CN106361746A - Compound medicine preparation capable of treating secondary hypertension - Google Patents
Compound medicine preparation capable of treating secondary hypertension Download PDFInfo
- Publication number
- CN106361746A CN106361746A CN201610968065.4A CN201610968065A CN106361746A CN 106361746 A CN106361746 A CN 106361746A CN 201610968065 A CN201610968065 A CN 201610968065A CN 106361746 A CN106361746 A CN 106361746A
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- compound
- compound preparation
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- hypertension
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a compound medicine preparation capable of treating secondary hypertension. The compound medicine preparation is mainly prepared from the following medical ingredients in parts by weight: a mixture including 30-150 parts of metoprolol tartrate and 50-90 parts of enalapril maleate capsules. The invention provides a compound hypertension-resistant preparation which is convenient to take and safe in use and contains metoprolol tartrate and an RAS inhibitor. The compound hypertension-resistant preparation is mainly used for omnibearingly controlling systolic pressure and thus certainly achieving decrease of diastolic pressure. The compound medicine preparation is capable of not only relieving an ET vasoactive effect, but also relieving an AngII vasoactive effect, furthermore relieving pathologic blood vessel proliferative effects of ET and AngII. By aiming at currently-known main pathologic neurohumor factors of causing hypertension, the compound medicine preparation has an effect of reducing systolic pressure to the greatest extent and also bringing an effect of reducing diastolic pressure.
Description
Technical field
The present invention relates to a kind of drug compound preparation treating secondary hypertension.
Background technology
Since nineteen ninety-five stern proposes " common soil " theory, people are to hypertension, coronary heart disease, obesity, 2 type sugar
The pathogenic factor of the diseases such as urine disease, blood fat disorder has more deep understanding, and in essence, these diseases are all one and are total to
With longer different performance is become on pathologic basis.In treatment, these diseases have common remedy measures and medicine.
At present, in addition to hypertension (secondary hypertension), need to control the sickness rate of the disease of blood pressure to increase, such as 2 types
Diabetes, chronic secondary disease, coronary heart disease, apoplexy etc., wherein cardiovascular and cerebrovascular disease has become as the primary cause of death.Control
Blood pressure is significant for the treatment of these diseases, is common remedy measures.
At present, the medicine for the treatment of hypertension mainly has following a few class:
1st, suppress vasoconstriction: secondary element-hypertensin system (ras) inhibitor (including acei and arb), Ca2+ overloading
Agent, vasodilation
2nd, suppress myocardial contraction: beta-blocker.
3rd, reduce blood volume: diuretic.
Wherein most widely used is ras inhibitor, produces because having the effect blocking angiotensin ii (angii)
Vasodilation, reaches blood pressure lowering purpose, especially has bigger antihypertensive effect to systolic pressure.Reduce systolic pressure for preventing cardiac muscle
Infarction and cerebral hemorrhage have bigger meaning than reducing diastolic pressure.But not all of high convergency die mould hypertension can be led to
The use crossing ras inhibitor reaches therapeutic purposes, because causing vasoconstrictive factor not only angii, Endothelin has higher
Cause high convergency die mould hypertension ability.
Endothelin (et) is a kind of vaso-excitor material the most powerful so far just finding in 1988, its contracting vascular effect
It is 10 times of angii, be the important neuro humor cause of disease of hypertension.
Spectinomycin hydrochloride, as class endothelin-receptor antagonists, has vasoconstriction and acts on and blood pressure lowering, blood pressure lowering
Effect is embodied in reduction systolic pressure, and meanwhile, spectinomycin hydrochloride oral formulations are national medical insurance Class B medicines, as a class
New non-peptide-like endothelin receptor antagonist, is widely used in arteriosclerosis, coronary heart disease, cerebrovascular, secondary bead disease, lung move
The auxiliary treatment of vascular conditions and leukocyte and the thrombocytopenia such as arteries and veins high pressure, diabetic angiopathy change, vasculitiss, also
Can be used for the treatment of migraine, vascular headache.
Content of the invention
The technical problem to be solved is to provide a kind of drug compound preparation treating secondary hypertension.
The present invention solves the above problems a kind of the technical scheme is that medicaments compound system treating secondary hypertension
Agent, mainly the mixture by 30～150 parts of spectinomycin hydrochloride and 50～90 parts of enalapril maleate is by weight
Medicinal component is constituted.
