CN101879167B - Antihypertension drug compound preparation - Google Patents
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- CN101879167B CN101879167B CN201010164686XA CN201010164686A CN101879167B CN 101879167 B CN101879167 B CN 101879167B CN 201010164686X A CN201010164686X A CN 201010164686XA CN 201010164686 A CN201010164686 A CN 201010164686A CN 101879167 B CN101879167 B CN 101879167B
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- hydrochlorothiazide
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Abstract
The invention discloses an antihypertension drug compound preparation. The compound preparation is mainly constituted by taking the mixture of 20-400 parts by weight of piperazine ferulate and 5-10 parts by weight of hydrochlorothiazide as medicinal components. The invention provides a compound antihypertension preparation which is convenient to take, safe to use and formed by the piperazine ferulate and the diuretic of hydrochlorothiazide. The compound antihypertension preparation can omnidirectionally control the blood pressure, namely the piperazine ferulate can block the blood pressure elevation effect of the ET while reduce systolic blood pressure; the hydrochlorothiazide can reduce diastolic blood pressure by reducing blood volume through diuretic effect, so that the invention has the most reasonable blood reduction effect.
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, like 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 several types:
1, suppresses vasoconstriction: RAS (RAS) inhibitor (comprising ACEI and ARB), calcium antagonist, vasodilation
2, suppress myocardial contraction: beta-blocker.
3, reduce blood volume: diuretic.
Wherein suppress vasoconstrictive depressor systolic pressure is had bigger antihypertensive effect, limited to the antihypertensive effect of diastolic pressure, and increasing for having more directly of coronary heart disease chronic heart failure of diastolic pressure acts on.Therefore, should be presented as the control of blood pressure and both to have fallen systolic pressure, fall diastolic pressure again.Since diastolic pressure main with body in effective circulating blood volume have bigger relatedly, therefore to reduce diastolic pressure, can be that blood volume realizes through reducing effective circulating blood volume, the method for the best is diuresis.
Piperazine ferulate is as one type of 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 one type of new non-peptide-like endothelin receptor antagonist; 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: Antihypertension drug compound preparation is that medicinal component constitutes by 20～400 parts of mixture with 5～100 parts of hydrochlorothiazide of piperazine ferulate by weight.
Particularly, said compound preparation also comprises 12～220 parts of inert solids as pharmaceutical carrier, and the admixture that inert solid and medicinal component form constitutes compound preparation.
Said inert solid is a kind of or above-mentioned multiple mixture that constitutes with arbitrary proportion in 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.
Said compound preparation also comprises 160～1200 parts of inert fluids as pharmaceutical carrier, and the admixture that inert fluid and medicinal component form constitutes compound preparation.
Said inert fluid is an additive.
Said inert fluid is a diluent.
The dosage form of said compound preparation is tablet, capsule, granule.
Perhaps, the dosage form of said compound preparation is suspensoid and syrup
Antihypertensive compound preparation of the present invention can be according to known method preparation in the industry, promptly gets through piperazine ferulate and hydrochlorothiazide and suitable inert solid or liquid medicine carrier are admixed.Can process 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 carrier and/or adjuvant commonly used in the pharmaceuticals industry.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 the suitable mixture of chemical compound soft or hard gelatine capsule kind and makes.Suspensoid and syrup can add the suitable mixture of chemical compound in the diluent that is mixed with suspending agent, antiseptic etc. processes aqueous solution; Said diluent is preferably distilled water; Suspending agent is preferably the tragakanta; Antiseptic is preferably nipalgin second, third fat, preferably adds correctives in the syrup, and correctives is a sucrose.
The pharmacology of piperazine ferulate:
These article are non-peptide-like endothelin receptor antagonist, but the vasoconstriction that the antagonism Endothelin causes, boost and vascular smooth muscle cell proliferation; Increase the synthetic of NO, lax vascular smooth muscle; Anticoagulant, anticoagulation, improve the hemorheology characteristic.These article 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 through to the healthy adult male dog next day, can supply clinical use.Genotoxicity research shows: through Wistar kind rat is not seen tangible embryotoxic effect and teratogenic effect with two kinds of approach experiments of lumbar injection and filling stomach, show that this medicine is being safe and reliable basically aspect the teratogenesis tire.The carcinogenecity result of study shows: through to the mutagenesis of piperazine ferulate to Salmonella typhimurium TA98, TA100; Piperazine ferulate bone marrow micronucleus test and piperazine ferulate show these article non-carcinogenesis to the distored influence test of mouse marrow cell chromosome.
The pharmacokinetics of piperazine ferulate: these article 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.These article distribute wider in vivo, in liver, kidney blood, distribute more, it is also more in stomach, small intestinal fat, to distribute, these article are discharged mainly from urinating, discharging the 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.
Method in order to controlling blood pressure adopts the several drugs administering drug combinations more now.So, the part compound preparation is also arranged, like the compound recipe of RAS inhibitor and diuretic---losartan potassium hydrochlorothiazide, but do not see that so far piperazine ferulate and other depressor especially compound preparation of diuretic are arranged.
