CN1270711C - Aminochlorodipin, irbesartan compound preparation - Google Patents
Aminochlorodipin, irbesartan compound preparation Download PDFInfo
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- CN1270711C CN1270711C CN 03150996 CN03150996A CN1270711C CN 1270711 C CN1270711 C CN 1270711C CN 03150996 CN03150996 CN 03150996 CN 03150996 A CN03150996 A CN 03150996A CN 1270711 C CN1270711 C CN 1270711C
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- irbesartan
- blood pressure
- amlodipine
- compound preparation
- hypertension
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an aminochlorodipin and irbesartan compound preparation and application. A novel blood pressure reduction compound preparation disclosed by the present invention is a medical composition prepared from aminochlorodipin and irbesartan which are used as active ingredients. The preferable weight ratio of the aminochlorodipin to the irbesartan is 1:10 to 50. The dosage of the compound preparation is obviously lower than that of each medical ingredient which is singly used. The effect of blood pressure reduction can be obviously strengthened, and the duration time of blood pressure reduction can be prolonged. The compound preparation is especially suitable for hypertension patients who simultaneously have angiocarpy reconstruction. Simultaneously, the compound preparation is also suitable for treatment of patients who have renal hypertension, hypertension with harm to renal functions or harm to renal functions of diabetes.
Description
Technical field:
The present invention relates to drug world, be specifically related to amlodipine, irbesartan compound preparation and application.
Background technology:
For many years, rescue by stages is the method for extensive use in the hypertension therapeutic always, the someone proposes individualized treatment use single medicine from minimum effective dose afterwards, but single medicine can only make 40%～50% patient's blood pressure controlled, increase dosage so have to, or use its medicine instead, or take drug combination.
From the end of the eighties, carried out the extensive clinical research of multicenter for the status of compound hypertension medicine in hypertension therapeutic of fixed dosage, different pharmaceutical combination.It is generally acknowledged that various existing drug combination treatments only need day clothes once promptly effectively.1993, U.S.'s prevention, the 5th report of the detection assessment and the treatment hypertension National Committee thought that most hypertensive patients need therapeutic alliance to reach the target of controlling blood pressure, and drug combination is suitable
Because hypertension is a cause of disease and the very complicated syndrome of pathogenesis, existing nerve also has the unusual of body fluid aspect, and often have influence on the 26S Proteasome Structure and Function of each organ of body, system, the patient most simultaneously with other disease after one's own heart, brain, kidney or angiopathy, insulin sensitivity reduction, dyslipidemia etc.Therefore, share the different depressor of mechanism of action and often can strengthen therapeutic effect, look after the different links in the hypertension incidence mechanism simultaneously, make multiple risk factor or and deposit disease and obtain Optimal Control, more help the protection of hypertension target organ 26S Proteasome Structure and Function, further reduce the incidence rate of cardiovascular event; Secondly, because when forming immobilised compound, the dosage of each single medicine all has minimizing, thereby the incidence rate of drug side effect reduces; About medical expense, reduce when using separately owing to used drug dose ratio, not only can not increase, may descend on the contrary, feasible benefit/expense ratio for the treatment of is significantly improved.Therefore patient's treatment compliance increases greatly, and quality of life also just obviously improves.The fixed compound preparation of antihypertensive low dose not only can be used as the two wires medicine, also can be used as a line medicine and is used for hypertensive treatment, and is all the more so when especially the patient has other complication or complication to exist simultaneously.
Summary of the invention:
Technical problem to be solved by this invention is existing antihypertensive drug amlodipine and irbesartan are studied, and provides a kind of consumption little, the significant novel compound preparation of antihypertensive effect.
Novel blood pressure lowering compound preparation disclosed by the invention is to be the pharmaceutical composition that active ingredient is formed with amlodipine or the physiologically acceptable salt of amlodipine and irbesartan.
Wherein the preferred weight ratio of amlodipine and irbesartan consists of 1: 10-50.
The physiologically acceptable salt of amlodipine of the present invention comprises amlodipine benzenesulphonate, maleate or other salt.
