CN107320462B

CN107320462B - A kind of sustained release preparation and preparation method thereof of levamlodipine or its salt

Info

Publication number: CN107320462B
Application number: CN201710621320.2A
Authority: CN
Inventors: 甘勇; 朱春柳; 杨彦玲; 刘彦; 朱全垒
Original assignee: Individual
Current assignee: SHIHUIDA PHARMA GROUP (JILIN) CO Ltd
Priority date: 2016-10-14
Filing date: 2016-10-14
Publication date: 2018-11-13
Anticipated expiration: 2036-10-14
Also published as: CN107320462A; CN106420738B; CN106420738A

Abstract

The present invention provides a kind of levamlodipine or the sustained release preparation of its salt, including quick-release phase and sustained release phase, mutually respectively independence or quick-release are mutually coated on outside sustained release phase quick-release phase with sustained release, the quick-release mutually part containing active constituents of medicine, it is sustained the mutually rest part containing active constituents of medicine, active constituents of medicine is levamlodipine or its salt, active constituents of medicine is calculated as 2.5mg~20mg with levamlodipine, in the dissolution medium for meeting sink conditions, more than 90% weight of active constituents of medicine discharged within 6 hours to 14 hours deenergized periods.The sustained release preparation of the present invention can not include quick-release phase.The present invention also provides related manufacturing processes.The levamlodipine of the present invention or the sustained release preparation of its salt are easy to use, and curative effect of medication is high, take that compliance is good, and adverse reaction is few, can quick acting, and for a long time maintain steady effective blood drug concentration, it is ingenious in design, it is simple for structure, there is good stability, be suitable for large-scale promotion application.

Description

A kind of sustained release preparation and preparation method thereof of levamlodipine or its salt

The application is that application No. is 14 days October 2016 201610898040.1, applying date, an a kind of entitled " left sides The divisional application of the sustained release preparation and preparation method thereof of rotation Amlodipine or its salt ".

Technical field

The present invention relates to technical field of medicine, more particularly to medicament slow release preparation technical field, in particular to one kind The sustained release preparation and preparation method thereof of levamlodipine or its salt.

Background technology

With the improvement of people's living standards, angiocardiopathy has become the primary disease of China's cause of death, it is prestige It coerces " number one killer " of people's health and life.China 18 years old or more adult hypertension illness rate is up to 33.5%, and total number of persons is super 3.3 hundred million are crossed, the death toll caused by hypertension and its complication is up to 9,400,000 every year in the whole world, and wherein there are about 200 every year in China Ten thousand people die of hypertension.With being further exacerbated by for China's aging degree, the morbidity and mortality of hypertension still have year by year Raised trend.

Although people achieve many progress in terms of the prevention of hypertension and coronary heart disease, detection and treatment in recent years, Hypertension is still an important public health problem.For many patients, the mode of making the life better is not sufficient to control disease Process, it is necessary to while giving drug therapy.Clinical test confirms that target control treatment can reduce cardiovascular danger, and be protected with kidney Shield acts on and reduces the danger of cerebrovascular events, and good drug therapy is for extending hypertensive patient's life and life matter Amount has positive meaning.

Hypertension be both the common complication of chronic glomerulonephritis and cause in glomerular capillary high pressure and Height filters and promotes glomerulosclerosis, further one of an important factor for damage kidney.Therefore, it reduces blood pressure, delay renal function Deteriorate, the renal function of protection kidney patient is the important link for treating chronic glomerulonephritis patients, the high blood of good treatment Pressure strategy should can stablize decompression and provide protective effect simultaneously for kidney again, the prevention renal function impaired because of hypertension into One step deteriorates.Therefore, it finds effectively decompression and improves the drug of renal function as the hot spot of clinical research.

So far, clinically used drug for hypertension mainly has 6 major class：Calcium ion antagonist (abbreviation Ca2+ overloading Agent), diuretics, beta-blocker, alpha-blocking agent, angiotensin converting enzyme inhibitor (ACEI) and angiotensins II receptor antagonist (ARB).In the drug for hypertension of all categories, calcium ion antagonist can reduce Stroke risk rate It is significant in efficacy, and have the effect of resisting coronary heart disease angina pectoris, it is metabolized to blood-fat and blood sugar and Water-Electrolyte has no adverse effects, patient's clothes Medicine compliance is high, is used for a long time still effective.Just because of calcium ion antagonist has the above remarkable treatment characteristic, in recent years respectively Treatment Guidelines for Hypertension (such as JNC- VII,《Chinese hypertension prevention and control guide》) in using calcium ion antagonist drug as recommending The first-line drug that hypertensive patient uses.

Levamlodipine besylate is the dihydropyridine calcium ion agonist drug that a new generation has cardioselective, is used In treating various Hypertension populations, it can block cardiac muscle and the calcium ion of vascular smooth muscle cells outer calcium ion toward cell membrane is logical Road enters intracellular.In addition, this kind of drug also has prominent advantage：Pressure reduction does not reduce the important vital organ such as the heart, brain, kidney Blood flow；It has no adverse effects to metabolins such as blood glucose, blood fat；Myocardial contractive power and Atrioventricular Conduction are influenced small；Pair is made With less.In addition, since it selects the height of petty action smooth muscle, there is slight row's sodium profit to the adrenal gland of vein smooth muscle Urine acts on, and so that water sodium is reduced in reabsorption, does not cause water-sodium retention, effective to primary and secondary hypertension.

Levamlodipine besylate, chemical name：(S)-(-) 3- ethyls 5- methyl -2- (2- ammonia ethoxymethyl) -4- (2- chlorphenyls)-Isosorbide-5-Nitrae-dihydro -6- methyl -3,5- pyridine dicarboxylate benzene sulfonates is Chinese the first chiral resolution optical voidness Drug and world's the first chiral resolution drug for hypertension.Use can be merged individually or with other drugs, there is anti-hypertension With treatment angina pectoris effect, clinically has and preferably applied.

Levamlodipine besylate absorbed following oral administration is complete, and blood concentration peaks within 6-12 hours.Absolute oral profit Expenditure is about 64%-80%, and apparent volume of distribution is about 21L/kg.Once a day, successive administration after 7-8 days blood concentration up to steady State.It is eliminated from blood plasma in a manner of two compartment model after absorption, inactive metabolin (90%) is metabolized as extensively in liver.Eventually It is 35 hours that half-life period healthy person is eliminated at end, and hypertensive patient is extended for 50 hours, the elderly 65 hours, liver function damage person 60 Hour, renal insufficiency person is unaffected.This product 10% is discharged in the form of metabolin from urine by prototype, 60%, 20%- 25% is discharged from bile or excrement.Levamlodipine besylate cannot be removed by haemodialysis, and renal insufficiency person is to benzene sulphur The pharmacokinetic characteristics of sour levamlodipine have no significant effect.Gerontal patient and dyshepatia patient are to the clear of this product Except rate reduces, area under the drug-time curve AUC about increases 40%-60%.The AUC elevation amplitudes of middle Serious heart Failure patient are similar.

Compared with other depressor, Levamlodipine besylate has drug effect long, and antihypertensive effect is slowly lasting, Bu Zhizao Hypertension rebound effect at low blood pressure and after being discontinued, tissue selectivity vasoactive rather than heart can be used safely in the heart The patient of force failure, bioavilability are high, can delay the process of left ventricular hypertrophy, can be used in combination with other drugs and not by The advantages that influence of dietary intake.In addition, Levamlodipine besylate is a kind of effective antianginal drug, especially to hat Arteries and veins spasmodic angina is more effective, it has higher affinity to blood vessel, and can significantly extend Ischemic Cardiomyopathy Run duration and the angina pectoris attacks time is moved to, reduces the consumption of anginal attack times and nitroglycerin.

Currently, clinically used amlodipine formulation is conventional tablet, used mainly for light, moderate hypertension patient. According to the literature, the therapeutic effect and its safety for research amlodipine to hypertension, has chosen 100 hypertensive patients It is included in research, is randomly divided into control group and treatment group, each 50.Treatment group is treated using amlodipine, and control group uses nitre Benzene Horizon sustained release tablets are treated.Observe simultaneously comparative analysis to two groups of patients' medication situations, antihypertensive effect, adverse reactions etc..Knot Total effective rate is higher than 74% (P of control group up to 92% after fruit shows treatment group's medication<0.05).After treatment end, treatment group Adverse reaction rate is 8%, is mainly shown as dizzy, weak, headache, flush, edema of lower extremity, nasal obstruction, palpitaition etc..Less than pair According to the 16% of group, adverse events are mainly shown as dizzy, weak, headache, flushing, insomnia, dry cough, rubefaction with slight skin Rash, nasal obstruction, palpitaition etc..In general, the clinical effectiveness of amlodipine is good, safe, effectively can control and reduce blood pressure, With clinical expansion meaning.

