CN106420738A

CN106420738A - Sustained release preparation of levamlodipine besylate tablets or salts thereof and preparation method of sustained release preparation

Info

Publication number: CN106420738A
Application number: CN201610898040.1A
Authority: CN
Inventors: 甘勇; 朱春柳; 刘彦; 朱全垒
Original assignee: 杨彦玲
Current assignee: Shihuida Pharma Group (Jilin) Co., Ltd.
Priority date: 2016-10-14
Filing date: 2016-10-14
Publication date: 2017-02-22
Anticipated expiration: 2036-10-14
Also published as: CN107320462A; CN106420738B; CN107320462B

Abstract

The invention provides a sustained release preparation of levamlodipine besylate tablets or salts thereof. The sustained release preparation comprises a quick release phase and a sustained release phase, wherein the quick release phase and the sustained release phase respectively independent or the quick release phase wraps the sustained release phase; the quick release phase contains part of active ingredients of the medicine; the sustained release phase contains the rest part of the active ingredients of the medicine; the active ingredients of the medicine comprise the levamlodipine besylate tablets or the salts thereof, and are counted as 2.5 mg-20 mg as the levamlodipine besylate tablets, and in a release medium which meets a sink condition, more than 90% by weight of the active ingredients of the medicine are released in a release period of 6-14 hours. The sustained release preparation cannot comprise the quick release phase. The invention further provides a related preparation method. The sustained release preparation of levamlodipine besylate tablets or salts thereof is convenient to use, high in curative effect, good in taking compliance and less in adverse reaction, and can take effect quickly. Stable and effective blood concentration can be maintained for a long time. The sustained release preparation is skillful in design and simple in structure, has good stability and is suitable for large-scale popularization and application.

Description

A kind of slow releasing preparation of Levamlodipine or its salt and preparation method thereof

Technical field

The present invention relates to technical field of medicine, more particularly to medicament slow release preparation technical field, specifically refers to one kind Slow releasing preparation of Levamlodipine or its salt and preparation method thereof.

Background technology

With the raising of living standards of the people, cardiovascular disease has become the primary disease of China's cause of death, is prestige Side of body people's health and " number one killer " of life.More than 18 years old adult hypertension prevalence of China is up to 33.5%, and total number of persons surpasses 3.3 hundred million are crossed, the whole world is every year because of the death toll up to 9,400,000 that hypertension and its complication cause, and wherein China there are about 200 every year Ten thousand people die from hypertension.With being further exacerbated by for China's aging degree, the M ＆ M of hypertension still has year by year Elevated trend.

Although people achieve many progress in terms of prevention, detection and the treatment of hypertension and coronary heart disease in recent years, Hypertension is still an important public health problem.For many patients, the mode of making the life better e insufficient to control disease Process, it is necessary to while giving Drug therapy.Clinical trial confirms, target control treatment can reduce cardiovascular danger, and protect with kidney Shield effect and the danger of reduction cerebrovascular events, good Drug therapy is for prolongation hyperpietic's life and life matter Amount has positive meaning.

Hypertension is both the common complication of chronic glomerulonephritiss, be again cause glomerular capillary inner high voltage power and Height is filtered and promotes glomerular sclerosiss, further one of key factor of infringement kidney.Therefore, reduce blood pressure, delay renal function Deteriorate, the renal function of protection kidney patient is the important step for treating chronic glomerulonephritis patients, the high blood of good treatment Pressure strategy should stablize blood pressure lowering again can be while provide protective effect for kidney, the prevention renal function impaired because of hypertension enters One step deteriorates.Therefore, the medicine that finds effective blood pressure lowering and improve renal function becomes the focus of clinical research.

So far, clinical conventional antihypertensive drug mainly has 6 big class：Calcium ion antagonist (abbreviation Ca2+ overloading Agent), diuretic, beta-blocker, alpha-blocking agent, angiotensin converting enzyme inhibitor (ACEI) and angiotensin II receptor antagonist (ARB).In the antihypertensive drug of all categories, calcium ion antagonist can reduce Stroke risk rate Evident in efficacy, and have resisting coronary heart disease angina pectoriss to act on, it has no adverse effects to blood-fat and blood sugar metabolism and Water-Electrolyte, and patient takes Medicine compliance height, life-time service is still effective.Just because of calcium ion antagonist has above remarkable treatment characteristic, in recent years respectively Treatment Guidelines for Hypertension (as JNC- VII,《Chinese hypertension prevention and control guide》) in all using calcium ion antagonist medicine as recommending The first-line drug that hyperpietic uses.