Described pharmaceutical composition comprises for according to the difference of clinical practice active ingredient and pharmaceutic adjuvant are made various medically acceptable oral formulations: tablet, capsule or granule etc.
Another technical problem to be solved by this invention is to disclose above-mentioned irbesartan and the amlodipine compound preparation is light in the preparation treatment, the application in the moderate hypertension medicine.
Medicine particularly of the present invention is applicable to the hyperpietic with Cardiovascular Remodeling, also is applicable to renal hypertension, hypertension companion's renal function injury or companion's diabetes renal function injury patient's treatment simultaneously.
Amlodipine is a calcium antagonist, and vascular smooth muscle is had stronger selection, the vascular smooth muscle that can directly relax, and the expansion peripheral blood vessel reduces the peripheral blood vessel drag overall; But also coronary blood flow increasing, myocardial contraction and cardiac output simultaneously; Compare with similar medicine, have unique binding characteristic with calcium channel.Oral back acting duration is long, and taking once is sustainable blood pressure lowering 24 hours, is mainly used in the treatment of essential hypertension and stable angina pectoris, and effective dose is 5-10mg/ day.
Irbesartan is an Angiotensin II (AT) receptor antagonist, to AT
1Receptor has the affinity of height and special selectivity, comprehensive antagonism AT in body circulation and local organization
1Receptor is to AT
1The affinity of receptor is than AT
2Strong about 2000 times of receptor, selectivity also is higher than like product, but antagonism is by AT
1Activate arteries contraction, sympathetic activation and physiological effecies such as the increase of pressure receptor sensitivity, increased blood pressure that the back is produced, bring high blood pressure down, weaken myocardial cell and shrink, and retardance kidney AT
1Activate the water-sodium retention that the back produces; Also can reverse by AT
1The cardiac muscle of mediation and the hypertrophy and the plumpness of arterial blood tube wall smooth muscle delay the process of myocardial hypertrophy and kidney interstitial fibrosis, reduce the sickness rate and the case fatality rate of heart failure.This medicine went on the market in Britain first in 1997, be mainly used in the treatment of light, moderate essential hypertension and chronic heart failure, clinical adult's usual amounts is 150～300mg/ day, and effect is mild, do not have the obviously first phenomenon of crossing, hypotensive effect is sustainable more than 24 hours after each medication.
Amlodipine of the present invention and irbesartan compound preparation meet the Therapeutic Principle of hypertension drug combination.At first, go up from the pharmacology, this two medicine share, irbesartan acts on the effect of the end eventually link in the feritin one angiotensin booster system, and the direct boosting of blocking-up Angiotensin II (AngII) also is reduced in the tension force that has the sympathetic nervous system of important function in the blood pressure regulating process; Amlodipine then acts on the target organ of various neuro humor factors in the blood pressure regulating process---and blood vessel wall tension force, the two can carry out complementation from pharmacotoxicological effect mechanism, strengthens the hypotensive effect of the two.Secondly, can reduce the relative consumption of each medicine after share, reduce the generation of adverse effect, improve patient's compliance, reach the target that improves the hypertension control rate; Once more, the pharmacokinetics feature of two medicines is similar substantially, all can medication on the one once can keep 24 hours hypotensive effects, and the suitable feature of pharmacokinetics is arranged; In addition, the two, share and may improve total effective rate all between 83%～95% light, moderate hypertension patient's blood pressure lowering total effective rate; At last; this two classes drug combination is better to the hypertension induced effect of chronic kidney hypofunction institute; after share, two medicines can delay the progress of kidney disease; and this drug effect can be explained with active and effective hypotensive activity; if and kidney damage is obviously changed, more should use two medicines and share with renal function protecting.Share the back except that light, the moderate hypertension patient who can be used for not having any complication, also be specially adapted to hyperpietic, also be applicable to the patient's of renal hypertension, hypertension companion's renal function injury or companion's diabetes renal function injury treatment simultaneously with Cardiovascular Remodeling.
The present invention passes through the various dose combination to amlodipine and irbesartan, observes the hypotensive effect to spontaneous hypertensive rat, handles by two factors, three horizontal factor analysiss, and filter out efficacy of antihypertensive treatment and stablize lastingly, and the combination of dosage minimum doses.