Further, described compound preparation also includes 10～150 parts of inert solid as pharmaceutical carrier, inert solid and medicine
Constitute compound preparation with the admixture that composition is formed.
Described inert solid is one of excipient, disintegrating agent, lubricant, cosolvent, correctivess, binding agent or above-mentioned
Multiple mixture with arbitrary proportion composition.Excipient, disintegrating agent, lubricant, cosolvent, correctivess, binding agent include breast
Sugar, starch, dextrin, Microcrystalline Cellulose, polyvidone, gelatin, micropowder silica gel, Polyethylene Glycol etc..
Described compound preparation also includes 300～750 parts of inert fluid as pharmaceutical carrier, inert fluid and medicinal component shape
The admixture becoming constitutes compound preparation.
Described inert fluid is one of diluent, wetting agent, additive or above two is constituted with arbitrary proportion
Mixture.
The antihypertensive compound preparation of the present invention can be prepared according to method known in the industry, that is, pass through tartaric acid is beautiful
Tuo Luoer and ras inhibitor is admixed and is obtained with suitable inert solid or liquid pharmaceutical carrier.Can make and be suitable for oral answering
Square preparation, the dosage form being suitable for oral compound preparation can be tablet, granule, capsule, suspensoid, syrup.Wherein tablet,
Granule, capsule can be containing conventional carrier in pharmaceuticals industry and/or adjuvant.For example Icing Sugar, starch, absorbent (are for example pasted
Essence), disintegrating agent (such as tween 80), lubricant (such as 50% ethanol), magnesium stearate etc..Wherein suspensoid, syrup also may be used
With containing the industrial conventional carrier of system and/or adjuvant.Such as diluent (such as water, distilled water, ethanol, Polyethylene Glycol, glycerol
Deng), conventional additive (such as suspending liquid, preservative, correctivess etc.).Tablet, granule can be by dry or wet granulating process
Preparation.The suitable mixture of compound can be inserted soft or hard gelatine capsule kind and be obtained by capsule.Suspensoid and syrup can
Aqueous solution will be made, described diluent is in the diluent mixed with suspending agent, preservative etc. for the suitable mixture addition of compound
It is well distilled water, suspending agent is preferably tragakanta, and preservative is preferably nipalgin second, the third fat, is preferably added taste masking in syrup
Agent, correctivess are sucrose.
The pharmacology of spectinomycin hydrochloride:
This product is non-peptide-like endothelin receptor antagonist, can antagonism the Endothelin vasoconstriction, boosting and the blood vessel that cause put down
Sliding muscle cell multiplication；Increase the synthesis of no, lax vascular smooth muscle；Suppress platelet aggregation, anticoagulation, improve hemorheology
Feature.This product also can suppress the synthesis of cholesterol, reduction blood fat, removes free radical, prevents and treats lipid peroxidation injury；Impact is mended
Body, strengthens immune function, and has certain analgesia, spasmolysises.
The toxicity of spectinomycin hydrochloride:
Acute toxicity testing result shows: one-level Kunming mouse is administered orally ld50 and is: 3580.1 ± 251.7mg/kg, credible
It is limited to 95%.Long term toxicity result of study shows: by intravenous spectinomycin hydrochloride 300mg the next day healthy adult male dog
The long term toxicity test result of (continuous 30 times) proves that spectinomycin hydrochloride toxicity is less, is available for Clinical practice.Genotoxicity
Research shows: through to wistar kind rat with lumbar injection and the experiment of two kinds of approach of gavage have no obvious embryo's toxic action and
Teratogenic effect, shows that this medicine is substantially safe and reliable in terms of teratogenesis tire.Carcinogenecity result of study shows: by winestone
The mutagenesises to Salmonella typhimurium ta98, ta100 for the sour metoprolol, spectinomycin hydrochloride bone marrow micronucleus test and wine
The impact test that stone acid metoprolol distorts to mouse marrow cell chromosome, shows this product non-carcinogenesis.
The pharmacokineticss of spectinomycin hydrochloride: be 29 minutes between this product oral absorption peak time, distribution mutually partly declines
Phase (t1/2 α) is 27 minutes, eliminates the phase half-life (t1/2 β) for 5.5 hours.This product is distributed more widely in vivo, except liver, secondary blood
It is distributed more outer in liquid, be distributed also more in stomach, small intestinal fat, this product is discharged and mainly discharged from urine, feces.Tire can be passed through
Disk barrier.