Currently, common Levamlodipine besylate preparation is conventional tablet, clinically it is widely used, main needle Light, moderate hypertension patient is used；During clinical application, Levamlodipine besylate ordinary preparation still have it is following not Foot place：1. the general initial dose of this product should gradually adjust dosage since low dose, cumbersome dosage adjusts process to clinic Medication brings certain inconvenience；2. the effect of to the hypertension and patient with angina pectoris of moderate and severe, is not good enough；3. the high blood of severe It presses and usually requires medication 2 times a day on patient clinical, easily lead to bad kickback of using medicine (including postural hypotension, headache, head The symptoms such as portion's fever, oedema).

Through patent retrieval, formulation patent ublic specification of application related with Levamlodipine besylate includes：Benzene sulphur Sour levo amido chloro diping oral disintegration tablet (CN1813726A), Levamlodipine beaylate tablets (CN104257619A), benzene sulphur Sour amido chloro diping dispersion tablet (CN1686121A), L-amlodipine besilate dripping pill (CN1899268A), benzene sulfonic acid ammonia chlorine Flat micro-balloon injection (CN101530396A) etc. is specific as follows：

Chinese patent application prospectus CN101559043A disclose a kind of Levamlodipine beaylate tablets and its Preparation method.The Levamlodipine beaylate tablets (in terms of 1000) of the invention, containing Levamlodipine besylate 1~ 10g, particularly preferably 2.5g；50~100g of lactose, preferably 67~87g, particularly preferably 80g；Low substituted hydroxy-propyl fiber Element 5~55g, preferably 20~40g, particularly preferably 30g；2~20g of crosslinked polyvinylpyrrolidone, preferably 5g；Stearic acid 0.5~2.5g of magnesium, preferably 1.5g.

Chinese patent application prospectus CN101766582A provide a kind of Levamlodipine besylate tablet and Preparation method.The tablet is by using Levamlodipine besylate the label of active constituent and to be wrapped in outer membrane clothing group At wherein the diluent in label contains one or both of diatomite and differential silica gel, also contains pharmaceutically acceptable Other auxiliary materials, outer membrane clothing account for the 8%~12% of piece weight, can play the role of it is moisture-proof, be protected from light, so that medicine stability is obtained Large increase.

Chinese patent application prospectus CN102846565A discloses a kind of system of Levamlodipine beaylate tablets Preparation Method mixes after Levamlodipine besylate, filler, disintegrant pulverize and sieve, and lubricant granulation, pressure is added Piece.Levamlodipine beaylate tablets are prepared using the method for fluid-bed marumerization, reduce Levamlodipine besylate The related substance of piece, improves stability, while simplifying preparation process, shortens the time, optimize technological parameter, significantly increases Add the dissolution rate of product, improves product quality.

Chinese patent application prospectus CN101947210A discloses a kind of Levamlodipine besylate liposome Tablet and its application in the drug for preparing treatment essential hypertension.The Levamlodipine besylate liposome Tablet includes the substance of following weight ratio：Levamlodipine besylate：Egg yolk lecithin：Cholesterol：PLURONICS F87： Other pharmaceutically acceptable excipient=1：4-10:0.5-5:1-3:35-50.The liposome tablet of the invention greatly improves a benzene sulfonic acid left side Revolve the stability and dissolution rate of Amlodipine, Small side effects, more remarkable treatment effect.

Chinese patent application prospectus CN1899268A provides a kind of L-amlodipine besilate dripping pill and system Preparation Method, formula are made of Levamlodipine besylate, dripping pill matrix, antioxidant, surfactant, coating material etc., Preparation method is that Levamlodipine besylate is prepared into the fine powder that fineness is 150 mesh or more first.Take the base of formula ratio After matter heating melting, adds Levamlodipine besylate fine powder and related auxiliary material, be mixed into dispersion liquid, instill in condensate liquid, drop Ball is made, coating or not coated drop pill is made.

Chinese patent application prospectus CN101530396A discloses a kind of preparation method of amlodipine microballoon, The drug that the microballoon prepared is wrapped up is Amlodipine and its organic salt, and the carrier material of the microballoon is polylactic acid (PLA), gathers The biodegradable materials such as lactic acid-hydroxyacetic acid copolymer (PLGA) or polylactic acid-ethylene glycol block copolymer (PLA-mPEG), and Using surfactant solution, monosaccharide or polysaccharide solution, polyhydric alcohol solutions, cellulose solution, colloidal solution as decentralized medium, lead to Emulsion solvent evaporation is crossed, amlodipine microsphere is prepared under mechanical agitation or high speed shear effect.The load of the patent application Use can be subcutaneously injected in medicine microballoon, in vivo the slow release drug with the degradation of high molecular material, and rate of release is approximation Zero-order release profile, drug percutaneous undertissue absorbed into serum can maintain the maintenance level of blood concentration long-time (2 weeks-March), Compared with common tablet, the blood concentration variation that frequent oral medication is brought is avoided, reduces the generation of toxic side effect, carries The drug safety of high patient.

In above-mentioned patent retrieval, the relevant report about Levamlodipine besylate oral slow-releasing preparation is had no.Research Show that levamlodipine removes dextrorotation ingredient, adverse reaction rate can be reduced to a certain extent.But due to the high blood of renal Pressure often needs large dosage treatment, patient to be also easy to produce some side effects, such as flushed face, dizziness, headache, edema of lower extremity blood vessel Expansion reaction etc..And gerontal patient's dosage start treatment when should since low dose start gradually adjust dosage, wait for that patient can Therapeutic dose is gradually increased to when tolerance again.

As it can be seen that still having following shortcoming during the ordinary preparation clinical application of Levamlodipine besylate：① Initial dose should gradually adjust dosage since low dose, and cumbersome dosage adjustment process brings certain to clinical application It is inconvenient；2. the effect of to the hypertension and patient with angina pectoris of moderate and severe, is not good enough；3. on renal hypertension patient clinical usually Large dosage for the treatment of is needed, bad kickback of using medicine (including diseases such as postural hypotension, headache, Head And Face fever, oedema are easily led to Shape), the fluctuation of blood concentration is larger.

To further increase the clinical efficacy of levamlodipine, hypertensive patient (renal hypertension patient) medication is reduced Adverse reaction afterwards increases the compliance of patient's medication, needs to carry out rational dosage form and Formulation, with optimizing left-handed ammonia chlorine Flat release behavior makes drug while reducing adverse reaction, plays maximum curative effect.

Accordingly, it is desirable to provide the sustained release preparation of a kind of levamlodipine or its salt, easy to use, curative effect of medication is high, It is good to take compliance, adverse reaction is few, can quick acting, and for a long time maintain steady effective blood drug concentration.

Invention content

In order to overcome the disadvantages of the prior art mentioned above, it is an object of the present invention to provide a kind of levamlodipines Or the sustained release preparation of its salt, easy to use, curative effect of medication is high, takes that compliance is good, and adverse reaction is few, is suitable for large-scale promotion Using.

Another object of the present invention is to provide a kind of levamlodipine or the sustained release preparations of its salt, can quickly rise Effect, and steady effective blood drug concentration is maintained for a long time, it is suitable for large-scale promotion application.

It is ingenious in design another object of the present invention is to provide a kind of levamlodipine or the sustained release preparation of its salt, It is simple for structure, there is good stability, be suitable for large-scale promotion application.

Another object of the present invention is to provide the preparation method of a kind of levamlodipine or the sustained release preparation of its salt, It is ingenious in design, simplicity is prepared, the sustained release preparation of levamlodipine or its salt obtained is easy to use, and curative effect of medication is high, takes Compliance is good, and adverse reaction is few, is suitable for large-scale promotion application.

Another object of the present invention is to provide the preparation method of a kind of levamlodipine or the sustained release preparation of its salt, It is ingenious in design, prepare it is easy, the sustained release preparation of levamlodipine or its salt obtained can quick acting, and maintain for a long time flat Steady effective blood drug concentration is suitable for large-scale promotion application.

Another object of the present invention is to provide the preparation method of a kind of levamlodipine or the sustained release preparation of its salt, It is ingenious in design, simplicity is prepared, the sustained release preparation of levamlodipine or its salt obtained is ingenious in design, simple for structure, has good Good stability is suitable for large-scale promotion application.

To achieve the above objectives, in the first aspect of the present invention, a kind of levamlodipine or the sustained release system of its salt are provided Agent, its main feature is that, including it is sustained phase, the sustained release mutually contains active constituents of medicine, and the active constituents of medicine is left-handed ammonia chlorine Horizon or its salt, the active constituents of medicine are calculated as 2.5mg~20mg with the levamlodipine, are meeting sink conditions In dissolution medium, more than 90% weight of the active constituents of medicine discharged within 6 hours to 12 hours deenergized periods.

The sustained release can mutually have any suitable composition, preferably, the sustained release mutually also contains sustained release phase carrier, institute Active constituents of medicine is stated included in the sustained release phase carrier.

