CN102370965A - Pharmaceutical composition containing pharmaceutically acceptable salts of levoamlodipine and pharmaceutically acceptable salts of perindopril - Google Patents
Pharmaceutical composition containing pharmaceutically acceptable salts of levoamlodipine and pharmaceutically acceptable salts of perindopril Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition, characterized by containing a certain amount of pharmaceutically acceptable salts of levoamlodipine, pharmaceutically acceptable salts of perindopril, and carriers or excipients which are acceptable in the preparation process. The pharmaceutical composition is used for treating various types of hypertension or angina pectoris and congestive cardiac failure. Compared with the prior art, the dissolvability, stability and dissolution rate of the preparation are improved obviously, and the synergism of combining two ingredients is obviously reinforced. The pharmaceutical composition can be prepared into various preparations, such as tablet, double-layer or multi-layer tablet, capsule, softgel, oral disintegrating tablet, chewing tablet, buccal tablet, sublingual tablet, dripping pills, particulate agent, electuary, powder, suspension, sustained release tablet or capsule, solution and other dosage forms. The dosage forms can contain various pharmaceutically acceptable excipient, disintegrating agent, adhesive, lubricant, flavoring, colouring agent, emulsifier and diluent and various combination thereof.
Description
Technical field
The present invention relates to treat the pharmaceutical composition of various types of hypertension or angina pectoris and congestive heart failure, belong to medical technical field.
Background technology
Hypertension is a kind of not only common but also serious chronic disease, and along with increasing substantially of living standard and life-span, hypertensive sickness rate is increasingly high, has become one of healthy main killer of harm humans.China's national hypertension investigation more than 15 years old the population prevalence be 13.6%.Annual newly-increased hyperpietic is about 3,500,000 people, and existing hyperpietic surpasses 100,016,000, and increases year by year, and cause that because of hypertension the cardiovascular and cerebrovascular disease death toll is more than 2,600,000 every year.
The long-term hypertension that continues causes multiple complications; Like apoplexy, congestive heart failure, ischemic heart desease, renal failure etc.; But also can cause coronary atherosclerosis and cardiac hypertrophy, and then develop into myocardial ischemia, angina pectoris and myocardial infarction etc., human beings'health in serious harm.Epidemiologic data proves: if can effectively control hypertension, can reduce human mortality rate, reduce the sickness rate of coronary heart disease and hypertensive heart disease, infringement and other consequence of prevention and minimizing target organ.
In the depressor commonly used at present thiazide diuretic, beta-Blocking agent, calcium antagonist, angiotensin-convertion enzyme inhibitor (ACEI), alpha-2-adrenoceptor blocker and angiotensin ii receptor antagonist are arranged.The treatment of thiazide diuretic and receptor blocking agent can make this risk factor of hypertension be able to control, but the effect of rising blood fat or blood glucose is arranged simultaneously; Many after the vasodilation blood pressure lowering with reflexive sympathetic activation and plasma renin activity increase.Angiotensin-convertion enzyme inhibitor (ACEI) is the antihypertensive of one type of highly effective and safe; But not being specificity ground, it does not influence renin angiotensin aldosterone system (RAAS); But, the Kallidin I effect is strengthened and side effect such as generation cough through suppressing the hydrolysis that invertase suppresses peptide classes such as kininase.
Calcium channel blocker claims that again (Calcium Channel Blocker is one of best antihypertensive drugs of present clinical effectiveness CCB) to calcium ion antagonist, is one of five big types of line antihypertensive drugs of WHO/ISH recommendation, can be used for the hypertensive treatment of various degree.It can stop flow of calcium ions, directly acts on vascular smooth muscle, diastole coronary vasodilator and whole body blood vessel, and coronary blood flow increasing brings high blood pressure down.Levamlodipine Besylate can block L-type calcium channel, directly the vasodilator smooth muscle.Through with calcium channel on corresponding receptor (DHP, PAA, BTZ) form complex, thereby and embed calcium channel retardance Ca
2+Interior stream.Because all kinds medicine is different with the affinity of receptor, so also there were significant differences for its blood vessel selectivity and pharmaco-kinetic properties.Secondly, Levamlodipine Besylate can promote the release of nitric oxide (NO).NO is as a kind of strong effect vasodilator material, vasodilator smooth muscle indirectly, and can bring into play the effect of antiplatelet aggregation, demonstrate the dose dependent antioxidant effect through suppressing lipid peroxidation.Once more, Levamlodipine Besylate has study of anti-atherogenic effect.Mainly be through minimizing lipid peroxidation, smooth muscle cell proliferation, alleviate mononuclear cell to the adhesion of endotheliocyte and the expression that strengthens ldl receptor protein, the removing of LDL realizes in the acceleration cycle, and then reaches the hypertensive effect of treatment.
Compare with first generation CCB nifedipine as calcium antagonist amlodipine of new generation; Overcome the pharmacokinetics defective of calcium antagonist in the past preferably; Advantages such as it is long to have biological half-life, and untoward reaction is few, the present treatment that has been widely used in essential hypertension clinically.
Amlodipine is long-acting dihydropyridine blood-pressure reducing medicine; This chemical compound has left-handed and two kinds of homotype isomers of dextrorotation; The levo form calcium antagonistic activity is nearly 1000 times of d-isomer, is 2 times of raceme, and Levamlodipine dosage is a half of raceme in theory; Identical efficacy of antihypertensive treatment can be arranged, and side effect simultaneously reduces.Levamlodipine besylate at first adopts disassemble technique to obtain this product by sky, Jilin Province wind Pharmaceutical Co; And listing at home; Abroad still do not go public, compare with similar medicine, its consumption is little, long-acting; There is the research report that effects such as coronary artery dilator, allevating angina pectoris are still arranged, so have a extensive future.Levamlodipine besylate has been used for the clinical treatment of essential hypertension, and multinomial research has confirmed that it is light in treatment, the curative effect of moderate essential hypertension.Levamlodipine and other antihypertensive drugs relatively, untoward reaction is less, is mostly flushing, headache, feeling of fullness in the head, cardiopalmus, the slight edema of lower limb etc., degree is lighter, maybe be relevant with the vasodilative effect of itself, general decrement or drug withdrawal can recover.