Hydrochlorothiazide is a kind of diuretic, has 1. diuresis of following effect, and urine sodium, potassium, chlorine, phosphorus and magnesium plasma are drained and increased, and UCaE is reduced.This type of mechanism of drug action mainly suppresses the heavily absorption to sodium chloride of distal tubule leading portion and proximal tubule (acting on lighter), thereby increases the Na of distal tubule and collecting tubule
+-K
+Exchange, K
+Secretion increasing.This type of medicine can both suppress the carbonic anhydrase activity to some extent, so can explain its effect to proximal tubule.This type of medicine can also suppress phosphodiesterase activity, reduces picked-up and the mitochondrion oxygen consumption of renal tubules to fatty acid, thereby suppresses renal tubules to Na
+, Cl
-Active heavily absorb.2. hypotensive effect.Except that the effect of diuresis row sodium, possibly also have the outer mechanism of action of kidney to participate in blood pressure lowering, possibly be to increase gastrointestinal tract to Na
+Drainage.
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 diuretic hydrochlorothiazide, it focuses on comprehensive controlling blood pressure: the rising blood pressure of piperazine ferulate ET capable of blocking and fall systolic pressure; Hydrochlorothiazide can reduce blood volume through diuresis and reduce diastolic pressure, has the most reasonably hypotensive effect.
The specific embodiment
Below in conjunction with embodiment the present invention is done further detailed description, but embodiment of the present invention is 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:
Adopt two kinds of oral drugs of piperazine ferulate and hydrochlorothiazide to mix simultaneously to take the therapeutic effect that carries out and show; The effect of 5 usefulness piperazine ferulates and hydrochlorothiazide all is superior to single a kind of medicine of using, thereby is 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 hydrochlorothiazide 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 hydrochlorothiazide group | 100 milligrams of hydrochlorothiazide |
| One group of compound recipe | 20 milligrams of piperazine ferulates, 5 milligrams of hydrochlorothiazide |
| Two groups of compound recipes | 20 milligrams of piperazine ferulates, 50 milligrams of hydrochlorothiazide |
| Three groups of compound recipes | 20 milligrams of piperazine ferulates, 100 milligrams of hydrochlorothiazide |
| Four groups of compound recipes | 200 milligrams of piperazine ferulates, 5 milligrams of hydrochlorothiazide |
| Five groups of compound recipes | 200 milligrams of piperazine ferulates, 50 milligrams of hydrochlorothiazide |
| Six groups of compound recipes | 200 milligrams of piperazine ferulates, 100 milligrams of hydrochlorothiazide |
| Seven groups of compound recipes | 400 milligrams of piperazine ferulates, 5 milligrams of hydrochlorothiazide |
| Eight groups of compound recipes | 400 milligrams of piperazine ferulates, 50 milligrams of hydrochlorothiazide |
| Nine groups of compound recipes | 400 milligrams of piperazine ferulates, 100 milligrams of hydrochlorothiazide |
Medication: compound recipe group medicine is diluted with water to scattered paste shape, every day gastric infusion, po, qd; Continuous 5 weeks.
The result: after 5 weeks, measure the blood pressure of each treated animal, table two, table three are seen in each treated animal mediodespidine average and statistical result, get P＜0.05 for there were significant differences; P＜0.01 is for there being utmost point significant difference.
The meansigma methods and the statistical result of each treated animal systolic pressure of table two
| Group | Systolic pressure (mmHg) |
| Model group | 160.3 |
| The piperazine ferulate group | 96.5 A |
| The hydrochlorothiazide group | 144.3 aJ |
| One group of compound recipe | 158.0 JK |
| Two groups of compound recipes | 156.6 JK |
| Three groups of compound recipes | 146.2 J |
| Four groups of compound recipes | 117.6 ABCDJK |
| Five groups of compound recipes | 112.7 ABCDeJK |
| Six groups of compound recipes | 98.6 ABCDEfJK |
| Seven groups of compound recipes | 97.2 ABCDEfK |
| Eight groups of compound recipes | 96.3 ABCDEfgK |
| Nine groups of compound recipes | 94.2 ABCDEFghijK |
The meansigma methods and the statistical result of each treated animal diastolic pressure of table three
| Group | Diastolic pressure (mmHg) |
| Model group | 138.5 |
| The piperazine ferulate group | 104.3 A |
| The hydrochlorothiazide group | 96.2 AjK |
| One group of compound recipe | 137.2JK |
| Two groups of compound recipes | 125.6 AbJK |
| Three groups of compound recipes | 94.1 ABCJ |
| Four groups of compound recipes | 85.3 ABCdJK |
| Five groups of compound recipes | 79.6 ABCDeJK |
| Six groups of compound recipes | 72.3 ABCDEfJK |
| Seven groups of compound recipes | 98.9 ABCdEFGJ |
| Eight groups of compound recipes | 72.4 ABCDEfhJK |
| Nine groups of compound recipes | 65.7 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 indicate by that analogy.
According to the result of table two, table three, visible:
1, when piperazine ferulate in the compound recipe or one of them dose of hydrochlorothiazide 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 when another becomes divided dose to increase in the compound recipe (P＜0.05 or P＜0.01).