The sustained release phase carrier can be any suitable sustained release phase carrier, and more preferably, the sustained release phase carrier is selected from slow Release the sustained release for being sustained label and coated pellet of piece, sustained release ball, the sustained-release matrix in tablet, the slow release layer in double-layer tablets, coating tablet At least one of capsule core.

The active constituents of medicine can be any suitable levamlodipine or its salt, preferably, the drug is lived Property ingredient be levamlodipine, Levamlodipine besylate, maleic acid levo amido chloro diping.

In the second aspect of the present invention, the preparation method of a kind of levamlodipine or the sustained release preparation of its salt is provided, Feature is, the sustained release preparation of the levamlodipine or its salt is the left-handed ammonia chlorine of above-mentioned the first aspect of the present invention The preparation method of the sustained release preparation of flat or its salt sustained release preparation, the levamlodipine or its salt includes step：By institute Active constituents of medicine is stated included in the sustained release phase.

The sustained release can mutually have any suitable composition, preferably, the sustained release mutually also contains sustained release phase carrier, In the step, the active constituents of medicine is included in the sustained release phase carrier.

In the third aspect of the present invention, a kind of levamlodipine or the sustained release preparation of its salt are provided, its main feature is that, including Mutually the respective independent or described quick-release is mutually coated on the sustained release phase for quick-release phase and sustained release phase, the quick-release phase and the sustained release Outside, mutually the part containing active constituents of medicine, the sustained release mutually contain its remaining part of the active constituents of medicine to the quick-release Point, the active constituents of medicine is levamlodipine or its salt, and the active constituents of medicine is in terms of the levamlodipine It is more than 90% weight of the active constituents of medicine small 6 in the dissolution medium for meeting sink conditions for 2.5mg~20mg It is discharged up in 14 hours deenergized periods.

The active constituents of medicine can be included in the quick-release phase and the sustained release phase with any suitable weight ratio In, preferably, 0% weight of a part for the active constituents of medicine >=active constituents of medicine and the≤drug is lived 50% weight of property ingredient, the active constituents of medicine of the weight of the rest part of the active constituents of medicine >=50% and≤ 100% weight of the active constituents of medicine.

The active constituents of medicine can be included in the quick-release phase and the sustained release phase with any suitable weight ratio In, more preferably, 10% weight of a part >=active constituents of medicine of the active constituents of medicine and the≤drug 45% weight of active constituent, the active constituents of medicine of the weight of the rest part of the active constituents of medicine >=55% and The 90% weight of≤active constituents of medicine.

The active constituents of medicine can be included in the quick-release phase and the sustained release phase with any suitable weight ratio In, further, 15% weight of a part >=active constituents of medicine of the active constituents of medicine and≤it is described 40% weight of active constituents of medicine, the pharmaceutical activity of the weight of the rest part of the active constituents of medicine >=60% at Point and the 85% weight of≤active constituents of medicine.

A part >=active constituents of medicine of the active constituents of medicine 0% weight and the≤drug is lived 50% weight of property ingredient, the active constituents of medicine of the weight of the rest part of the active constituents of medicine >=50% and≤ In the case of 100% weight of the active constituents of medicine, in the dissolution medium, in the quick-release phase and the sustained release phase The active constituents of medicine can have any suitable release behavior, more preferably, in the dissolution medium, the quick-release It more than 90% weight of the active constituents of medicine in phase was discharged within 30 minutes deenergized periods, the institute in the sustained release phase 90% weight of active constituents of medicine or more is stated to discharge within 6 hours to 14 hours deenergized periods.

In the dissolution medium, the active constituents of medicine in the quick-release phase and the sustained release phase, which can have, appoints What suitable release behavior, further, in the dissolution medium, the active constituents of medicine in the quick-release phase It more than 90% weight was discharged within 15 minutes deenergized periods, 90% weight of the active constituents of medicine in the sustained release phase It was discharged within 6 hours to 12 hours deenergized periods above.

The quick-release phase and the sustained release can mutually have any suitable composition, preferably, the quick-release mutually also contains A part for quick-release phase carrier, the active constituents of medicine is included in the quick-release phase carrier, and the sustained release mutually also contains It is sustained phase carrier, the rest part of the active constituents of medicine is included in the sustained release phase carrier, the quick-release phase carrier It is respectively independent or the quick-release phase carrier is coated on outside the sustained release phase carrier with the sustained release phase carrier.

The quick-release phase carrier can be any suitable quick-release phase carrier, and more preferably, the quick-release phase carrier is selected from speed Release the quick-release coatings of the quick-release matrix in piece, quick-release ball, tablet, the release layer in double-layer tablets and coating tablet or coated pellet At least one of.

In the fourth aspect of the present invention, the preparation method of a kind of levamlodipine or the sustained release preparation of its salt is provided, It is characterized in that, the sustained release preparation of the levamlodipine or its salt is the left-handed ammonia chlorine of above-mentioned the third aspect of the present invention The preparation method of the sustained release preparation of the sustained release preparation of Horizon or its salt, the levamlodipine or its salt includes following step Suddenly：

(1) by a part for the active constituents of medicine be included in the quick-release phase in, by the pharmaceutical activity at The rest part divided is included in the sustained release phase；

(2) make the quick-release phase mutually respectively independent with the sustained release, or the quick-release is mutually coated on the sustained release phase Outside.

The quick-release phase and the sustained release can mutually have any suitable composition, preferably, the quick-release mutually also contains Quick-release phase carrier, the sustained release mutually also contains sustained release phase carrier, in the step (1), by the active constituents of medicine A part is included in the quick-release phase carrier, and the rest part of the active constituents of medicine, which is included in the sustained release, mutually to be carried In body；In the step (2), keep the quick-release phase carrier and the sustained release phase carrier respectively independent, or by the quick-release Phase carrier is coated on outside the sustained release phase carrier.

Beneficial effects of the present invention essentially consist in：

1, the sustained release preparation of levamlodipine of the invention or its salt includes sustained release phase, sustained release mutually contain pharmaceutical activity at Point, active constituents of medicine be levamlodipine or its salt, active constituents of medicine with levamlodipine be calculated as 2.5mg~ 20mg more than 90% weight of active constituents of medicine was released in the dissolution medium for meeting sink conditions at 6 hours to 12 hours Release in the period is put, therefore, easy to use, curative effect of medication is high, takes that compliance is good, and adverse reaction is few, is suitable for large-scale promotion Using.

2, the sustained release preparation of levamlodipine of the invention or its salt includes quick-release phase and sustained release phase, quick-release phase and sustained release Mutually respectively independence or quick-release are mutually coated on outside sustained release phase, and mutually the part containing active constituents of medicine, sustained release mutually contain quick-release The rest part of active constituents of medicine, active constituents of medicine are levamlodipine or its salt, and active constituents of medicine is with left-handed ammonia Flordipine is calculated as 2.5mg~20mg, in the dissolution medium for meeting sink conditions, it is more than 90% weight of active constituents of medicine Discharged in 6 hours to 14 hours deenergized periods, therefore, can quick acting, and for a long time maintain steady effective blood drug concentration, fit In large-scale promotion application.

3, the sustained release preparation of levamlodipine of the invention or its salt includes quick-release phase and sustained release phase, quick-release phase and sustained release Mutually respectively independence or quick-release are mutually coated on outside sustained release phase, and mutually the part containing active constituents of medicine, sustained release mutually contain quick-release The rest part of active constituents of medicine, active constituents of medicine are levamlodipine or its salt, and active constituents of medicine is with left-handed ammonia Flordipine is calculated as 2.5mg~20mg, in the dissolution medium for meeting sink conditions, it is more than 90% weight of active constituents of medicine It is discharged in 6 hours to 14 hours deenergized periods, it is therefore, ingenious in design, it is simple for structure, there is good stability, be suitable for big rule Mould promotes and applies.

4, the preparation method of the sustained release preparation of levamlodipine of the invention or its salt includes step：By pharmaceutical activity at Subpackage is contained in sustained release phase, and active constituents of medicine is levamlodipine or its salt, and active constituents of medicine is with levamlodipine It is calculated as 2.5mg~20mg, to which the sustained release preparation of levamlodipine or its salt be made, in the dissolution medium for meeting sink conditions In, it more than 90% weight of active constituents of medicine was discharged within 6 hours to 12 hours deenergized periods, therefore, ingenious in design, system Standby easy, the sustained release preparation of levamlodipine or its salt obtained is easy to use, and curative effect of medication is high, and it is good to take compliance, no Good reaction is few, is suitable for large-scale promotion application.