Amlodipine is used to treat hypertension and angina pectoris: spontaneous angina pectoris especially.Treating hypertensive predose is 5mg (1), and once a day, maximal dose is 10mg (2), once a day.Weakness or gerontal patient, be 2.5mg (1/2) with hepatic insufficiency patient predose, once a day, this dosage also can be other antihypertensive drug treatment of former use need add the dosage of treating with these article.Dose titration should be carried out according to the individual patients reaction.General dose titration should begin to carry out after 7～14 days.Like clinical needs, after the patient is carried out complete coverage, starting dose adjustment quickly.Treating anginal predose is 5～10mg (1～2), and once a day, the patient of old age and hepatic insufficiency advises using than low dose treatment.Most of people's effective dose is 10mg every day (2).
Amlodipine tolerates well, is a kind of comparatively ideal depressor.Big recklessly first-class research shows that the benzenesulfonic acid Levamlodipine Besylate can reduce hypertensive patient's systolic pressure and diastolic pressure effectively, and is particularly remarkable to the reduction effect of systolic pressure.After taking blood drug level for a long time and reaching stable state, miss still controlling blood pressure preferably once in a while.In addition, in the time of this medicine coronary artery dilator and peripheral vessels, sinuatrial node, atrioventricular node and myocardium shrinkage function are not had obvious influence, more do not have negative inotropic action, can be used safely in the senile chronic patients with heart failure.
The benzenesulfonic acid Levamlodipine Besylate is effective nephrectasia blood vessel also.Because it is higher to this susceptibility perception to be in the blood vessel of contraction state, so can increase kidney blood flow and glomerular filtration rate (GFR) after using this medicine, thus the protective effect of performance kidney.In addition, this medicine does not have influence to lipid, carbohydrate metabolism, does not also have negative effects such as rising plasma triglyceride that beta-blocker and diuretic cause and T-CHOL, and effectively stops the accumulation of cholesterol at arterial wall.
Recklessly big first-class about benzenesulfonic acid Levamlodipine Besylate and Amlodipine Besylate Tablet treat hypertensive multicenter, at random, double blinding, parallel study show that benzenesulfonic acid Levamlodipine Besylate blood pressure lowering effectiveness is high than Amlodipine Besylate Tablet, and the former adverse reaction rate reduces 60% than the latter.24h ambulatory blood pressure monitoring 60 routine light, moderate primary hypertension patient treatment 4 all front and back circadian rhythm of blood pressure rhythm and pace of moving things are passed through in a research in addition, have contrasted the effectiveness and the safety of amlodipine and Levamlodipine Besylate.The result shows that two medications are imitated significantly and steadily, each time point blood pressure of treatment back all significantly reduces before the treatment, to liver, renal function, and blood glucose, blood fat, blood electrolyte does not make significant difference; All do not cause the alteration in heart rate that clinical meaning is arranged.This shows that the benzenesulfonic acid Levamlodipine Besylate is comparatively ideal antihypertensive drugs, especially be fit to old, the allorhythmic patients with hypertension of circadian rhythm of blood pressure.
Levamlodipine Besylate all obviously is being superior to Nifedipine sustained release tablets aspect the stationarity of kinestate, decreased heart rate, reduction DBP and 24h ambulatory blood pressure reduction DBP.Dong Fengqi etc. pass through the 70 routine essential hypertensions merging left ventricular hypertrophy patients treatments in 24 weeks by a definite date, the effectiveness of comparative study benzenesulfonic acid Levamlodipine Besylate and felodipine and safety.The result shows that two medicines all significantly bring high blood pressure down and reverse left ventricular hypertrophy, and benzenesulfonic acid Levamlodipine Besylate effect is more excellent; The benzenesulfonic acid Levamlodipine Besylate also is superior to felodipine aspect adverse reaction rate.
The multicenter that Guo Jizhen etc. carry out, at random, single blind, parallel study, compared benzenesulfonic acid Levamlodipine Besylate and losartan to efficacy of antihypertensive treatment and safety light, moderate essential hypertension person.The result shows, and is more more remarkable than losartan to the range of decrease of blood pressure in the benzenesulfonic acid Levamlodipine Besylate 24h, and is 100% for the total effective rate of New Development hypertension case, apparently higher than 84% of losartan, do not have 1 routine patient in the research process and withdraws from because of untoward reaction.
Therefore, Levamlodipine is compared with amlodipine, and curative effect is more excellent, less adverse effect, and administration once a day, antihypertensive effect is kept length, belongs to long-acting antihypertensive drugs.
Perindopril is a novel angiotensin converting enzyme inhibitor.
It is dangerous that hypertension increases the cardiovascular diseases, the blood pressure lowering of many medicines abilities, but be not can check with the reverse blood vessel relevant with hypertension to reinvent.Perindopril surpasses 10 years in European countries' clinical practice, and clinical data proves that this medicine is an effective blood pressure lowering, well-tolerated long-acting depressor.Its unique pharmacological action can provide the target organ function and protecting to the hypertensive patient, improves arterial compliance, recovers cardiac function, effectively reverses blood vessel and reinvents.