Mouse oral median lethal dose(LD 50) (ld50) is 3.2g/kg.Rat oral gavage is administered 600mg/kg, once a day, continuously
Administration 3 months, hematology and blood biochemical analysis Indexs measure result all belong to normal, and main organs histopathologic examination does not find
Drug-induced pathological change.
Enalapril maleate is a kind of acei1 of high tissue affinity.Pharmacology (1) blood pressure lowering: this product is hydrolyzed in liver
Benazeprilat, becomes a kind of emulative angiotensin converting enzyme inhibitor, stops angiotensin i from being converted to blood vessel tight
Open plain ii, so that vascular resistance is reduced, Aldosterone Secretion reduces, blood plasma secondary element activity increases.Benazeprilat also suppresses slow and swashs
The degraded of peptide, also makes vascular resistance reduce, produces hypotensive effect.(2) lower cardiac load: this product expansion artery and vein, fall
Low peripheral vascular resistance or cardiac afterload, reduce pulmonary capillary and snap or cardiac preload, also reduce pulmonary vascular resistance, from
And improve cardiac output, make exercise tolerance and time lengthening.2. toxicity rat and mice sustained oral benazepril 2 years, dosage
For daily 150mg/kg, do not find that this product has carcinogenecity.(this dosage is pressed mg/kg and is calculated, and is 110 times of mankind's research on maximum utilized quantity；Press
mg/m2Calculate, be 18 times and 9 times of mankind's research on maximum utilized quantity).No matter in bacteria test, the suckling still cultivated in vitro is moved
All do not find in thing test cell line that this product has mutagenicity.Female, male Oral Administration in Rats benazepril, dosage is daily 50-150mg/
Kg, does not find this product impact reproductive performance.(this dosage is pressed mg/kg and is calculated, and is 37～375 times of mankind's research on maximum utilized quantity；By mg/
m2Calculate, be 6～60 times of mankind's research on maximum utilized quantity).
Because ras inhibitor can block the contracting blood vessel function of angiotensin ii (angii), but the contracting blood of et can not be blocked
Pipe acts on；The liter blood pressure that spectinomycin hydrochloride can block et acts on and blood pressure lowering, but is unable to the contracting vascular effect of antagonism angii,
It is thus desirable to drug combination just can better control over blood pressure, especially systolic pressure.But so far there are no spectinomycin hydrochloride and
The compound preparation of other depressor.
In sum, the invention has the beneficial effects as follows: the invention provides a kind of taking convenience, using safety tartaric acid
Metoprolol and the compound antihypertensive preparation of ras inhibitor, it focuses on comprehensive control systolic pressure, certainly necessarily brings diastole
The decline of pressure.It can release the contracting vascular effect of et, also can release the contracting vascular effect of angii, also relieve the two simultaneously
Pathologic vessels multiplication effect, have been directed to the current known main pathologic Neurohormonal factor causing hypertension, have
Reduce systolic pressure effect to greatest extent, bring the effect reducing diastolic pressure simultaneously.
Specific embodiment
With reference to embodiment, the present invention is described in further detail, but embodiments of the present invention not limited to this.
The compound oral administration preparation of the present embodiment using with the preparation of pharmaceuticals industry known method, the concrete consumption of each component referring under
Table:
Mixed using two kinds of oral drugs of spectinomycin hydrochloride and enalapril maleate simultaneously and take the treatment carrying out
Effect shows, is superior to a kind of alone medicine using the effect of spectinomycin hydrochloride and enalapril maleate, thus for grinding
The compound preparation of two kinds of medicines reasonable 5 of system is laid a good foundation.
The therapeutic effect checking of hypertensive rat model:
Purpose: the compound preparation of different ratio observing spectinomycin hydrochloride joint enalapril maleate is to doca
The impact of (desoxycorticosterone acetate (DOCA)) hypertensive rat blood pressure (bp), is made with inquiring into the blood pressure lowering under various dose collocation in compound recipe
With.
Method: sd rat 96, ♂, body weight 180～190g.After excision right side secondary is dirty under the aseptic condition, secondary weekly
Only give doca 5mg/, sc, and raise with 1% sodium chloride solution；It is randomly divided into 12 groups, every group 8, be specifically grouped and dispose feelings
Condition such as table one.