5, the preparation method of the sustained release preparation of levamlodipine of the invention or its salt includes the following steps：(1) by institute A part for the active constituents of medicine stated is included in the quick-release phase, and the rest part by the active constituents of medicine includes In the sustained release phase；(2) make the quick-release phase and the sustained release mutually respectively independent, or described in the quick-release is mutually coated on It is sustained outside phase, wherein active constituents of medicine is that levamlodipine or its salt, active constituents of medicine are calculated as with levamlodipine 2.5mg~20mg, to which the sustained release preparation of levamlodipine or its salt be made, in the dissolution medium for meeting sink conditions, It more than 90% weight of active constituents of medicine was discharged within 6 hours to 14 hours deenergized periods, it is therefore, ingenious in design, it prepares Simplicity, the sustained release preparation of levamlodipine or its salt obtained can quick acting, and maintain steady effectively blood medicine dense for a long time Degree is suitable for large-scale promotion application.

6, the preparation method of the sustained release preparation of levamlodipine of the invention or its salt includes the following steps：(1) by institute A part for the active constituents of medicine stated is included in the quick-release phase, and the rest part by the active constituents of medicine includes In the sustained release phase；(2) make the quick-release phase and the sustained release mutually respectively independent, or described in the quick-release is mutually coated on It is sustained outside phase, wherein active constituents of medicine is that levamlodipine or its salt, active constituents of medicine are calculated as with levamlodipine 2.5mg~20mg, to which the sustained release preparation of levamlodipine or its salt be made, in the dissolution medium for meeting sink conditions, It more than 90% weight of active constituents of medicine was discharged within 6 hours to 14 hours deenergized periods, it is therefore, ingenious in design, it prepares The sustained release preparation of simplicity, levamlodipine or its salt obtained is ingenious in design, simple for structure, has good stability, is suitable for Large-scale promotion application.

These and other objects, feature and the advantage of the present invention, by following detailed descriptions, drawings and claims obtain To fully demonstrate, and can be achieved by means, device and the combination thereof specially pointed out in appended claims.

Description of the drawings

Fig. 1 is that the main view perspective of the first specific embodiment of the levamlodipine of the present invention or the sustained release preparation of its salt is shown It is intended to, for the capsule containing quick-release ball 1 and sustained release ball 2.

Fig. 2 is that the main view perspective of the second specific embodiment of the levamlodipine of the present invention or the sustained release preparation of its salt is shown It is intended to, for the capsule containing fast-release tablet 3 and sustained release tablets 4.

Fig. 3 is that the main view perspective of the third specific embodiment of the levamlodipine of the present invention or the sustained release preparation of its salt is shown It is intended to, to contain the external capsule with the coated pellet of quick-release coatings 5, inside with sustained release capsule core 6.

Fig. 4 is that the main view perspective of the 4th specific embodiment of the levamlodipine of the present invention or the sustained release preparation of its salt is shown It is intended to, to be enclosed with the tablet of sustained release ball 2 in quick-release matrix 7.

Fig. 5 is that the main view perspective of the 5th specific embodiment of the levamlodipine of the present invention or the sustained release preparation of its salt is shown It is intended to, for the bilayer tablet that quick-release matrix 8 is contained on upper layer, sustained-release matrix 9 is contained in lower layer.

Fig. 6 is that the main view perspective of the 6th specific embodiment of the levamlodipine of the present invention or the sustained release preparation of its salt is shown It is intended to, be that external to have sustained-release coating layer 10, internal lower layer be boosting layer 11, the coating tablet that inside upper layer is medicine-containing particle 12.

Fig. 7 is that the main view perspective of the 7th specific embodiment of the levamlodipine of the present invention or the sustained release preparation of its salt is shown It is intended to, being outside has quick-release coatings 13, the coating tablet that inside is sustained release tablets 4.

Fig. 8, which is the levamlodipine of the present invention or the sustained release preparation of its salt, has the tablets in vitro of single-phase drug release behavior bent Line.

Fig. 9, which is the levamlodipine of the present invention or the spansule of its salt, has the tablets in vitro of two-phase drug release behavior bent Line.

Figure 10 is the tablets in vitro that the levamlodipine of the present invention or the sustained-release tablet of its salt have two-phase drug release behavior Curve.

Figure 11 is that beasle dog takes orally blood medicine after the levamlodipine of the present invention or the sustained-release tablet and reference preparation of its salt Concentration time curve；

Specific implementation mode

The present invention provides a kind of levamlodipine or the sustained release preparation of its salt, containing sustained release mutually or containing quick-release phase and Sustained release phase within 6 hours to 14 hours deenergized periods, there is 90% weight or more in the dissolution medium for meeting sink conditions Active constituents of medicine release, active constituents of medicine here is levamlodipine or its salt.

To reach the release purpose of rapid-onset, preferably quick-release phase is mutually combined with sustained release, and release behavior is according to two-phase Release profile, the first phase are quick-release phase, and the second phase is sustained release phase.

" active constituents of medicine total amount " refers to the intact (sustained release phase or quick-release phase (if any) and sustained release phase) of the present invention Included in active constituents of medicine total amount.

The sustained release preparation of levamlodipine or its salt provided by the invention contains 2.5mg~20mg (with left-handed ammonia chlorine Flat meter) active constituents of medicine levamlodipine and its pharmaceutically acceptable salt, preferably Levamlodipine besylate.

The active constituents of medicine total amount of the sustained release preparation of levamlodipine or its salt based on the present invention, according to drug The sustained release preparation of the demand of specification and treatment, levamlodipine of the invention or its salt, quick-release phase pharmaceutical active ingredient account for 0wt%~50wt% of active constituents of medicine total amount, preferably 10wt%~45wt%, more preferably 15wt%~40wt%； Sustained release phase pharmaceutical active ingredient accounts for 50wt%~100wt%, the preferably 55wt%~90wt% of active constituents of medicine total amount, More preferably 60wt%~85wt%.

The sustained release preparation of the levamlodipine or its salt with two-phase drug release behavior of the present invention, the design of quick-release phase can To ensure discharging rapidly for drug well, meets the needs of drug rapid-onset, be rapidly achieved treatment concentration；Sustained release phase is set Meter can guarantee the steady release of active constituent, it is ensured that on blood pressure level higher daytime, active constituent sustained release makes hypertension The blood pressure held stationary of patient, and at blood pressure level lower night, plasma drug level can be adjusted correspondingly.

The levamlodipine of the present invention or the sustained release preparation of its salt, when the quick-release phase pharmaceutical active ingredient is 0wt%, when sustained release phase pharmaceutical active ingredient is 100wt%, that is, when only containing sustained release phase, according to Chinese Pharmacopoeia 2015 editions The requirement of drug release determination, in the dissolution medium for meeting sink conditions, active constituents of medicine discharges the time of 90wt% or more Preferably 6 hours to 12 hours.

The levamlodipine of the present invention or the sustained release preparation of its salt, when the quick-release phase pharmaceutical active ingredient is 0wt%~50wt%, when sustained release phase pharmaceutical active ingredient is 50wt%~100wt%, according to 2015 editions releases of Chinese Pharmacopoeia The requirement measured is spent, in the dissolution medium for meeting sink conditions, in the quick-release phase pharmaceutical active ingredient preferably 30 minutes There is 90wt% or more to discharge, there is 90wt% or more to discharge in more preferable 15 minutes；The sustained release phase pharmaceutical active ingredient release The time of 90wt% or more is preferably 6 hours to 14 hours, more preferably 6 hours to 12 hours.

The levamlodipine of the present invention or the sustained release preparation of its salt include quick-release phase carrier and sustained release phase carrier；Quick-release phase In the active constituents of medicine to be discharged be included in quick-release phase carrier, and the active constituents of medicine to be discharged includes in being sustained phase In sustained release phase carrier.

In the levamlodipine of the present invention or the sustained release preparation of its salt, the quick-release phase carrier is mutually carried with the sustained release Body, preferably capsule, tablet, double-layer tablets, coating tablet and its any form of combination.

Specifically, the quick-release phase carrier in the present invention is preferably but not limited to fast-release tablet or quick-release ball, the quick-release in tablet The quick-release coatings of matrix, the release layer in double-layer tablets, coating tablet or coated pellet；Sustained release phase carrier in the present invention is preferably but not It is limited to sustained release tablets or sustained release ball, the sustained-release matrix in tablet, the slow release layer in double-layer tablets, the sustained release tablets in coating tablet or coated pellet Core or sustained release capsule core.

The quick-release of the present invention is mutually a kind of rapid-release vehicle containing unit immediate release dose active constituents of medicine, and the quick-release carries Body be preferably but not limited to fast-release tablet, quick-release ball, the fast-release tablet for being formulated as several units or quick-release matrix in quick-release ball, tablet, The quick-release coatings that are wrapped in outside tablet or capsule core, the release layer matrix being attached in double-layer tablets and its any form of combination.

Correspondingly, the sustained release is mutually a kind of slow-released carrier containing unit sustained-release dosage active constituents of medicine, described slow Release the sustained release base that carrier is preferably but not limited to sustained release tablets, is sustained ball, is formulated as the sustained release tablets of several units or is sustained in ball, tablet Slow-released carrier in matter, tablet or capsule core, the slow release layer matrix being attached in double-layer tablets and its any form of combination.