Perindopril has shown the inhibition angiogenesis in animal test model, the generation of restriction VEGF (VEGF).Its half-life is longer, each 4～8mg.Its paddy p-ratio is stabilized in 75～100%, so it meets the conduct medicine of dosage once-a-day.
Perindopril and clinical important drugs interaction potential impact are very low, more importantly with the treatment CHF possibly the medicine of usefulness do not interact.In long-term perindopril treatment down, to 24h Gaoxin TG-AUC fifty-fifty, the digoxin peak concentration, peak concentration time and oral clearance rate afterwards all do not have obvious influence.Therefore the normal patient of CHF renal function, when digoxin and perindopril therapeutic alliance, its dosage need not adjustment.Pharmacokinetics influences each other bigger between more antihypertensive drug and other type medicine; Especially outstanding in the old people; But the important drug drug interaction of the less relatively generation of perindopril; When perindopril and anticoagulant, on-steroidal AID etc. are used, clinically all do not find deleterious interaction.
Clinical test results proof perindopril treatment hypertension be safe and toleration very good; In extensive 12 months study on monitoring 47351 routine patients; Because of the only 5 kinds of side reactions of this medicine therapist are removed in the perindopril side reaction: cough, gastrointestinal upset, faint, headache and dizzy incidence rate＞1%; Other rare side reactions still have insomnia, xerostomia, erythra, hyposexuality, edema of lower limbs and dysgeusia etc.The first dose of hypotension that in perindopril is used, occurs with treat in the hyperkalemia side reaction more much lower relatively than other similar medicine incidence rates.
Have experiment to show that perindopril has the effect that right ventricle is plump, reduce myocardium interstitial collagen content that reverses, maybe with reduce circulation in and the Ang II of cardiac muscle relevant.The result shows from the comparative study of perindopril comfort, and it is the same effective with a daily amount multiple dosing to obey diindyl Puli dosage once a day, and the generation pressure reduction effect is relevant with dosage during total agent 8mg on the one.80% patient, perindopril is administration once-a-day separately, or the merging SHUANGKE can reduce diastolic pressure＜90mmHg.Perindopril and other ACEI comparative study disclose, and it is suitable with enalapril once-a-day that the perindopril pressure reduction effect is superior to the captopril of twice administration on the one.People such as Zannad use randomized, double-blind; Parallel mode to the 96 routine patients of diastolic pressure 90～106mmHg carry out perindopril (4～8mgPd) with calcium antagonist amlodipine (5～10mgPd); 60 days comparative study by a definite date; Pressure reduction effect zero difference, 24hABPM diastolic pressure paddy-peak ratio be respectively 0.81 and 0.80, two kind of drug resistance good; People such as same thurston carry out multicenter to 173 routine clinostatism diastolic pressure 95～125mmHg patients, random double blind test with perindopril relatively (4～8mgPd) with beta-Blocking agent atenolol (50～100mgPd) effectiveness.Use SHUANGKE 25mgPd if add when diastolic pressure maintains 90mmHg, 3 months finish, and perindopril group diastolic pressure decline＜90mmHg accounts for 78%, and ammonia only accounts for 58% for Luo Er.Aspect therapeutic alliance hypertension, reach primary amine and all get satisfied clinical effectiveness no matter perindopril adds SHUANGKE or Yin.In special hypertension colony, perindopril also demonstrates its superiority.People such as Qrerlack have proved that also perindopril is combined hyperlipidemia; Type 2 diabetes mellitus; Arrhythmia, peripheral arterial obliterans, companion's albuminuria nephropathy; Chronic obstructive pulmonary disease and osteoarthritis etc. be with all effectively blood pressure lowerings of perindopril in the nonsteroid anti-inflammatory drugs treatment etc., and each is organized the pressure reduction effect no significant difference.
Except resisting hypertension, perindopril can also be used to treat heart failure.Drug effect takes place gradually, and first dose of causing danger property of hypotension is low, and low dose can not produce the blood pressure adverse effect normal blood pressure diseases people; Miss dosage and can still keep effectiveness, the effect of positivity hemodynamics reverses left ventricular hypertrophy and blood vessel and reinvents; Drug safety; Rate of side effects is low, to heart rate, and blood fat; The blood glucose metabolism does not have definite influence, and it is outer and can improve cardiac function rank, total heart failure order of severity integration and cardiothoracic ratio that people such as Lechat research confirms that also perindopril treatment decapacitation improves treadmill and dull and stereotyped movement time.People such as Flammang estimate serious patient CHF of cardiac function III～IV and use perindopril 4mgPd, short-term and for a long time to hemodynamic effects, and treating second day CI increases by 21%; PCWP and MBP reduce by 54% and 21% respectively; Treat after 3 months, Cl increases by 3%, and PCWP and MBP descend 44% and 19% respectively; Perindopril has been proved the compliance that can improve resistance vessel, reverses left ventricular hypertrophy and can improve cardiac function.Perindopril is preferable medicament selection to patient's CHF treatment undoubtedly.
People such as Sihm use the perindopril treatment and detect and treat not good enough essential hypertension people recently; The treatment before with the treatment 9 months after; Carry out the inspection of buttocks living tissue specimen, the microscopically assessment, clear and definite perindopril can effectively reduce footpath, thickness P chamber, media ratio.
People such as Schwartzkopff prove that also perindopril also has obvious structure influence to arteria coronaria.Use the coronary blood flow deposit and under vein cardiac muscle endocardium biopsy to estimate.The small artery fibre deformation alleviates to confirm to cause the treatment of prolonged application perindopril on every side, and the interstitial collagen proteinosis reduces, and makes arteria coronaria small artery structure be able to repair.Relate to the 2394 routine hypertensive patients of 19 countries and use perindopril 4～8mgPd treatment; Be engaged in 6 months the extensive clinical research of Complior; Systolic pressure and diastolic pressure are reduced to 134P83mmHg by 158P99 respectively, and femoral artery pulse rates mensuration is reduced to 10.5mPs by 11.0mPs, and blood pressure and pulse rates return analysis more; Further the proof perindopril can obviously improve the compliance of tremulous pulse, and this effect possibly be independent of the mechanism outside the blood pressure.