One, material and method
1, is subjected to the reagent thing
Amlodipine Besylate Tablet, off-white powder, content 100.6% (w/w); Irbesartan, the off-white color crystalline powder, content 99.65%, two medicine provides by Shanghai Jiahua Medicine Sci. ﹠ Tech. Co., Ltd..
Two medicines all use 0.5% carboxymethyl cellulose (CMC) to be prepared into suspension, are mixed with stock solution by 10 times that irritate stomach concentration, and it is standby that 4 ℃ of refrigerators keep in Dark Place, and faces with preceding and dilute with 0.5%CMC.
2, laboratory animal
Adopt male spontaneous hypertensive rat in 18-24 age in week, 10 every group, available from Institute of Experimental Animals, Chinese Academy of Medical Sciences, the animal quality certification number: SCXK11-00-0006.
Animal is raised with full price rat pellet, is aided with cleaning drinking-water, and receptacle and laboratory environment temperature are 25 ± 3 ℃, and the light and shade cycle is 14h: 10h.Buy the back adaptability and raise a week, carry out basic blood pressure and measure, and reject the rat that blood pressure is lower than 200mmHg.
3, test method
3.1 medication
Adopt gastric infusion by clinical plan with route of administration, the administration capacity is 1ml/kg,, matched group gives equal-volume 0.5%CMC.
3.2 blood pressure measuring method:
With clear-headed rat arteria caudalis manometry, earlier rat is placed in the homemade taper cloth cover before the pressure measurement, the Mus tail that exposes is placed in the rat tails heating cabinet, thermal source is a 40W far infrared bulb, apart from Mus tail 30cm local irradiation, be 20 ± 5min heat time heating time.Because only the tail local heat can not exert an influence to rat body metabolism and blood pressure.Blood pressure measurement adopts rat arteria caudalis blood pressure determination instrument (Xiangya Medical College, Zhongnan Univ product) to be connected in computer, carries out the collection and the processing of blood pressure signal by MD2000 bio signal acquisition analysis system (Nanjing Medical University).
3.3 the blood pressure determination time:
Every treated animal is all measured basic blood pressure in the morning, irritate stomach after basic blood pressure is measured 30 minutes and be subjected to the reagent thing, observes after the administration influence to blood pressure of 2,6,12 and 24 hours medicines respectively.
Two, EXPERIMENTAL DESIGN
1, design
Test is two kinds of different processing factors for the optimal dose ratio of screening two medicine prescriptions, and every medicine is divided into 3 dosage groups, is respectively 3 levels.According to the experimental design principle, adopt the 3 horizontal factorial designs of 2 factors, will establish 3
2=9 experimental grouies.
2, dosage is selected and grouping
Amlodipine (A) and irbesartan (I) various dose are combined as following 9 kinds, see Table 1:
9 kinds of dosage combinations of table 1. amlodipine (A) and irbesartan (I)
| I 1 | I 2 | I 3 | |
| A 1 | A 1I 1 | A 1I 2 | A 1I 3 |
| A 2 | A 2I 1 | A 2I 2 | A 2I 3 |
| A 3 | A 3I 1 | A 3I 2 | A 3I 3 |
3, the selection foundation of first amount of reagent
Prescription screening will be used spontaneous hypertensive rat (SHR), according to the commonly used effective dose of bibliographical information two medicines to SHR, select the large, medium and small dosage of two prescription time spent blood pressure lowerings at the beginning of respectively, with this as prescription original reference dosage.According to the literature, amlodipine 15mg/kg/d can reduce SHR blood pressure and prevention of stroke
[6]Generation, but the 6mg/kg/d blood pressure lowering, the protection kidney
[7], there is hypotensive effect in 4 weeks of 3mg/kg/d successive administration
[8], 1,3,10mg/kg/d can influence blood pressure rhythm
[9]Irbesartan 10mg/kg is once oral to cause blood pressure lowering, and effect is kept 24h at least
[10], continuous 4 weeks of 50mg/kg/d
[11]Or continuous 4 weeks of 10mg/kg/d
[12]Certain pressure reduction effect is all arranged.As seen the single medicine blood pressure lowering of rat effective dose commonly used is amlodipine 3～10mg, irbesartan 10～50mg.