The present invention levamlodipine or its salt sustained release preparation may be used capsule, tablet, double-layer tablets, coating tablet, The form of coated pellet realizes drug release behavior of the present invention.

1, capsule

The levamlodipine of the present invention or the capsule of one of the dosage form of sustained release preparation of its salt can in the following manner, Realize drug release behavior of the present invention.

(1) capsule containing quick-release ball 1 and sustained release ball 2, as shown in Figure 1

Quick-release ball 1 can be by passing through wet granulation, extrusion spheronization by active constituents of medicine, diluent and other auxiliary materials etc. It is prepared etc. conventional method well-known to those skilled in the art；Drug can also be lived in such a way that fluidized bed coating carries medicine Property ingredient, adhesive, diluent are dispersed or dissolved in coating solvent, are contained in being formed in blank capsule core.

Be sustained ball 2 can by by active constituents of medicine, sustained-release matrix matrix, hydrophilic polymers, diluent and its His auxiliary material etc. prepares matrix type sustained release by the conventional method well-known to those skilled in the art such as wet granulation, extrusion spheronization Ball；Active constituents of medicine can also be disperseed in such a way that fluidized bed coating carries medicine or be contained to carry medicine in formation in blank capsule core Then capsule core is formed in load one layer of extended release coatings membrane material of pill core outsourcing.

Above-mentioned quick-release ball and sustained release ball are proportionally weighed, is uniformly mixed, it is filling then to carry out capsule.

(2) contain the external coated pellet with quick-release coatings 5, inside with sustained release capsule core 6 (referred to as to contain quick-release to be coated Layer 5 coated pellet) capsule, as shown in Figure 3

Outside of the present invention with quick-release coatings 5, it is internal there is the coated pellet for being sustained capsule core 6, can be by will be upper The sustained release ball 2 stated in (1) carries out 5 operation preparation of subsequent packet quick-release coatings as sustained release capsule core 6.Specifically, can by institute Active constituents of medicine and suitable amount of adhesive are dispersed or dissolved in packet by the sustained release ball 2 stated in such a way that fluidized bed coating carries medicine In clothing solvent, the outside described on sustained release ball 2, being formed is contained with quick-release coatings 5, the internal packet with sustained release capsule core 6 Clothing ball；It is finally that the outside is filling with quick-release coatings 5, the internal coated pellet progress capsule with sustained release capsule core 6.

(3) capsule containing fast-release tablet 3 and sustained release tablets 4, as shown in Figure 2

The fast-release tablet 3 of the present invention can be by directly pressing the mixture of active constituents of medicine, diluent and other auxiliary materials It is prepared by piece.Any technical staff known selection to these functional excipients and diluent in this field.Alternatively, quick-release Piece 3 can be whole by by the mixture of active constituents of medicine, diluent and other auxiliary materials, being pelletized by the way of wet granulation Grain is simultaneously dry, lubricant is added, then carry out tabletting preparation.

The sustained release tablets 4 of the present invention can be by by active constituents of medicine, sustained-release matrix matrix, hydrophilic polymers, diluent And other auxiliary materials etc., it is equal by tabletting after the conventional method granulation well-known to those skilled in the art such as wet granulation or mixing Matrix sustained release tablet is prepared using direct tablet compressing after even；This fields staff such as fluid bed, high-efficiency coating pot can also be passed through Well known coating mode, is coated the fast-release tablet containing active constituents of medicine, in label expoeridium extended release coatings membrane material shape At.

Finally, it is filling to be subjected to capsule according to required active constituent dosage strengths for the fast-release tablet 3 and sustained release tablets 4.

2. tablet

The tablet of one of the sustained release preparation dosage form of levamlodipine or its salt of the invention can pass through as shown in Figure 4 The tablet being made of quick-release matrix 7 and sustained release ball 2, realizes drug release behavior of the present invention.

In the levamlodipine of the present invention or the sustained release preparation of its salt, the quick-release is mutually quick-release in the present embodiment Matrix, the sustained release are mutually sustained release ball；Gross weight based on active constituents of medicine is 100% weight meter, and the quick-release mutually contains The active constituents of medicine of 0wt%~50wt%, the sustained release mutually active constituents of medicine containing 50wt%~100wt% are described Active constituents of medicine in terms of levamlodipine gross weight be 2.5mg~20mg.

The tablet that the quick-release matrix 7 and sustained release ball 2 forms includes quick-release matrix 7 and sustained release ball in structure composition 2；The quick-release matrix 7 can be by being sufficiently mixed or passing through wet method system by active constituents of medicine, diluent and other auxiliary materials Grain is prepared.Wherein, the gross weight based on quick-release matrix is 100% weight meter, and the quick-release matrix includes 0wt%~5wt% Active constituents of medicine, the diluent of 50wt%~95wt% and other auxiliary materials of 1wt%~45wt%.

The sustained release ball 2 can by by active constituents of medicine, sustained-release matrix matrix, hydrophilic polymers, diluent with And other auxiliary materials etc. prepare matrix type by the conventional method well-known to those skilled in the art such as wet granulation, extrusion spheronization and delay Release ball；Active constituents of medicine can also be disperseed in such a way that fluidized bed coating carries medicine or be contained to carry in formation in blank capsule core Then pill core is formed in load one layer of extended release coatings membrane material of pill core outsourcing.Gross weight based on sustained-release coating layer is 100% weight Meter, the sustained-release coating layer include the active constituents of medicine of 1wt%~25wt%, 10wt%~70wt% extended release coatings membrane materials, The antiplastering aid of 1wt%~3wt%, the diluent of 0wt%~70wt% and other auxiliary materials of 0wt%~10wt%.

Finally, it by quick-release matrix 7 and sustained release ball 2, is uniformly mixed according to the specification ratio of active constituent, then by carrying spy The tablet press machine of different agitating function, it is tabletted.

3. double-layer tablets

The double-layer tablets of one of the dosage form of sustained release preparation of levamlodipine or its salt of the invention can be by with lower section Formula realizes drug release behavior of the present invention.

In the levamlodipine of the present invention or the sustained release preparation of its salt, the quick-release is mutually quick-release in the present embodiment Layer, the sustained release are mutually slow release layer；Gross weight based on active constituents of medicine is 100% weight meter, and the quick-release mutually contains 0wt% The active constituents of medicine of~50wt%, the sustained release mutually live by the active constituents of medicine containing 50wt%~100wt%, the drug Property ingredient gross weight in terms of levamlodipine is 2.5mg~20mg.

The double-layer tablets of the sustained release preparation of the levamlodipine or its salt with two-phase drug release behavior, are shown in Fig. 5 institutes Show, including quick-release matrix 8 and sustained-release matrix 9, respectively as the release layer and slow release layer in double-layer tablets；Wherein quick-release matrix 8 can By the way that active constituents of medicine, diluent and other auxiliary materials are sufficiently mixed or are prepared by wet granulation；Wherein, it is based on The gross weight of release layer is 100% weight meter, and the release layer includes the active constituents of medicine of 0wt%~10wt%, 50wt%~ The diluent of 95wt% and other auxiliary materials of 1wt%~45wt%.

Sustained-release matrix 9 can be by by active constituents of medicine, sustained-release matrix matrix, diluent and other auxiliary materials etc., passing through The conventional method well-known to those skilled in the art such as wet granulation is prepared；Gross weight based on slow release layer is 100% weight Meter, the slow release layer include the active constituents of medicine of 5wt%~10wt%, 10wt%~75wt% sustained-release matrix matrix, The diluent of 20wt%~60wt%, other auxiliary materials of 0.1wt%~20wt%.

Finally, it by quick-release matrix 8 and sustained-release matrix 9, is separately added into the hopper of tablet press machine, is pressed into double-layer tablets.

4. coating tablet

The coating tablet of one of the dosage form of sustained release preparation of levamlodipine or its salt of the invention can be by with lower section Formula realizes drug release behavior of the present invention.

When the quick-release phase pharmaceutical active ingredient is 0wt%, and sustained release phase pharmaceutical active ingredient is 100wt%, i.e., In the absence of the quick-release phase, as shown in Figure 6, can by by active constituents of medicine, hydrophilic polymers, osmotic pressure accelerating agent with And other auxiliary materials etc., it is pelletized after mixing by conventional method well-known to those skilled in the art, obtains medicine-containing particle；It will Promote osmopolymer, osmotic pressure accelerating agent and other auxiliary materials etc., is mixed by conventional method well-known to those skilled in the art Granulation, obtains boosting layer particle after uniformly；Medicine-containing particle and boosting layer particle are separately added into bi-layer tablet press, suppress double-layer tablets Core；Using coating method well-known to those skilled in the art, in double-deck core expoeridium extended release coatings membrane material；Using laser boring Machine is punched, and levamlodipine or the sustained release coating piece of its salt are formed.