Use perindopril treatment can causing resistance vessel compliance at the hypertension philtrum and improve and reduce afterload, generation is to the negativity effect of myocardial hypertrophy.People such as Schulte accompany 40 examples of left ventricular hypertrophy with the therapeutic effect difference to not receiving treatment; Light moderate essential hypertension people uses perindopril 4～8mgPd; Diastolic pressure do not drop to＜and 90mmHg person adds SHUANGKE 25mgPd; Perindopril treatment back left ventricular mass drops to 240 ± 12g by 280 ± 11g.People's such as Grandi research confirms that more perindopril reverses the remarkable effect of left ventricular hypertrophy.The comparison of author's using ultrasound kinetocardiogram and ABPM, (4～8mgPd) treat effect after 6 months with isradipine (5mgPd) to use perindopril.After treatment finished, two groups showed identical remarkable reduction 24h systolic pressure and diastolic pressure, descend respectively 15P12mmHg and 16P13mmHg, and the reduction of cardiac weight index is respectively 30gPm2 and 20gPm2, perindopril obviously is superior to the isradipine group.
Perindopril treatment hypertension is significantly effective, and has clinical key character: drug effect takes place gradually, steadily controls the 24h blood pressure; Miss 1 time and still can keep effectiveness; And treatment hypertension is widely used, and the application of perindopril can reverse the blood vessel relevant with hypertension and reinvent and left ventricular hypertrophy, improves arterial compliance; Alleviating afterload and change cardiac function, also is the preferable medicament selection of CHF patient.
Levamlodipine and perindopril action target spot have nothing in common with each other, and Levamlodipine is directly expanded peripheral blood vessel, but do not have perindopril the reverse ventricular hypertrophy, reduce effect such as myocardium interstitial collagen content; The two share mutual supplement with each other's advantages, also can produce synergy, makes antihypertensive effect more powerful; And significantly reduce untoward reaction; Share the microalbumin that also can reduce in the urine, renal function protecting, the hypertension effect that reduces due to the diabetic nephropathy is more obvious.
The pharmacokinetics of Levamlodipine and perindopril and characteristics have determined the two can process compound preparation, and the two all belongs to durative action preparation, are once a day and take, and all have steady controlling blood pressure effect from the drug action characteristics.The perindopril drug drug interaction is few, and simultaneously it can also be checked with the reverse blood vessel relevant with hypertension and reinvents.Its unique pharmacological action can provide the target organ function and protecting to the hypertensive patient, improves arterial compliance, recovers cardiac function, effectively reverses blood vessel and reinvents.
The more important thing is that innovation part of the present invention is: research worker finds to adopt Levamlodipine and perindopril specific salts to share can significantly improve the diastole of blood vessel endothelium dependency, reverses hyperpietic's vascular endothelium dysfunction.Effect obviously is superior to the two single usefulness, and be superior to Levamlodipine and perindopril or other except that several kinds of specific salts compositions, and be superior to Levamlodipine and other Puli's class drug combination.
The water solublity of perindopril own is very poor; Had a strong impact on medicine dissolution, stripping and absorption, caused drug effect to be affected, low, the easy liquefaction of perindopril fusing point simultaneously; Character is unstable; Several kinds of specific salt such as the butylamine hydrochlorate of perindopril, arginine salt have then overcome above-mentioned shortcoming, form that stripping character and medicine stability are moreover improved behind the new Pharmaceutical composition, thereby on pharmacodynamics, show.
The pharmaceutical composition that is formed by Levamlodipine pharmaceutically acceptable salt and perindopril pharmaceutically acceptable salt of the present invention compared with prior art; The dissolubility of medicine, stability, and the preparation dissolution obviously improve, both share synergistic therapeutic action and obviously strengthen.
Summary of the invention
The present invention has overcome the defective of prior art and a kind of pharmaceutical composition that can effectively treat various types of hypertension or angina pectoris and congestive heart failure is provided; Compared with prior art; The dissolubility of medicine, stability, and the preparation dissolution obviously improve, both share synergistic therapeutic action and obviously strengthen.
Pharmaceutical composition of the present invention is characterized in that being made up of acceptable carrier or excipient in Levamlodipine pharmaceutically acceptable salt, perindopril pharmaceutically acceptable salt and the preparation process.
The Levamlodipine pharmaceutically acceptable salt is selected from Levamlodipine benzene sulfonate, Levamlodipine maleate, Levamlodipine mesylate or Levamlodipine benzoate in the compositions of the present invention, and described perindopril pharmaceutically acceptable salt is selected from perindopril tert-butylamine salt, perindopril arginine salt, perindopril maleate, perindopril mesylate, perindopril citrate or perindopril same regimen acid salt.
More specifically, the content in Levamlodipine Levamlodipine pharmaceutically acceptable salt in the described compositions is 1.0mg～50.0mg, is preferably 2.5mg～25mg; Content in perindopril perindopril pharmaceutically acceptable salt is 1.0mg～40.0mg, is preferably 2.0mg～20.0mg.
In the pharmaceutical composition of the present invention the weight ratio of Levamlodipine pharmaceutically acceptable salt and perindopril pharmaceutically acceptable salt be preferably 1: 0.1～1: 10, more preferably 1: 0.4～1: 4.
