose of benazepril fixedly the time, along with the rising of another medicine dosage, antihypertensive effect is good more, no matter is diastolic pressure or systolic pressure be not always the case (P＜0.05 or P＜0.01);
2, when dose of components in the compound recipe is identical with single dosage with this medicine, the antihypertensive effect of compound recipe is always greater than the antihypertensive effect of single medicine, especially along with in the compound recipe during another composition consumption increase (P＜0.05 or P＜0.01).
3, when two medicines are all got partly measuring of single pharmaceutical quantities in the compound recipe (five groups of compound recipes), the antihypertensive effect (piperazine ferulate group or benazepril group, P＜0.01) when its antihypertensive effect is better than wherein arbitrary single component full dose
4, compound recipe is calculated as follows the maximum reducing effect of the diastolic pressure antihypertensive effect sum greater than two compositions in the compound recipe:
Nine groups=135.8-67.6 of model group-compound recipe (mmhg)=68.2mmhg＞
(model group-piperazine ferulate group)+(model group-benazepril group)=(135.8-117.6) mmhg+ (135.8-100.2) mmhg==53.8mmhg
Untoward reaction is observed: each treated animal there is no death, administration group and model group are not seen tangible animal behavior difference, each main organs after one's own heart behind the sacrifice of animal, liver, kidney, brain, spleen, lung, testis, intestine and small intestine, stomach etc. there is no acute pathological changes such as hemorrhage, scorching change, do not see the difference on other pathology yet, do not observe significant side effects yet.
Conclusion:
When piperazine ferulate in the compound recipe or one of them dose of benazepril fixedly the time, along with the rising of another medicine dosage, antihypertensive effect is good more, no matter is that diastolic pressure or systolic pressure are not always the case; When piperazine ferulate adopts maximal dose and benazepril adopts the antihypertensive effect of the compound recipe (seven groups of compound recipes) of lowest dose level will be weaker than that piperazine ferulate adopts lowest dose level and benazepril adopts the compound recipe (three groups of compound recipes) of maximal dose, show that Puli of Abbe plays bigger hypotensive effect in compound recipe; When piperazine ferulate was got maximum, along with the dosage of benazepril increases (seven, eight, nine groups of compound recipes), antihypertensive effect increased, and when piperazine ferulate and benazepril are all got maximal dose (nine groups of compound recipes), antihypertensive effect is best.Vice versa.Comprehensive, this compound recipe is to the maximum reducing effect of the diastolic pressure antihypertensive effect sum greater than two compositions in the compound recipe.
No matter this shows, be piperazine ferulate or benazepril, and the compound recipe of the two formation can reach bigger antihypertensive effect, is better than single preparations of ephedrine separately; And compound preparation its can not bring extra side effect or untoward reaction, can not bring different in side effect and the untoward reaction yet.Show that the compound preparation that piperazine ferulate and benazepril form not only has bigger hypotensive effect, and be safe in the use.
As mentioned above, just can realize the present invention preferably.
Claims (6)
1. an Antihypertension drug compound preparation is characterized in that, is that medicinal component constitutes by 20～400 parts of mixture with 2～40 parts of benazeprils of piperazine ferulate mainly by weight.
2. a kind of Antihypertension drug compound preparation according to claim 1 is characterized in that, described compound preparation also comprises 10～120 parts of inert solids as pharmaceutical carrier, and the admixture that inert solid and medicinal component form constitutes compound preparation.
3. a kind of Antihypertension drug compound preparation according to claim 2 is characterized in that, described inert solid is a kind of or above-mentioned multiple mixture that constitutes with arbitrary proportion in excipient, disintegrating agent, lubricant, cosolvent, correctives, the binding agent.
4. a kind of Antihypertension drug compound preparation according to claim 1 is characterized in that, described compound preparation also comprises 160～1000 parts of inert fluids as pharmaceutical carrier, and the admixture that inert fluid and medicinal component form constitutes compound preparation.
5. a kind of Antihypertension drug compound preparation according to claim 4 is characterized in that, described inert fluid is a kind of or above-mentioned two kinds of mixture that constitute with arbitrary proportion in diluent, wetting agent, the additive.
6. according to any described a kind of Antihypertension drug compound preparation of claim 1 to 5, it is characterized in that the dosage form of described compound preparation comprises tablet, capsule, granule, suspensoid and syrup.
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| CN2010101646770A CN101879168B (en) | 2010-05-06 | 2010-05-06 | Antihypertensive drug compound preparation |
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| CN2010101646770A CN101879168B (en) | 2010-05-06 | 2010-05-06 | Antihypertensive drug compound preparation |
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| CN101879168B CN101879168B (en) | 2012-07-04 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101491493A (en) * | 2008-01-25 | 2009-07-29 | 成都摩尔生物医药有限公司 | Ferulic acid piperazine slow-release medicine preparation |
| CN101690724A (en) * | 2009-05-05 | 2010-04-07 | 成都亨达药业有限公司 | Piperazine ferulate enteric preparation and preparation method thereof |
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2010
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101491493A (en) * | 2008-01-25 | 2009-07-29 | 成都摩尔生物医药有限公司 | Ferulic acid piperazine slow-release medicine preparation |
| CN101690724A (en) * | 2009-05-05 | 2010-04-07 | 成都亨达药业有限公司 | Piperazine ferulate enteric preparation and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 《中国中西医结合肾病杂志》 20021231 高祖华 等 依那普利与阿魏酸哌嗪对降低2型糖尿病患者尿微量白蛋白的初步观察 720-721 1-6 第3卷, 第12期 2 * |
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