When the quick-release phase pharmaceutical active ingredient is 0wt%~50wt%, sustained release phase pharmaceutical active ingredient is When 50wt%~100%, can by by active constituents of medicine, sustained-release matrix matrix, hydrophilic polymers, diluent and other Auxiliary material etc. uses by tabletting after conventional method well-known to those skilled in the art granulation or after mixing direct tablet compressing system Standby sustained release tablets (sustained release phase)；Then by the method using above-mentioned sustained release tablets (sustained release phase) expoeridium quick-release clothing layer (quick-release phase) Prepare the sustained release coating piece of levamlodipine or its salt with two-phase drug release behavior.

In the levamlodipine of the present invention or the sustained release preparation of its salt, the active constituents of medicine is levamlodipine And its pharmaceutically acceptable salt, preferably Levamlodipine besylate.

Diluent of the present invention is selected from following material well-known to those skilled in the art, microcrystalline cellulose, pre- glue Change one or more in starch, sucrose, mannitol, sorbierite, sucrose, starch, sodium carboxymethyl starch.

Sustained-release matrix matrix of the present invention includes following material well-known to those skilled in the art, hydroxy propyl cellulose Element, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, ethyl cellulose, sodium alginate, povidone, copolyvidone, One or more and their mixture in acrylic resin；Preferably hydroxypropyl cellulose.

Extended release coatings membrane material of the present invention includes following material well-known to those skilled in the art, acetate fiber In element, ethyl cellulose, acrylic resin, cellulose acetate-phthalate, hydroxypropyl methylcellulose acetate succinate It is one or more.

Osmotic pressure accelerating agent of the present invention includes following material well-known to those skilled in the art, sodium chloride, chlorine Change one or more in potassium, lactose, mannitol, sorbierite, glucose, sucrose, fructose.

Hydrophilic polymer of the present invention includes following material well-known to those skilled in the art, and povidone is total to Povidone, polyoxyethylene, carbomer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium alginate, Huang It is one or more in virgin rubber, Arabic gum, chitin.

Rush osmopolymer of the present invention includes following material well-known to those skilled in the art, polyoxyethylene, Hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, povidone In it is one or more.

Blank capsule core of the present invention is selected from cane sugar core, starch capsule core, microcrystalline cellulose pellet, silica ball One kind in core, hydroxypropyl cellulose capsule core.

One or more of other auxiliary materials, including lubricant, colorant, adhesive of the present invention；

Lubricant of the present invention is selected from magnesium stearate, stearic acid, sodium stearyl fumarate, talcum powder and superfine silica gel powder In it is one or more；

Colorant of the present invention is selected from iron oxide red, iron oxide yellow, iron oxide purple, iron oxide black, titanium dioxide In it is one or more.

Adhesive of the present invention be selected from hydroxypropyl methyl cellulose, povidone, copolyvidone, hydroxyethyl cellulose, One or more and their mixture in methylcellulose, hydroxypropyl cellulose.

In order to be more clearly understood that the technology contents of the present invention, spy are lifted following embodiment and are described in detail.All hundred Divide and be weight percentage than, unless otherwise specified.

Embodiment 1：Capsule containing sustained release ball

I pill core) is carried

II) packet barrier gown

III) packet extended release coatings

1.1 carry the preparation of medicine coating solution

It weighs adhesive (hydroxypropyl cellulose, copolyvidone or povidone) in right amount, is scattered in 95% ethanol solution, It is configured to the coating solution that solid content is 10%, is sufficiently mixed uniformly；The levamlodipine for weighing recipe quantity again, is uniformly dispersed It is spare as the load medicine coating solution of sustained release phase in above-mentioned coating solution.

1.2 carry medicine

Fluid bed is added in blank capsule core (microcrystalline cellulose pellet or cane sugar core), adjusts intake, inlet air temperature, mist Change the operating parameters such as pressure, sprays into prepared sustained release and mutually carry medicine coating solution, carry out load medicine, as load pill core；Sustained release is wrapped Clothing liquid aqueous dispersion (Sulisi or Utech) is added suitable aqueous solution and is diluted to the sustained release clothing film coating that solid content is 15% Liquid is injected to and is carried on pill core, sustained release ball is made by the way of the spray coating of fluid bed bottom.

Capsule is filling：It is filling to carry out capsule for the sustained release ball that above-mentioned preparation is completed.

Drug release determination (Rotating shaker)

This product is taken, according to dissolution method (four 0,931 first methods of Chinese Pharmacopoeia version in 2015), with hydrochloric acid solution (0.9 → 1000) 500mL be dissolution medium, rotating speed be 75 turns per minute, operate in accordance with the law, through 15min, 30min, 45min, 1h, 2h, When 4h, 6h, 8h, 10h, 12h, 14h, solution 5ml is taken, is centrifuged (8000rpm, 15min), while supplementing mutually synthermal, same volume Long-pending dissolution medium, takes supernatant as test solution；Separately take levamlodipine reference substance appropriate, accurately weighed, solubilization It is diluted in every 1mL containing about 20 μ g of levamlodipine with dissolution medium after agent dissolving, as a contrast product solution.Take above two Solution is measured by UV-VIS spectrophotometry (four general rules 0401 of Chinese Pharmacopoeia version in 2015) at the wavelength of 237nm Absorbance calculates every stripping quantity.

Wherein, 2 releasing result of prescription is shown in Fig. 8, and drug release 6 hours, drug release amount reaches 90%.

Embodiment 2：Capsule containing sustained release tablets

Preparation method is as follows：

By Levamlodipine besylate and diluent (mannitol), sustained-release matrix matrix (hydroxypropyl cellulose, poly- dimension Ketone, carbomer or polyoxyethylene), after mixing using equivalent gradually-increased, fluid bed is added；Using 80% ethanol solution as viscous Mixture is pelletized；It is dry to be less than 5% to moisture, 20 mesh sieves are crossed, magnesium stearate, mixing, as benzene sulfonic acid is then added Levamlodipine slow-releasing granules；According to recipe quantity, it is pressed into the suitable sustained release tablets of hardness.

Capsule is filling：It is filling to carry out capsule for the sustained release tablets that above-mentioned preparation is completed.

Drug release determination method is the same as embodiment 1；

Wherein, 4 releasing result of prescription is shown in Fig. 8, and drug release 10 hours, drug release amount reaches 90%.

Embodiment 3：The sustained release coating piece of the layer containing boosting

1. medicated layer

2. boosting layer

3. semi-transparent clothing film

4. moisture-proof clothing film

Preparation method is as follows：

The preparation of medicated layer：By maleic acid levo amido chloro diping and hydrophilic polymer (povidone, copolyvidone), oxidation After mixing using equivalent gradually-increased fluid bed is added in iron oxide yellow；Spray into 95% ethanol-water solution granulation；It dries to water Divide content to be less than 5%, cross 20 mesh sieve, whole grain obtains medicine-containing particle, magnesium stearate is then added, and mixing is spare；

The preparation of boosting layer：By sodium carboxymethyl starch, hydroxypropyl methyl cellulose K15M, sodium chloride, copolyvidone S630 And fluid bed is added after mixing in iron oxide red, sprays into 95% ethanol-water solution granulation；Drying to moisture is less than 5%, 20 mesh sieve is crossed, whole grain obtains boosting layer particle, then, magnesium stearate is added, mixing is spare；

The compacting of double-deck core：Medicated layer that above-mentioned preparation is completed, boosting layer are according to recipe quantity, using bi-layer tablet press It is pressed into the suitable double-deck core of hardness；

Packet extended release coatings：Cellulose acetate is dissolved in acetone soln, Macrogol 4000 is dissolved in aqueous solution, two kinds molten Liquid is hybridly prepared into semi-permeable membrane coating solution；The double-deck core of above-mentioned inspection qualification is set in high-efficiency coating pot, using semi-permeable membrane packet Clothing liquid is coated；Product after coating is 12 hours dry under the conditions of 45 DEG C, removes extra organic solvent and moisture；

The punching of coating tablet：By the way of laser boring, an a diameter of 0.9mm is broken into the drug containing layer surface of tablet Release hole；

Wrap moisture-proof clothing：It by Opadry coating powder, is dissolved in and being dispersed in water, be configured to moisture-proof clothing Coating Solution；Then it will beat Controlled release tablet behind hole is coated using moisture-proof clothing Coating Solution；Under the conditions of 45 DEG C, dry 12 hours to get.

Drug release determination (paddle method)

This product is taken, according to dissolution method (four 0,931 second methods of Chinese Pharmacopoeia version in 2015), with hydrochloric acid solution (0.9 → 1000) 500mL be dissolution medium, rotating speed be 75 turns per minute, operate in accordance with the law, through 15min, 30min, 45min, 1h, 2h, When 4h, 6h, 8h, 10h, 12h, 14h, solution 5ml is taken, is centrifuged (8000rpm, 15min), while supplementing mutually synthermal, same volume Long-pending dissolution medium, takes supernatant as test solution；Separately take maleic acid levo amido chloro diping reference substance appropriate, precision claims It is fixed, it is diluted in every 1mL containing about 20 μ g of maleic acid levo amido chloro diping with dissolution medium after solubilizer dissolving, product are molten as a contrast Liquid.Above two solution is taken, according to UV-VIS spectrophotometry (four general rules 0401 of Chinese Pharmacopoeia version in 2015), Absorbance is measured at the wavelength of 237nm, calculates every stripping quantity.