The Pharmaceutical composition that the present invention relates to contains a certain amount of Levamlodipine and a certain amount of perindopril specific salts or the two pharmaceutically useful addition salts and pharmaceutically suitable carrier or diluent, can be made into various forms of oral formulations.
The Pharmaceutical composition that the present invention relates to, oral formulations comprise dosage forms such as tablet, bilayer or multilayer tablet, capsule, soft capsule, oral cavity disintegration tablet, chewable tablet, buccal tablet, Sublingual tablet, drop pill, granule, electuary, powder, suspensoid, slow releasing tablet and slow releasing capsule, solution, suspension, pill.These dosage forms can contain various excipient such as calcium carbonate, sodium citrate, microcrystalline Cellulose, lactose etc.; Various disintegrating agents such as starch and some composition silicate, mannitol, hypromellose; Contain binding agent such as polyvinylpyrrolidone, sucrose, gelatin and arabic gum, lubricant such as magnesium stearate, sodium lauryl sulphate, Pulvis Talci etc.Sweeting agent, correctives, coloring agent, emulsifying agent and diluent such as water, ethanol, propylene glycol, glycerol and various forms thereof make up.
Any one Pharmaceutical composition that the present invention relates to can be used for treating various types of hypertension or angina pectoris and congestive heart failure, and selects the Pharmaceutical composition of different UDs according to the state of an illness.
Pharmaceutical composition involved in the present invention can be used for human or animal's individuality.
A preferred version of the present invention is that described Levamlodipine pharmaceutically acceptable salt is selected from the Levamlodipine benzene sulfonate, and described perindopril pharmaceutically acceptable salt is selected from perindopril tert-butylamine salt.
Description of drawings
Fig. 1 is the experimental result of embodiment 12:
Left-handed Amlodipine Besylate Tablet, left-handed Amlodipine Besylate Tablet add perindopril, left-handed Amlodipine Besylate Tablet adds the influence of perindopril tert-butylamine salt to aorta vessel diastole effect under the Ach variable concentrations
The specific embodiment
Embodiment 1:
Left-handed Amlodipine Besylate Tablet and perindopril tert-butylamine salt sheet
Preparation technology:
With medicine Amlodipine Besylate Tablet (in amlodipine) and perindopril tert-butylamine salt, diluent, filler microcrystalline Cellulose, lactose, pregelatinized Starch, disintegrating agent polyvinylpolypyrrolidone etc. are crossed 80 mesh sieves respectively; As binding agent, prepare soft material with above-mentioned mixed powder with the aqueous solution of 2.5% 30 POVIDONE K 30 BP/USP 30,20 mesh sieves are granulated; Cross 18 mesh sieve granulate after putting 60 ℃ of oven drying 3.0h; Add the fluidizer magnesium stearate, tabletting behind the mix homogeneously promptly gets.
Embodiment 2:
Left-handed amlodipine maleate and perindopril arginine salt capsule
Preparation technology:
Supplementary material is crossed 80 mesh sieves respectively, and is subsequent use; The left-handed amlodipine maleate of recipe quantity, perindopril arginine salt, carboxymethyl starch sodium, calcium hydrogen phosphate (two water things) are progressively increased behind the method mix homogeneously and the microcrystalline Cellulose mix homogeneously according to equivalent successively again; As binding agent, prepare soft material with above-mentioned mixed powder, the dry 3.0h of 60 ℃ of constant temperature convection oven are granulated, put to 18 mesh sieves with the aqueous solution of 2.5% 30 POVIDONE K 30 BP/USP 30, the granule of oven dry is taken out; Cross 16 eye mesh screen granulate; Add magnesium stearate and carry out always mixing, filling capsule promptly gets.
Embodiment 3:
Left-handed Amlodipine Besylate Tablet and perindopril maleate granule
Preparation technology's method
Supplementary material is crossed 100 mesh sieves.With orange distinguish the flavor of essence, stevioside mix homogeneously, again with lactose, medicine mixed evenly after, adopt equivalent progressively increase method and filler sucrose, mannitol, mix homogeneously such as correctives stevioside.
Prepare 5% 30 POVIDONE K 30 BP/USP, 30 solution 1000ml as binding agent with 70% alcoholic solution; Add 4.0g antiseptic ethyl hydroxybenzoate and fully dissolve, as binding agent, prepare soft material with above-mentioned mixed powder with this mixed liquor with an amount of toner lemon yellow; Cross 16 eye mesh screens and granulate, put 60 ℃ of oven drying 3.0h.
The dried granule of oven dry was taken out 16 eye mesh screen granulate.
Get an amount of granule, press under the assay item and to measure content, confirm the granule loading amount, by loading amount drug particles is packed in the aluminium plastic bag, thermoplastic seals.
Embodiment 4:
Left-handed Amlodipine Besylate Tablet and perindopril tert-butylamine salt slow releasing tablet
Method for preparing:
Raw material, 60 ℃ of dryings of adjuvant elder generation 6 hours, it is subsequent use to cross 80 mesh sieves after all pulverizing; Press recipe quantity with medicine, HPMC (K100M), PVP K30 by behind the abundant mixing of equivalent incremental method, add an amount of 1%HPMC (K100M) 90% alcoholic solution.Process soft material, granulate with 18 mesh sieves, 40～50 ℃ of dryings 2～3 hours are taken out, and with 18 mesh sieve granulate, add the magnesium stearate mixing, survey in the granule drug content qualified after with special-shaped drift tabletting.
Embodiment 5:
Left-handed Amlodipine Besylate Tablet and perindopril mesylate dispersible tablet
Method for preparing:
Raw material, 60 ℃ of dryings of adjuvant elder generation 6 hours are all pulverized the back and are crossed 80 mesh sieves, by behind the abundant mixing of equivalent incremental method, add an amount of 95% alcoholic solution.Process soft material, granulate with 20 mesh sieves, 50 ℃ of dryings 2～3 hours are taken out, with 18 mesh sieve granulate, and mixings such as adding disintegrating agent CMS-Na, PPVP, tabletting.