Table one animal packet and pharmaceutical formulation, medication
Medication: compound recipe group medicine is diluted with water to scattered paste shape, daily gastric infusion, and po, qd (oral, one day one
Secondary)；Continuous 5 weeks
Result: after 5 weeks, measure the blood pressure of each group animal, each group animal blood pressure meansigma methodss and statistical result are shown in Table two, table
Three, take p ＜ 0.05 to be that there were significant differences；P ＜ 0.01 is taken to be to have pole significant difference.
The meansigma methodss of table two each group animal systolic pressure and statistical result
| Group | Systolic pressure (mmhg) |
| Model group | 167.4 |
| Spectinomycin hydrochloride group | 130.5a |
| Enalapril maleate group | 128.7a |
| One group of compound recipe | 158.4ajk |
| Two groups of compound recipe | 144.6abjk |
| Three groups of compound recipe | 126.5abc |
| Four groups of compound recipe | 146.2abdjk |
| Five groups of compound recipe | 122.8abcejk |
| Six groups of compound recipe | 113.7abcdejk |
| Seven groups of compound recipe | 132.8abcefg |
| Eight groups of compound recipe | 116.7abbcdefhjk |
| Nine groups of compound recipe | 110.9abcdefghijk |
The meansigma methodss of table three each group animal diastolic pressure and statistical result
| Group | Diastolic pressure (mmhg) |
| Model group | 135.8 |
| Spectinomycin hydrochloride group | 117.6a |
| Enalapril maleate group | 100.2aj |
| One group of compound recipe | 133.2jk |
| Two groups of compound recipe | 126.5abjk |
| Three groups of compound recipe | 98.7abccj |
| Four groups of compound recipe | 124.8abdk |
| Five groups of compound recipe | 87.3abcdejk |
| Six groups of compound recipe | 73.3abcdefjk |
| Seven groups of compound recipe | 115.4abcefgk |
| Eight groups of compound recipe | 102.4abcefghj |
| Nine groups of compound recipe | 67.6abcdefghijk |
Note: compare with model group,aP ＜ 0.05；aP ＜ 0.01
Compare with spectinomycin hydrochloride group,jP ＜ 0.05；jP ＜ 0.01
Compare with enalapril maleate group,kP ＜ 0.05；kP ＜ 0.01
With compound recipe, one group is compared,bP ＜ 0.05；bP ＜ 0.01
With compound recipe, two groups are compared,cP ＜ 0.05；cP ＜ 0.01
With compound recipe, three groups are compared,dP ＜ 0.05；dP ＜ 0.01
With compound recipe, four groups are compared,eP ＜ 0.05；eP ＜ 0.01
With compound recipe, five groups are compared,fP ＜ 0.05；fP ＜ 0.01
With compound recipe, six groups are compared,gP ＜ 0.05；gP ＜ 0.01
With compound recipe, seven groups are compared,hP ＜ 0.05；hP ＜ 0.01
With compound recipe, eight groups are compared,iP ＜ 0.05；iP ＜ 0.01
In table two and table three, there is a or a to indicate after each data, indicate this group experimental data and model group experimental data phase
Statistic analysis result relatively, a shows that this group experimental data p ＜ 0.01 compared with model group experimental data, a show that this group is real
Test data p ＜ 0.05 compared with model group experimental data；The meaning that b～k, b～k indicate is by that analogy.
Visible according to the result of table two and table three:
1st, when compound recipe mesotartaric acid metoprolol or the one of dose of enalapril maleate are fixing, with another
The rising of individual medicine dosage, antihypertensive effect is better, and either diastolic pressure or systolic pressure are not always the case (p ＜ 0.05 or p ＜
0.01)；
2nd, when the dosage of one of compound recipe composition is identical with the dosage of this medicine alone, the antihypertensive effect of compound recipe is always big
In the antihypertensive effect of single medicine, when increasing especially with Ingredient Amount another in compound recipe (p ＜ 0.05 or p ＜ 0.01).