Wherein, 9 releasing result of prescription is shown in Fig. 8, and drug release 12 hours, drug release amount reaches 90%.

Embodiment 4：Capsule containing quick-release ball and sustained release ball

1. quick-release ball

2. being sustained ball

I pill core) is carried

II) packet barrier gown

III) packet extended release coatings

Preparation method is as follows：

Quick-release ball：Levamlodipine and adhesive (copolyvidone) are dissolved or dispersed in 95% ethanol solution, It is made the load medicine coating solution of quick-release phase；By blank capsule core (microcrystalline cellulose pellet or cane sugar core) be added fluid bed, adjust into The operating parameters such as air quantity, inlet air temperature, bed temperature, flow velocity, atomizing pressure spray into prepared quick-release and mutually carry medicine coating solution, as Quick-release ball.

It is sustained ball：

1.1 carry the preparation of medicine coating solution

It weighs adhesive (copolyvidone or povidone) in right amount, is scattered in 95% ethanol solution, is configured to solid content For the coating solution of 10% povidone, it is sufficiently mixed uniformly；The levamlodipine for weighing recipe quantity again is evenly dispersed in above-mentioned It is spare as the load medicine coating solution of sustained release phase in coating solution.

1.2 carry medicine

Fluid bed is added in blank capsule core (microcrystalline cellulose pellet or cane sugar core), adjusts intake, inlet air temperature, mist Change the operating parameters such as pressure, sprays into prepared sustained release and mutually carry medicine coating solution, carry out load medicine, as load pill core；Sustained release is wrapped Clothing liquid aqueous dispersion (Sulisi, Utech) is added suitable aqueous solution and is diluted to the sustained release clothing film coating that solid content is 15% Liquid is injected to and is carried on pill core, sustained release ball is made by the way of fluidized bed coating.

Capsule is filling：The quick-release ball and sustained release ball that above-mentioned preparation is completed, after being mixed well according to prescription ratio, carry out glue Capsule is filling.

Drug release determination method is the same as embodiment 1；

Wherein, 10 releasing result of prescription is shown in Fig. 9, and drug release, mutually drug release amount reaches immediate release dose to 15 minutes quick-releases 90%, mutually drug release amount reaches the 90% of sustained-release dosage to 6 hours sustained releases, and drug release amount reaches active constituents of medicine total amount within 6 hours 90%.

Embodiment 5：The capsule formed containing fast-release tablet and sustained release tablets

1. fast-release tablet

2. sustained release tablets

Preparation method is as follows：

Fast-release tablet：By Levamlodipine besylate and diluent (microcrystalline cellulose, pregelatinized starch or mannitol), adopt After mixing with equivalent gradually-increased, fluid bed is added；It is pelletized using aqueous solution as adhesive；Drying to moisture is less than 5%, 20 mesh sieves are crossed, magnesium stearate, mixing, as Levamlodipine besylate immediate-release granules is then added；According to place Fang Liang is pressed into the suitable fast-release tablet of hardness.

Sustained release tablets：By Levamlodipine besylate and diluent (mannitol), sustained-release matrix matrix (hydroxy propyl cellulose Element, povidone, carbomer or polyoxyethylene), after mixing using equivalent gradually-increased, fluid bed is added；It is molten with 80% ethyl alcohol Liquid is pelletized as adhesive；It is dry to be less than 5% to moisture, 20 mesh sieves are crossed, magnesium stearate is then added, mixing is made For Levamlodipine besylate slow-releasing granules；According to recipe quantity, it is pressed into the suitable sustained release tablets of hardness.

Capsule is filling：The fast-release tablet and sustained release tablets that above-mentioned preparation is completed combine mixing according to prescription ratio, carry out capsule It is filling.

Drug release determination method is the same as embodiment 1；

Wherein, 13 releasing result of prescription is shown in Fig. 9, and mutually drug release amount reaches the 90% of immediate release dose to 15 minutes quick-releases, and 8 hours slow It releases mutually drug release amount and reaches the 90% of sustained-release dosage, 8 hours drug release amounts of drug release reach the 90% of active constituents of medicine total amount.

Embodiment 6：Capsule prepared by the coated pellet of the coatings containing quick-release

I pill core) is carried

II) packet barrier gown

III) packet extended release coatings

IV) packet quick-release clothing

Preparation method is as follows：

Carry medicine：First, by maleic acid levo amido chloro diping and adhesive (hydroxypropyl cellulose, copolyvidone or poly- dimension Ketone), it is dissolved or dispersed in 95% ethanol solution, is configured to carry drug solns, by the way of fluidized bed coating, spray into recipe quantity Blank capsule core (microcrystalline cellulose or cane sugar core) on, as carry pill core；

Packet extended release coatings：Suitable aqueous solution dilution, mixing, as sustained release clothing film packet is added in sustained release coating liquid aqueous dispersion Clothing liquid is injected to and is carried on pill core, sustained release ball is made by the way of fluidized bed coating.

Packet quick-release clothing：It is scattered in maleic acid levo amido chloro diping and adhesive in 95% ethanol solution, mixing, makees It is injected on sustained release ball by the way of fluidized bed coating for quick-release clothing coating solution, the coating containing quick-release coatings is made Ball.

Capsule is filling：The coated pellet containing quick-release coatings that above-mentioned preparation is completed carries out capsule filling according to recipe quantity Dress.

Drug release determination method is the same as embodiment 1；

Wherein, 18 releasing result of prescription is shown in Fig. 9, and drug release, mutually drug release amount reaches immediate release dose to 30 minutes quick-releases 90%, mutually drug release amount reaches the 90% of sustained-release dosage to 12 hours sustained releases, and drug release amount reaches active constituents of medicine total amount within 12 hours 90%.

Embodiment 7：The tablet being made of quick-release matrix and sustained release ball

1. quick-release matrix (1000)

2. being sustained ball

I pill core) is carried

II) packet extended release coatings

Preparation method is as follows：

Quick-release matrix：By levamlodipine and diluent (pregelatinized starch, mannitol or microcrystalline cellulose), using etc. Amount progressively increases method after mixing, and fluid bed is added；Spray into the granulation of 10% povidone aqueous solution；Drying to moisture is less than 5%, 20 mesh sieve is crossed, then magnesium stearate, mixing, as levamlodipine quick-release matrix is added in whole grain.

It is sustained ball：First, it by levamlodipine and adhesive (hydroxypropyl cellulose, povidone), is dissolved or dispersed in In aqueous solution, it is configured to load drug solns and sprays into the blank capsule core (microcrystalline cellulose of recipe quantity by the way of fluidized bed coating Or cane sugar core) on, as load pill core；Extended release coatings membrane material (ethyl cellulose or acrylic resin), talcum powder are distinguished It is scattered in suitable ethanol solution, mixing, load is injected to by the way of fluidized bed coating as sustained release clothing film coating liquid On pill core, sustained release ball is made.

Tabletting：Quick-release matrix that above-mentioned preparation is completed, sustained release ball are uniformly mixed according to recipe quantity, it is suitable to be pressed into hardness Tablet.

Drug release determination method is the same as embodiment 3；

Wherein, 20 releasing result of prescription is shown in Figure 10, and drug release, mutually drug release amount reaches immediate release dose to 15 minutes quick-releases 90%, mutually drug release amount reaches the 90% of sustained-release dosage to 10 hours sustained releases, and drug release amount reaches active constituents of medicine total amount within 10 hours 90%.

Embodiment 8：Quick-release matrix and the substrate composed double-layer tablets of sustained release

1. quick-release matrix (1000)

2. sustained-release matrix

Preparation method is as follows：

Quick-release matrix：By Levamlodipine besylate and diluent, (microcrystalline cellulose, mannitol, gathers pregelatinized starch Tie up ketone), after mixing using equivalent gradually-increased, fluid bed is added；It is pelletized using aqueous solution as adhesive；Drying to moisture contains Amount is less than 5%, crosses 20 mesh sieve, then magnesium stearate, mixing, as Levamlodipine besylate quick-release matrix is added in whole grain.

Sustained-release matrix：By Levamlodipine besylate and diluent (mannitol, copolyvidone), sustained-release matrix matrix After mixing using equivalent gradually-increased stream is added in (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose) Change bed；It is pelletized using 95% ethanol solution as adhesive；It is dry to be less than 5% to moisture, 20 mesh sieve is crossed, then whole grain adds Enter magnesium stearate, mixing, as Levamlodipine besylate sustained-release matrix.