Embodiment 6: left-handed Amlodipine Besylate Tablet and perindopril tert-butylamine salt chewable tablet
Method for preparing:
Raw material, 60 ℃ of dryings of adjuvant elder generation 6 hours are all pulverized the back and are crossed 80 mesh sieves, by behind the abundant mixing of equivalent incremental method, add an amount of 0.5%PVP-K30 alcoholic solution and process soft material; Granulate with 16 mesh sieves, drying is taken out; With 12 mesh sieve granulate, add mixings such as correctives aspartame and Fructus Citri Limoniae essence, tabletting.
Embodiment 7:
Left-handed amlodipine maleate and perindopril tert-butylamine salt buccal tablet
Method for preparing:
Raw material, 60 ℃ of dryings of adjuvant elder generation 6 hours are all pulverized the back and are crossed 80 mesh sieves, by behind the abundant mixing of equivalent incremental method, add an amount of 95% alcoholic solution.Process soft material, granulate with 20 mesh sieves, 50 ℃ of dryings 2～3 hours are taken out, with 18 mesh sieve granulate, and mixings such as adding essence, tabletting.
Embodiment 8:
Left-handed Amlodipine Besylate Tablet and perindopril tert-butylamine salt double-layer tablet
Granule A (containing left-handed Amlodipine Besylate Tablet part):
Preparation technology:
Took by weighing 60 ℃ of dryings of medicine and adjuvant elder generation 5 hours by recipe quantity, all pulverize the back and cross 80 mesh sieves,, add an amount of 95% alcoholic solution by behind the abundant mixing of equivalent incremental method.Process soft material, granulate with 20 mesh sieves, 50 ℃ of dryings 2～3 hours are taken out, and with 18 mesh sieve granulate, mixings such as magnesium stearate are subsequent use.
Granule B (containing the perindopril tert-butylamine salt part):
Preparation technology's method:
Took by weighing 60 ℃ of dryings of medicine and adjuvant elder generation 5 hours by recipe quantity, all pulverize the back and cross 80 mesh sieves,, add an amount of 95% alcoholic solution by behind the abundant mixing of equivalent incremental method.Process soft material, granulate with 20 mesh sieves, 50 ℃ of dryings 2～3 hours are taken out, and with 18 mesh sieve granulate, mixings such as magnesium stearate are subsequent use.
The method for preparing of double-layer tablet:
During film-making, earlier above-mentioned A granule is added, special-shaped tablet machine is processed workprint.By the rate of charge requirement, add the B granule again, press double-layer tablet, after the passed examination, packing.Available bi-layer tablet press compacting in the production.
Embodiment 9:
Perindopril and multi-form salt dissolubility in water thereof
Trial drug: make by oneself by Xianyu Science and Technology Co., Ltd., Nanjing
Assay method: with reference to " two ones of Chinese pharmacopoeia versions in 2005
Table 1 perindopril and multi-form salt solubility test result in water thereof
The result shows: several kinds of specific salts of perindopril are like tert-butylamine salt, arginine salt, maleate etc.; Compare with perindopril; Quantity of solvent has reduced more than tens times even 1000 times and can also in water, dissolve, and explains that these several kinds its water solublity of specific salt are greatly improved.
The change of the dissolution properties of these several kinds of specific salts makes the stripping character of itself and Levamlodipine compositions also be significantly improved.
Embodiment 10:
The multi-form salt of perindopril compares with the Pharmaceutical composition dissolution that contains Levamlodipine
Adopt that multi-form salt and Levamlodipine are formed several kinds of Pharmaceutical compositions and process conventional tablet after adopt following method to measure the dissolution situation of two kinds of compositions:
Trial drug: make by oneself by Xianyu Science and Technology Co., Ltd., Nanjing
Assay method:
The amlodipine dissolution determination method: getting test sample, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C, second method), is solvent with 0.1mol/L hydrochloric acid solution 500ml; Rotating speed is that per minute 75 changes; Operation in accordance with the law in the time of 30 minutes, is got solution 20ml; Filter, get subsequent filtrate as need testing solution; Other gets Amlodipine Besylate Tablet reference substance 15mg, accurate claims surely, puts in the 100ml measuring bottle, adds to add the 0.1mol/L hydrochloric acid solution after an amount of dissolving of methanol and be diluted to scale; Shake up, precision is measured 5ml, puts in the 50ml measuring bottle; Add 0.1mol/L hydrochloric acid and be diluted to scale, shake up, as reference substance solution.Get above-mentioned two kinds of solution,, measure trap respectively in the 237nm wavelength according to spectrophotography (two appendix IV of Chinese Pharmacopoeia version in 2005 A).Calculate every stripping quantity, limit is 80% of a labelled amount, should be up to specification.
The perindopril dissolution determination method: it is an amount of to get test sample, according to dissolution method (Chinese Pharmacopoeia 2005 version cadre the appendix X C three therapeutic methods of traditional Chinese medicine), puts in the 10ml measuring bottle; The mobile phase that adds under the assay item is an amount of, and jolting makes abundant dissolving, puts cold; Be diluted to scale with mobile phase, shake up, filter; Get subsequent filtrate, as need testing solution; Precision is measured in right amount, adds mobile phase and processes the solution that contains 20 μ g among every 1ml, as reference substance solution, according to the chromatographic condition under the assay item, measures in accordance with the law, calculates every stripping quantity, and limit is 75% of a labelled amount.