3, this compound recipe calculates as follows the maximum reducing effect of the systolic pressure antihypertensive effect sum greater than two compositions in the compound recipe:
(model group-piperazine ferulate group)+(model group-hydrochlorothiazide group)=(160.3-96.5) mmhg+ (160.3-144.3) mmhg=63.8+16.0 (mmhg)=79.8mmhg＞
Nine groups=160.3-94.2=66.1mmhg of model group-compound recipe
4, when two medicines are all got partly measuring of single pharmaceutical quantities in the compound recipe (five groups of compound recipes); Antihypertensive effect when its antihypertensive effect is superior to piperazine ferulate full dose wherein; When especially the antihypertensive effect of diastolic pressure being surpassed arbitrary composition full dose (piperazine ferulate group or benazepril group, P＜0.01)
Untoward reaction is observed: each treated animal is not all seen 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. all do not see 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 hydrochlorothiazide 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 hydrochlorothiazide adopts the antihypertensive effect of the compound recipe (seven groups of compound recipes) of lowest dose level to be better than that piperazine ferulate adopts lowest dose level and hydrochlorothiazide adopts the compound recipe (three groups of compound recipes) of maximal dose, show that piperazine ferulate plays bigger hypotensive effect in compound recipe; When piperazine ferulate was got maximum, along with the dosage of hydrochlorothiazide increases (seven, eight, nine groups of compound recipes), antihypertensive effect increased, and when piperazine ferulate and hydrochlorothiazide are all got maximal dose (nine groups of compound recipes), antihypertensive effect is best.Vice versa.Comprehensive, this compound recipe is substantially equal to the antihypertensive effect sum of two compositions in the compound recipe to the maximum reducing effect of systolic pressure.
No matter this shows, be piperazine ferulate or hydrochlorothiazide, and the compound recipe of the two formation can reach bigger antihypertensive effect, is superior to single preparations of ephedrine separately; And compound preparation its can not bring extra side effect, can not bring the difference in the side effect yet.Show that the compound preparation that piperazine ferulate and hydrochlorothiazide form not only has bigger hypotensive effect, and be safe in the use.
As stated, just can realize the present invention preferably.
Claims (8)
1. Antihypertension drug compound preparation is characterized in that, is that medicinal component constitutes by 20～400 parts of mixture with 5～100 parts of hydrochlorothiazide of piperazine ferulate by weight.
2. Antihypertension drug compound preparation according to claim 1 is characterized in that, said compound preparation also comprises 12～220 parts of inert solids as pharmaceutical carrier, and the admixture that inert solid and medicinal component form constitutes compound preparation.
3. Antihypertension drug compound preparation according to claim 2 is characterized in that, said inert solid is a kind of or above-mentioned multiple mixture that constitutes with arbitrary proportion in disintegrating agent, lubricant, cosolvent, correctives, the binding agent.
4. Antihypertension drug compound preparation according to claim 1 is characterized in that, said compound preparation also comprises 160～1200 parts of inert fluids as pharmaceutical carrier, and the admixture that inert fluid and medicinal component form constitutes compound preparation.
5. Antihypertension drug compound preparation according to claim 4 is characterized in that, said inert fluid is an additive.
6. Antihypertension drug compound preparation according to claim 5 is characterized in that, said inert fluid is a diluent.
7. according to claim 2 or 3 described a kind of Antihypertension drug compound preparations, it is characterized in that the dosage form of said compound preparation is tablet, capsule.
8. according to any described a kind of Antihypertension drug compound preparation of claim 4 to 6, it is characterized in that the dosage form of said compound preparation is suspensoid and syrup.
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|---|---|---|---|
| CN201010164686XA CN101879167B (en) | 2010-05-06 | 2010-05-06 | Antihypertension drug compound preparation |
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|---|---|---|---|
| CN201010164686XA CN101879167B (en) | 2010-05-06 | 2010-05-06 | Antihypertension drug compound preparation |
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| CN101879167B true CN101879167B (en) | 2012-01-25 |
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|---|---|---|---|
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1742726A (en) * | 2005-09-23 | 2006-03-08 | 北京阜康仁生物制药科技有限公司 | Piperazine ferulate oral cavity disintegrating tablet and preparing method |
| 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 |
-
2010
- 2010-05-06 CN CN201010164686XA patent/CN101879167B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1742726A (en) * | 2005-09-23 | 2006-03-08 | 北京阜康仁生物制药科技有限公司 | Piperazine ferulate oral cavity disintegrating tablet and preparing method |
| 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 |
Non-Patent Citations (3)
| Title |
|---|
| 刘国仗，等.从ALLHAT结果看利尿剂在高血压病治疗中的地位.《中华心血管病杂志》.2003,第31卷(第8期),第625-626页. * |
| 华琦.高血压诊疗新进展.《中国心血管病研究杂志》.2006,第4卷(第2期),第85-88页. * |
| 张廷杰，等.高血压防治的研究进展.《心脑血管病防治》.2009,第9卷(第3期),第161-164页. * |
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