In view of the above, the single pharmaceutical quantities of preliminary examination is set and is seen Table 2
Table 2. amlodipine and irbesartan be amount of reagent (mg/kg/d) just
| Low dose of | Middle dosage | Heavy dose of | |
| The amlodipine irbesartan | 2 10 | 5 30 | 10 60 |
4, definite foundation of single pharmaceutical quantities in the prescription
According to first test result, choose the minimal effective dose of each medicine, determine single pharmaceutical quantities of prescription downwards with about 0.5 agent spacing, carry out the test of prescription hypotensive effect.
5, observation index
Clear-headed rat arteria caudalis systolic pressure, each time point are surveyed continuously and are averaged for 3 times, serve as effective with blood pressure drops 20mmHg after the medication
[13]
6, observing time
2,4,6,12 and 24 hours blood pressure behind basic blood pressure and the single-dose before the observation administration.
7, statistical disposition
Test data all use mean ± standard deviation (expression of x ± s), the blood pressure after the medication represent with the changing value before and after pressure value and the medication that respectively application Stata software carries out 3 * 3 factorial experiment variance analyses, with P＜0.05 for significant difference is arranged.
Three, result of the test
1, single medicine is to the influence of blood pressure
Single use amlodipine, 1 hour 3 treated animal blood pressure all has decline to a certain degree after medication, and wherein, 2mg/kg organizes after medication blood pressure drops and compares with basic blood pressure and do not have significant difference.5mg/kg group 1 hour obvious reduction of blood pressure after medication reaches peak value, gos up gradually subsequently.Blood pressure drops is obvious after the medication of 10mg/kg group, and the blood pressure lowering peak value is kept more than 24 hours and (seen Table 3) about after the medication between 2～4 hours.
The influence of table 3. amlodipine list to the SHR systolic pressure (x ± s, n=7)
| Blood pressure/mmHg (difference) | Amlodipine 2mg/kg | Amlodipine 5mg/kg | Amlodipine 10mg/kg |
| Behind the medication prodrug 1 hour 2 hours 4 hours 6 hours 12 hours 24 hours | 244±21 234±16(-4±26) 230±29(-14±28) 230±30(-12±38) 238±34(-5±38) 251±4(3±34) 238±18(-6±25) | 246±33 205±31(-32±11) 224±15(-20+25) 222±17(-23±29) 215±15(-18±45) 244±10(-24±18) 230±19(-14±19) | 246±27 181±32(-67±19) 176±27(-67±12) 173±22(-74±13) 189±28(-61±14) 216±45(-39±12) 211±29(-35±13) |
Annotate: difference is for bearing blood pressure drops after the expression medication; Difference is represented with back hypertension approximately for just.
The irbesartan list all has to a certain degree hypotensive effect with each dosage group of back, but 10mg/kg group blood pressure drops is not obvious, blood pressure drops reaches more than the 20mmHg after 30mg/kg and the medication of 60mg/kg group, blood pressure lowering peak value after administration 4～6 hours, 60mg/kg group pressure reduction effect can be kept 24 hours or more of a specified duration.
The influence of table 4. irbesartan list to the SHR systolic pressure (x ± s, n=7)
| Blood pressure mmHg (difference) | 10mg/kg | 30mg/kg | 60mg/kg |
| Behind the medication prodrug 2 hours | 256±34 248±43(-8±17) | 242±44 240±24(-15±14) | 257±28 235±26(-22±13) |
| 4 hours 6 hours 24 hours | 235±19(-15±20) 251±23(-5±19) 248±26(-9±13) | 229±25(-27±18) 234±30(-22±21) 243±26(-14±23) | 230±27(-27±14) 220±26(-38±19) 231±32(-28±21) |
Annotate: difference is for bearing blood pressure drops after the expression medication; Difference represents that for just medication bleeding from anus medicine raises.