Table 2 dissolution test result
Can find out from above result: the dissolution of two kinds of medicines of perindopril tert-butylamine salt soluble in water, arginine salt and multi-form amlodipine medicament composition is all greater than 99%; And the pharmaceutical composition that the bad salt of perindopril and dissolution properties thereof is formed not only the dissolution of perindopril is relatively poor, but also influenced the stripping of amlodipine.
Research worker therefore of the present invention is summed up: several kinds of specific salts of perindopril can obviously improve pharmaceutical properties such as dissolving, stripping than perindopril itself, share with Levamlodipine or its salt and can obviously improve drug effect.
Embodiment 11:
Observe that left-handed Amlodipine Besylate Tablet, perindopril, left-handed Amlodipine Besylate Tablet add perindopril, left-handed Amlodipine Besylate Tablet adds perindopril tert-butylamine salt influences the spontaneous hypertensive rat blood pressure
Receive the reagent thing:
Levamlodipine, Tian Feng pharmaceutcal corporation, Ltd in Jilin provides, perindopril, perindopril tert-butylamine salt, Xianyu Science and Technology Co., Ltd., Nanjing provides.
Animal:
40 of spontaneous hypertension rats, body weight 200-300g, male and female half and half are available from Institute of Experimental Animals, Chinese Academy of Medical Sciences.
Animal divides into groups:
Table 3 divides into groups and administration
| Group | Number of animals (only) | Dosage (mg/kg) |
| Sodium carboxymethyl cellulose group (blank group) | 10 | 0 |
| Left-handed Amlodipine |
10 | 2.0 |
| The |
10 | 2.0 |
| Left-handed Amlodipine Besylate Tablet adds the |
10 | 2.0+2.0 |
| Left-handed Amlodipine Besylate Tablet adds the perindopril tert- |
10 | 2.0+2.0 |
[0124] Administering mode:
Through the administration of gastric fistula pipe.
Experimental technique:
Use the polyethylene ductus arteriosus, in be full of heparinization polyvinylpyrrolidone liquid.Spontaneous hypertensive rat anesthesia back position is fixed.Femoral artery is inserted into the ventral aorta hypomere from the left side with ductus arteriosus.Every animal is all made the gastric fistula intubate in order to administration.Post-operative recovery 2 days, ductus arteriosus links to each other the computer recording fluctuation of blood pressure through the perfusion tee T with pressure receptor.
Experimental result:
The left-handed Amlodipine Besylate Tablet of table 4, perindopril, left-handed Amlodipine Besylate Tablet add perindopril, left-handed Amlodipine Besylate Tablet adds perindopril increased mean blood pressure in 24 hours to spontaneous hypertensive rat influence
Annotate: SBP, systolic pressure; DBP, diastolic pressure; N=8 compares with matched group,
*P＜0.05,
*P＜0.01
Table 4 experimental result shows: no matter be single with left-handed Amlodipine Besylate Tablet or perindopril 2mg/kg; Still share the two; All can significantly reduce by 24 hourly average blood pressures of spontaneous hypertensive rat; Share effect and obviously be superior to single usefulness, the left-handed Amlodipine Besylate Tablet of Combined application adds the perindopril tert-butylamine salt effect and obviously is superior to left-handed Amlodipine Besylate Tablet and adds perindopril.And no matter be that systolic pressure or diastolic pressure all obtain same conclusion.
Left-handed Amlodipine Besylate Tablet and perindopril tert-butylamine salt share the back and have explained for the research conclusion of spontaneous hypertensive rat blood pressure influence: after perindopril changes over tert-butylamine salt; Its dissolution properties has obtained increasing substantially; Its result of extraction has also obtained increasing substantially; After share with left-handed Amlodipine Besylate Tablet, also promote the effect of left-handed benzenesulfonic acid chlorine Flordipine, on pharmacodynamics, obtained reflection.
Embodiment 12:
Observe that left-handed Amlodipine Besylate Tablet, left-handed Amlodipine Besylate Tablet add perindopril, left-handed Amlodipine Besylate Tablet adds perindopril tert-butylamine salt to spontaneous hypertensive rat blood vessel endothelium effects on diastolic function
Receive reagent thing and reagent:
Left-handed Amlodipine Besylate Tablet, Tian Feng pharmaceutcal corporation, Ltd in Jilin provides, perindopril, perindopril tert-butylamine salt, Xianyu Science and Technology Co., Ltd., Nanjing provides.
Acetylcholine (Ach), Nanjing fine reagent company limited in evening
Instrument:
The Powerlab bio signal is gathered and analytical system, and the Australian Ai De of pressure transducer (ML T0380) company
Animal:
40 of spontaneous hypertension rats, male 13 ages in week, divide to advance 4 groups at random, and with 10 of all Wister-Kyoto in age (WKY) rats, the cleaning level is all available from Institute of Experimental Animals, Chinese Academy of Medical Sciences.
Table 5 animal divides into groups and administration:
Experimental technique:
With the arteria caudalis pressure testing method respectively at medication before with medication after 4,8,12W measures and respectively to organize rat blood pressure.Behind the last administration 24h, (1.5mg/kg, i.p.) thoracic aorta is got in anesthesia, puts in 4 ℃ of HEPES liquid with 20% urethane.Behind fat and the connective tissue, be cut into 3-4mm thing vascular ring around rejecting.Vascular ring runs through lumen of vessels with two miniature hooks of rustless steel, horizontally suspends that (contain HEPES liquid 10ml, constant temperature passes to 100%O for 37 ℃ in bathing pipe
2), and be connected with tonotransducer, use Powerlab bio signal acquisition analysis system record antiotasis to change.The all arteries ring all stimulates for many times with 60mmol/LKCL.When BIAO and BEN is stablized IR, begin test.