Tabletting：Quick-release matrix that above-mentioned preparation is completed, sustained-release matrix are pressed into according to recipe quantity using bi-layer tablet press The suitable double-layer tablets of hardness.

Drug release determination method is the same as embodiment 3；

Wherein, 22 releasing result of prescription is shown in Figure 10, and drug release, mutually drug release amount reaches immediate release dose to 15 minutes quick-releases 90%, mutually drug release amount reaches the 90% of sustained-release dosage to 8 hours sustained releases, and drug release amount reaches active constituents of medicine total amount within 8 hours 90%.

Embodiment 9：Sustained release coating piece containing quick-release coatings

1. the preparation (1000) of sustained release tablets

2. packet quick-release clothing

Preparation method is as follows：

The preparation of maleic acid levo amido chloro diping sustained release tablets：By maleic acid levo amido chloro diping and sustained-release matrix matrix (hydroxyl Propyl cellulose), adhesive (copolyvidone), after mixing using equivalent gradually-increased, be added fluid bed；Spray into 85% ethyl alcohol Aqueous solution is pelletized；It is dry to be less than 5% to moisture, 20 mesh sieve is crossed, then magnesium stearate is added in whole grain, then mixing is suppressed At the suitable sustained release tablets label of hardness；

Packet quick-release clothing：According to quick-release clothing prescription prepare quick-release clothing coating solution, by above-mentioned sustained release tablets set in high-efficiency coating pot into Scanning frequency releases clothing coating；It is 12 hours dry under the conditions of 45 DEG C, remove extra organic solvent and moisture；

Drug release determination method is the same as embodiment 3；

Wherein, 25 releasing result of prescription is shown in Figure 10, and drug release, mutually drug release amount reaches immediate release dose to 30 minutes quick-releases 90%, mutually drug release amount reaches the 90% of sustained-release dosage to 14 hours sustained releases, and drug release amount reaches active constituents of medicine total amount within 14 hours 90%.

Embodiment 10：Beagle dog Internal pharmacokinetics are studied

Healthy Beagle dogs 6, male 3, female 3,8~10kg of weight range, are randomly divided into two groups, every group 3, Single dose medicine-feeding test is carried out, dosage is 10mg/.Two groups of Beagle dogs give commercially available product (reference preparation (factory respectively Family：Shihuida Pharma Group (Jilin) Co., Ltd., the name of an article：Levamlodipine, specification：5mg/ pieces, totally 2) and benzene sulfonic acid it is left-handed Amlodipine sustained release tablets (make tablet recipe 20,22,25, specification by oneself in embodiment 7,8,9：10mg/ pieces, totally 1), every Beagle Dog takes for 0.5,1,2,3,4,5,6,8,10,12,16,24 and 50 hour before medication after (0h), medication in dog side foreleg vein Blood 2mL, sets in heparinised tubes, centrifuges (5000rpm, 10min), isolates blood plasma, frozen in -80 DEG C, for use；

Using the concentration of Levamlodipine besylate in liquid chromatography-tandem mass spectrometry blood plasma, internal blood medicine is dense Degree-time graph the result is shown in Figure 11.The result shows that the levamlodipine in quick-release phase can ensure that primary drugs are fast well Quick-release is put, and meets the needs of drug rapid-onset；It is sustained phase release time maintenance about 6 hours to 14 hours, is maintained more stable Blood concentration avoids blood pressure fluctuation of concentration, safer effective；This product can be in the single-dose for improving levamlodipine Dosage provides that a kind of compliance is good, adverse reaction is few on the basis of enhancing therapeutic effect, can quick acting, maintain to have for a long time Imitate the new sustained release preparation of blood concentration.

The present inventor is by the research to the physicochemical property of levamlodipine, stability and biological property, according to facing The treatment of bed needs and the demand of the compliance of patient medication, devises a kind of levamlodipine or the sustained release preparation of its salt, It has the following advantages that：

Compared with common quick release preparation

1. the sustained release of drug can be realized, the fluctuation of lasting medicine, blood concentration is small, reduces the bad of patient medication Reaction；

2. unit dosage form can be improved, during reducing ordinary preparation medication, the complicated processes of dosage adjustment, more Facilitate clinical application；

3. wherein, sustained release pellet also have the advantages that can dose fractionation, remain to keep original sustained release property after segmentation, be Clinic provides more flexible dosage.

Compared with common sustained release preparation

1. having slow drug release behavior, the principle of chronopharmacology is conformed better to, it can be (white in the physiological period of needs It) sustained release, it reduces blood pressure, and at activity level lower night, plasma drug level can be adjusted correspondingly, and be subtracted The generation of few drug resistance；

2. the quick-release with two-phase drug release behavior it is dense can to reach treatment with rapid-onset after mutually designing guarantee drug administration Degree, the design for being sustained phase ensures that the steady release of later stage active constituent, keeps relative constant blood concentration, reduction due to Adverse reaction caused by blood concentration is excessively high；

3. need to only take once daily, it is more suitable for the hypertension and patient with angina pectoris long-term administration of moderate and severe；

Therefore, the advantageous effect of this preparation is the drug release of the sustained release preparation of levamlodipine or its salt based on the present invention What behavior advantage embodied, it is embodied in：

(1) sustained release preparation with two-phase drug release behavior, the design of quick-release phase, it is ensured that risen rapidly after drug administration Effect；It is sustained the design of phase, then can make drug (daytime) sustained release in the physiological period of needs, reduce blood pressure, and in activity Horizontal lower night, plasma drug level can be adjusted correspondingly；

(2) dosage can be improved, eliminate the complicated processes of dosage adjustment, need to only take primary, gastrointestinal irritation daily Small, the good patient compliance of property；

(3) blood concentration is more steady, and adverse reaction is few, and medication is safer, is more suitable for the hypertension of moderate and severe And patient with angina pectoris long-term administration.

To sum up, the sustained release preparation of levamlodipine of the invention or its salt is easy to use, and curative effect of medication is high, takes and complies with Property it is good, adverse reaction is few, can quick acting, and for a long time maintain steady effective blood drug concentration, it is ingenious in design, it is simple for structure, tool There is good stability, is suitable for large-scale promotion application.

It can be seen that the purpose of the present invention is achieved completely and effectively.The function and structural principle of the present invention It is shown and is illustrated in embodiment, under without departing substantially from the principle, embodiment can make arbitrary modification.So this hair Bright includes all variant embodiments based on claim spirit and right.

Claims

1. the sustained release preparation of a kind of levamlodipine or its salt, it is characterised in that be by the piece of quick-release phase and sustained release phase composition Agent, the quick-release are mutually coated on outside the sustained release phase, wherein：

Mutually the part containing active constituents of medicine, the sustained release mutually contain its remaining part of the active constituents of medicine to the quick-release Point, a part for the active constituents of medicine is less than the pharmaceutical activity more than 0% weight of the active constituents of medicine The rest part of 50% weight of ingredient, the active constituents of medicine is small more than the active constituents of medicine of 50% weight In 100% weight of the active constituents of medicine；

The quick-release is mutually quick-release matrix, a part for the active constituents of medicine is contained in the quick-release matrix, pregelatinated forms sediment Powder, mannitol, microcrystalline cellulose, povidone and magnesium stearate；

It is described sustained release mutually be sustained release ball, it is described sustained release ball carry pill core in containing the active constituents of medicine rest part, The extended release coatings of microcrystalline cellulose pellet, cane sugar core, hydroxypropyl cellulose and povidone, the sustained release ball contain ethyl cellulose Element, acrylic resin and talcum powder；

The active constituents of medicine is levamlodipine or its salt, and the active constituents of medicine is in terms of the levamlodipine It is 2.5mg~20mg in the dissolution medium for meeting sink conditions, more than 90% weight of the active constituents of medicine at 6 hours It is discharged in 14 hours deenergized periods.

2. the sustained release preparation of a kind of levamlodipine or its salt, it is characterised in that it is the capsule containing quick-release phase and sustained release phase, The quick-release phase is mutually respectively independent with the sustained release, wherein：

The quick-release is mutually quick-release ball, and a part, the microcrystalline cellulose vegetable pill of the active constituents of medicine are contained in the quick-release ball Core, cane sugar core and copolyvidone；

The sustained release is mutually sustained release ball, and the load pill core of the sustained release ball contains the rest part, micro- of the active constituents of medicine The extended release coatings of crystalline cellulose capsule core, cane sugar core, hydroxypropyl cellulose, copolyvidone and povidone, the sustained release ball contain Sulisi and Utech；

3. the method for preparing the sustained release preparation as described in one of above claim, it is characterised in that include the following steps：

(1) part for the active constituents of medicine is included in the quick-release phase, by the active constituents of medicine Rest part is included in the sustained release phase；

(2) make the quick-release phase mutually respectively independent with the sustained release, or the quick-release is mutually coated on outside the sustained release phase.