According to first test result, least effective dose (LED) 5mg/kg with amlodipine, with the maximal dose of irbesartan least effective dose (LED) 30mg/kg as the participation prescription, take into account the convenience of prescription and reduce the repetition of same ratio group as far as possible, differential downward setting dosage group by 0.4～0.66, then 3 ascending dosage of amlodipine are respectively 1,2 and 5mg/kg; 3 ascending dosage of irbesartan are respectively 10,20 and 30mg/kg, and the formation and the ratio of 9 test group prescriptions see Table 5.
Table 5.9 kind of dosage combination and corresponding dosage ratio
| Amlodipine (A) dosage/mg/kg | Irbesartan (I) | Dosage/mg/kg | |
| 10 | 20 | 30 | |
| 1 2 5 | A 1I 10(1∶10) A 2I 10(1∶5) A 5I 10(1∶2) | A 1I 20(1∶20) A 2I 20(1∶10) A 5I 20(1∶4) | A 1I 30(1∶30) A 2I 30(1∶15) A 5I 30(1∶6) |
2, compound recipe is to the influence of blood pressure
The compound medicine of 9 kinds of combinations sees Table 6 and table 7 to the influence of blood pressure.Think effective according to blood pressure drops after " new drug (Western medicine) preclinical study guideline " medication greater than 20mmHg.Compare with the solvent control group, remove A after the medication
1I
10The combination hypotensive effect is not obvious, A
2I
10Combination and A
1I
20The combination hypotensive effect is kept outside the less than 12 hours, and all the other 6 kinds of combinations all have remarkable hypotensive effect, and hypotensive effect was kept more than 24 hours.
Dosage and each the prescription pressure reduction effect of two medicines in prescription is good dose-effect relationship.The irbesartan combination of amlodipine 5mg/kg and various dose very significant hypotensive effect is all arranged, and the persistent period was greater than 24 hours.The combination of the irbesartan of amlodipine 2mg/kg and various dose all can cause pressure reduction effect to SHR at irbesartan dosage 〉=20mg/kg.The irbesartan combination of amlodipine 1mg/kg and various dose only just presents the stable pressure reduction effect that continues when irbesartan is 30mg/kg.
Four, analysis and conclusion
1, with amlodipine and irbesartan list with comparing, form compound recipe with the amlodipine that is lower than or approach least effective dose (LED) with irbesartan, can obviously strengthen pressure reduction effect, the prolongation blood pressure lowering persistent period.
2, ideal enalapril meleate should have gentle, the lasting characteristics of hypotensive effect of acting on.Effective two prescriptions of each prescription of amlodipine 5mg/kg and 2mg/kg are comparatively violent because of hypotensive effect, should not be as common hypertensive daily medication; The prescription of amlodipine 1mg/kg and irbesartan 30mg/kg is stable lasting because of antihypertensive effect, and dosage is less, so be recommended as the optimal dose combination.
Applicable amlodipine of the present invention and irbesartan compound dose scope are: amlodipine: irbesartan=2-10mg: 50-300mg.
Above-mentioned result of the test shows: the compound preparation consumption of forming with amlodipine and irbesartan is starkly lower than the dosage of single usefulness respectively, and can obviously strengthen pressure reduction effect, prolongs the blood pressure lowering persistent period.Compound preparation of the present invention can increase hypertensive patient's the medication range of choice, simplifies Therapeutic Method, increases patient's treatment compliance, improves patient's controlling of blood pressure rate, the incidence rate of cardiovascular event and renal function injury when reducing hypertension.
The specific embodiment:
Embodiment 1 preparation tablets
| Composition | Proportioning (mg) |
| The cellulose crosslinked sodium carboxymethylcellulose PVP K30 of Amlodipine Besylate Tablet Irbesartan lactose microcrystal dolomol gross weight (mg) | (3.465 being equivalent to Amlodipine 2.500) 75.000 11.535 25.000 6.250 2.500 1.250 125.000 |
Raw material, adjuvant are crossed 80 mesh sieves respectively, 30 POVIDONE K 30 BP/USP 30 is mixed with suitable concentration as binding agent with pure water, except that magnesium stearate with other supplementary material with the equivalent dilution method mix homogeneously that progressively increases, the binding agent system soft material that reuse prepares, 60～65 ℃ of dryings are abundant, granulate, the magnesium stearate that adds recipe quantity is fully mixed, and compacting is in flakes.