The maximum shrinkage amplitude that brings out with PE is 100%, and the ratio between the amplitude peak of bringing out with antiotasis amplitude and the PE that adds behind the medicine reflects the variation of antiotasis.
Observe medicine to Ach (10
-9-10
-5Mol/L) influence of the endothelium-dependent relaxation diastole effect of cumulative concentration.
Experimental result:
(see accompanying drawing 1: left-handed Amlodipine Besylate Tablet, left-handed Amlodipine Besylate Tablet add perindopril, left-handed Amlodipine Besylate Tablet adds the influence of perindopril tert-butylamine salt to aorta vessel diastole effect under the Ach variable concentrations)
Experimental result shows: give 10
-9-10
-5Behind the Ach of mol/L cumulative concentration; The maximum diastole percentage ratio of each group of SHR significantly reduces than the WKY group; Left-handed Amlodipine Besylate Tablet group (SHR-1), left-handed Amlodipine Besylate Tablet add perindopril group (SHR-2), left-handed Amlodipine Besylate Tablet adds perindopril tert-butylamine salt group (SHR-3) and all can obviously improve the diastole of blood vessel endothelium dependency; Wherein left-handed Amlodipine Besylate Tablet add the more left-handed Amlodipine Besylate Tablet group of perindopril tert-butylamine salt group, left-handed Amlodipine Besylate Tablet add the perindopril group have improve P＜0.01 more significantly), and near normal value.Point out left-handed Amlodipine Besylate Tablet and perindopril tert-butylamine salt to share and obviously to improve the vasodilation ability, promote the recovery of vascular function.
The personnel of pharmaceutical field should be appreciated that the present invention can not only limit to specific embodiment described herein, and can carry out various changes and modification and the essence of the present invention and the scope that do not exceed claim and limited to it.
Claims (11)
1. a pharmaceutical composition is characterized in that being made up of acceptable carrier or excipient in Levamlodipine pharmaceutically acceptable salt, perindopril pharmaceutically acceptable salt and the preparation process.
2. pharmaceutical composition according to claim 1; Wherein said Levamlodipine pharmaceutically acceptable salt is selected from Levamlodipine benzene sulfonate, Levamlodipine maleate, Levamlodipine mesylate or Levamlodipine benzoate, and described perindopril pharmaceutically acceptable salt is selected from perindopril tert-butylamine salt, perindopril arginine salt, perindopril maleate, perindopril mesylate, perindopril citrate or perindopril same regimen acid salt.
3. pharmaceutical composition according to claim 2 is characterized in that, the content in Levamlodipine Levamlodipine pharmaceutically acceptable salt in the described compositions is 1.0mg～50.0mg.
4. pharmaceutical composition according to claim 3, wherein the content in Levamlodipine Levamlodipine pharmaceutically acceptable salt is preferably 2.5mg～25mg.
5. pharmaceutical composition according to claim 2 is characterized in that, the content in perindopril perindopril pharmaceutically acceptable salt in the described compositions is 1.0mg～40.0mg.
6. pharmaceutical composition according to claim 5, wherein the content in perindopril perindopril pharmaceutically acceptable salt is preferably 2.0mg～20.0mg.
7. pharmaceutical composition according to claim 2 is characterized in that, the weight ratio of Levamlodipine pharmaceutically acceptable salt and perindopril pharmaceutically acceptable salt is 1: 0.1～1: 10.
8. pharmaceutical composition according to claim 7 is characterized in that, the weight ratio of Levamlodipine pharmaceutically acceptable salt and perindopril pharmaceutically acceptable salt is preferably 1: 0.4～and 1: 4.
9. pharmaceutical composition according to claim 2 is characterized in that, dosage form is an oral formulations.
10. pharmaceutical composition according to claim 9 is characterized in that described oral formulations is selected from capsule, oral cavity disintegration tablet, chewable tablet, buccal tablet, Sublingual tablet, drop pill, granule, electuary, powder, suspensoid or slow releasing agent.
11. according to the described arbitrary pharmaceutical composition of claim 1-10; It is characterized in that; Described Levamlodipine pharmaceutically acceptable salt is preferably the Levamlodipine benzene sulfonate, and described perindopril pharmaceutically acceptable salt is selected from perindopril tert-butylamine salt.
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| CN103861081A (en) * | 2014-03-26 | 2014-06-18 | 东英（江苏）药业有限公司 | Perindopril amlodipine tablet and production process thereof |
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| US10894039B2 (en) | 2016-10-07 | 2021-01-19 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
| EP3522872A4 (en) * | 2016-10-07 | 2020-05-20 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
| US10959991B2 (en) | 2016-10-07 | 2021-03-30 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
| EP3960158A1 (en) * | 2016-10-07 | 2022-03-02 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
| US11364230B2 (en) | 2016-10-07 | 2022-06-21 | Azurity Pharmaceuticals, Inc. | Amlodipine formulations |
| US12053461B2 (en) | 2016-10-07 | 2024-08-06 | Azurity Pharmaceuticals, Inc. | Amlodipine formulations |
| US10799453B2 (en) | 2018-04-11 | 2020-10-13 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
| US11471409B2 (en) | 2018-04-11 | 2022-10-18 | Azurity Pharmaceuticals, Inc. | Amlodipine formulations |
| US11484498B2 (en) | 2018-04-11 | 2022-11-01 | Azurity Pharmaceuticals, Inc. | Amlodipine formulations |
| US11701326B2 (en) | 2018-04-11 | 2023-07-18 | Azurity Pharmaceuticals, Inc. | Amlodipine formulations |
| US11918685B2 (en) | 2018-04-11 | 2024-03-05 | Azurity Pharmaceuticals, Inc. | Amlodipine formulations |
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