3rd, when in compound recipe, two medicines all take half amount of single pharmaceutical quantities (five groups of compound recipe), its antihypertensive effect is better than wherein appointing
Antihypertensive effect (spectinomycin hydrochloride group or enalapril maleate group, p ＜ 0.01) during one single component full dose
4th, compound recipe is more than the antihypertensive effect sum of two compositions in compound recipe to the maximum reducing effect of diastolic pressure, calculates such as
Under:
Nine groups=135.8-67.6 of model group-compound recipe (mmhg)=68.2mmhg ＞
(model group-spectinomycin hydrochloride group)+(model group-enalapril maleate group)=(135.8-117.6)
Mmhg+ (135.8-100.2) mmhg==53.8mmhg
Untoward reaction is observed: each group animal is showed no death, and administration group is compared with model group and has no obvious animal behavior
Difference, at animal, after death each main organs such as heart, liver, secondary, brain, spleen, lung, testis, intestine and small intestine, stomach etc. is showed no bleeding, inflammation
The acute pathology such as change change, and also have no the difference on other pathology, also do not observe obvious side effect.
Conclusion:
When compound recipe mesotartaric acid metoprolol or the one of dose of enalapril maleate are fixing, with another
The rising of medicine dosage, antihypertensive effect is better, and either diastolic pressure or systolic pressure are not always the case；When spectinomycin hydrochloride is adopted
With maximal dose, enalapril maleate adopts the antihypertensive effect of the compound recipe (seven groups of compound recipe) of lowest dose level will be weaker than tartaric acid
Using lowest dose level, enalapril maleate, using the compound recipe (three groups of compound recipe) of maximal dose, shows Ah's maleic acid to metoprolol
Enalapril plays bigger hypotensive effect in compound recipe；When spectinomycin hydrochloride takes maximum, with maleic acid according to that
The dosage of Puli increases (seven, eight, nine groups of compound recipe), and antihypertensive effect increases, until spectinomycin hydrochloride and maleic acid Yi Napu
When profit all gets maximal dose (nine groups of compound recipe), antihypertensive effect is best.Vice versa.For synthesis, this compound recipe is to diastolic pressure
Maximum reducing effect is more than the antihypertensive effect sum of two compositions in compound recipe.
As can be seen here, either spectinomycin hydrochloride or enalapril maleate, the compound recipe that the two forms can reach
To bigger antihypertensive effect, better than respective single preparations of ephedrine；And compound preparation its will not bring extra side effect or bad
Reaction, also will not bring the difference in side effect and untoward reaction.Show spectinomycin hydrochloride and enalapril maleate shape
The compound preparation becoming not only has bigger hypotensive effect, and is safe on using.
As described above, just can preferably realize the present invention.
Claims (6)
1. a kind of drug compound preparation treating secondary hypertension is it is characterised in that mainly beautiful by tartaric acid by weight
The mixture of 30～150 parts of Tuo Luoer and 50～90 parts of enalapril maleate is constituted for medicinal component.
2. a kind of drug compound preparation treating secondary hypertension according to claim 1 is it is characterised in that described multiple
Square preparation also includes 10～150 parts of inert solid as pharmaceutical carrier, and the admixture that inert solid is formed with medicinal component is constituted
Compound preparation.
3. a kind of drug compound preparation treating secondary hypertension according to claim 2 is it is characterised in that described lazy
Property solid be one of excipient, disintegrating agent, lubricant, cosolvent, correctivess, binding agent or above-mentioned multiple with arbitrary proportion
The mixture constituting.
4. a kind of drug compound preparation treating secondary hypertension according to claim 1 is it is characterised in that described multiple
Square preparation also includes 300～750 parts of inert fluid as pharmaceutical carrier, and the admixture that inert fluid is formed with medicinal component is constituted
Compound preparation.
5. a kind of drug compound preparation treating secondary hypertension according to claim 4 is it is characterised in that described lazy
Property liquid be the mixture that one of diluent, wetting agent, additive or above two are constituted with arbitrary proportion.
6. a kind of drug compound preparation treating secondary hypertension according to claim 1 to 5 any one, its feature
It is, the dosage form of described compound preparation includes tablet, capsule, granule, suspensoid and syrup.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101254181A (en) * | 2008-03-10 | 2008-09-03 | 鲁南制药集团股份有限公司 | Pharmaceutical composition for treating hypertension |
| CN105943539A (en) * | 2016-05-24 | 2016-09-21 | 成都市斯贝佳科技有限公司 | Pharmaceutical compound preparation with effective and safe blood pressure lowering function |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101254181A (en) * | 2008-03-10 | 2008-09-03 | 鲁南制药集团股份有限公司 | Pharmaceutical composition for treating hypertension |
| CN105943539A (en) * | 2016-05-24 | 2016-09-21 | 成都市斯贝佳科技有限公司 | Pharmaceutical compound preparation with effective and safe blood pressure lowering function |
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