The preparation of embodiment 2 tablets
| Composition | Proportioning (mg) |
| The cellulose crosslinked sodium carboxymethylcellulose PVP K30 of Amlodipine Besylate Tablet Irbesartan lactose microcrystal dolomol gross weight (mg) | (6.931 being equivalent to Amlodipine 5.000) 150.000 23.069 50.000 12.500 5.000 2.500 250.000 |
Preparation method is with embodiment 1.
The preparation of embodiment 3 hard capsules
| Composition | Proportioning (mg) |
| The cellulose crosslinked sodium carboxymethylcellulose PVP K30 of Amlodipine Besylate Tablet Irbesartan lactose microcrystal dolomol gross weight (mg) | (3.465 being equivalent to Amlodipine 2.500) 50.000 11.535 25.000 6.250 2.500 1.250 100.000 |
Raw material, adjuvant are crossed 80 mesh sieves respectively, 30 POVIDONE K 30 BP/USP 30 is mixed with suitable concentration as binding agent with pure water, except that micropowder silica gel with other supplementary material with the equivalent dilution method mix homogeneously that progressively increases, the binding agent system soft material that reuse prepares, 60～65 ℃ of dryings are abundant, granulate, the micropowder silica gel that adds recipe quantity fully mixes, and fills No. 2 capsules (every dress 100mg) and No. 1 capsule (every dress 200mg) respectively.
Embodiment 4, granule preparation
| Composition | Proportioning (mg) |
| Amlodipine Besylate Tablet irbesartan aspartame sucrose hypromellose gross weight (mg) | (3.465 being equivalent to amlodipine 2.500) 100.000 10.000 896.535 15.000 1025.000 |
Raw material, adjuvant are crossed 80 mesh sieves respectively, hypromellose is mixed with suitable concentration as binding agent with pure water, the aspartame of recipe quantity is dissolved in wherein, simultaneously with surplus stock, adjuvant mix homogeneously, granulate with the binding agent for preparing, 60～65 ℃ of dryings, are sieved every packed 1.025g at granulate.
Claims (4)
1, a kind of compound preparation is characterized in that said preparation is to consist of 1 with weight ratio: physiologically acceptable salt of the amlodipine of 10-30 or amlodipine and irbesartan are the pharmaceutical composition that active ingredient is formed.
2, compound preparation according to claim 1 is characterized in that wherein said pharmaceutical composition is various medically acceptable oral formulations.
3, the application in compound preparation according to claim 1, the moderate hypertension medicine light in preparation treatment.
4, application according to claim 3 is characterized in that wherein said medicine is applicable to the hyperpietic with Cardiovascular Remodeling, the patient's of renal hypertension, hypertension companion's renal function injury or companion's diabetes renal function injury treatment.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101485657B (en) * | 2009-03-04 | 2010-12-01 | 浙江华海药业股份有限公司 | Diovan compound preparation and preparation method thereof |
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| CN100364532C (en) * | 2004-09-30 | 2008-01-30 | 江苏恒瑞医药股份有限公司 | Composition containing amlodipine and angiotensin II receptor inhibitor |
| KR20130135994A (en) * | 2005-06-27 | 2013-12-11 | 다이이찌 산쿄 가부시키가이샤 | Pharmaceutical preparation containing an angiotensin ii receptor antagonist and a calcium channel blocker |
| CN103860511B (en) * | 2012-12-09 | 2018-04-24 | 海南中济医药科技有限公司 | A kind of Pharmaceutical composition containing Irbesartan and Amlodipine Besylate Tablet and preparation method thereof |
| CN108578404B (en) * | 2018-04-28 | 2020-04-28 | 广州白云山天心制药股份有限公司 | Medicinal composition containing irbesartan and amlodipine and preparation method thereof |
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| CN101485657B (en) * | 2009-03-04 | 2010-12-01 | 浙江华海药业股份有限公司 | Diovan compound preparation and preparation method thereof |
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