Levamlodipine besylate is the dihydropyridine calcium ion agonist drug that a new generation has cardioselective, uses In various Hypertension populations are treated, it can block cardiac muscle and the outer calcium ion of vascular smooth muscle cell leads to toward the calcium ion of cell membrane Road enters intracellular.In addition, this kind of medicine also has prominent advantage：Pressure reduction does not reduce the important vital organ such as the heart, brain, kidney Blood flow；The metabolite such as blood glucose, blood fat are had no adverse effects；Little on myocardial contraction and Atrioventricular Conduction impact；Secondary work With less.Further, since its height to petty action smooth muscle is selected, to the adrenal gland of vein smooth muscle, there is slight row's sodium profit Urine is acted on, and so that water sodium is reduced in reabsorption, is not caused water-sodium retention, all effective to constitutional and secondary hypertension.

Levamlodipine besylate, chemical name：(S)-(-) 3- ethyl 5- methyl -2- (2- ammonia ethoxymethyl) -4- (2- chlorphenyl)-Isosorbide-5-Nitrae-dihydro -6- methyl -3,5- pyridine dicarboxylate benzene sulfonate, is China's the first chiral separation optical voidness Medicine, and world's the first chiral separation antihypertensive drug.Individually or with other drugs can merge use, with resisting hypertension With treatment angina pectoriss effect, clinically have and preferably applied.

Levamlodipine besylate absorbed following oral administration is complete, and 6-12 hour blood drug level peaks.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 drug level reach surely State.Being eliminated from blood plasma in the way of two-compartment model after absorption, inactive metabolite (90%) is extensively metabolized as in liver.Eventually It is 35 hours that end eliminates half-life healthy person, and hypertensive patient is extended for 50 hours, old people 65 hours, liver function damage person 60 Hour, renal insufficiency person is unaffected.This product 10% is discharged from urine in the form of metabolite with prototype, 60%, 20%- 25% discharges from bile or feces.Levamlodipine besylate can not be removed by hemodialysis, and renal insufficiency person is to benzene sulphur The pharmacokinetic characteristics of sour Levamlodipine have no significant effect.Gerontal patient and hepatic insufficiency 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 amplitude of middle Serious heart Failure patient is similar.

Compared with other depressor, it is long that Levamlodipine besylate has a drug effect, and hypotensive effect is slowly lasting, Bu Zhizao Hypertension rebound effect after becoming hypotension and being discontinued, tissue selectivity vasoactive rather than heart, can be used safely in the heart The patient of force failure, bioavailability height, the process of left ventricular hypertrophy can be delayed, can be used in combination with other drugs and not receive The advantages of impact of dietary intake.Additionally, Levamlodipine besylate is a kind of effective antianginal drug, especially to hat Arteries and veins spasmodic angina is more effective, and it has higher affinity to blood vessel, and can significantly extend Ischemic Cardiomyopathy Movement time and move to the angina pectoris attacks time, reduce the consumption of anginal attack times and nitroglycerin.

At present, clinical conventional amlodipine formulation is to use conventional tablet, mainly for light, moderate hypertension patient. According to the literature, it is research therapeutic effect and its safety of the amlodipine to hypertension, have chosen 100 hyperpietics Research is included, is randomly divided into matched group and treatment group, each 50.Treatment group is treated using amlodipine, and matched group uses nitre Benzene Horizon slow releasing tablet is treated.Two groups of patients' medication situations, antihypertensive effect, untoward reaction etc. are carried out observing and relative analyses.Knot Fruit shows, after treatment group's medication, total effective rate reaches 92%, higher than 74% (P of matched group<0.05).After treatment end, treatment group Untoward reaction rate is 8%, is mainly shown as dizzy, weak, headache, flush, lower limbs edema, nasal obstruction, cardiopalmus etc..Less than right According to 16% for organizing, adverse events are mainly shown as dizzy, weak, headache, flushing, insomnia, dry cough, skin rubefaction with slight skin Rash, nasal obstruction, cardiopalmus etc..In general, the clinical effectiveness of amlodipine is good, safe, and energy effective control simultaneously reduces blood pressure, With clinical expansion meaning.

At present, conventional Levamlodipine besylate preparation is conventional tablet, clinically widely uses, main pin Light, moderate hypertension patient is used；During clinical application, Levamlodipine besylate ordinary preparation remain following not Foot part：1. the general initial dose of this product should gradually adjust dosage from the beginning of low dose, and loaded down with trivial details dose titration process is to clinic Medication brings certain inconvenience；2. the curative effect of the hypertension and patient with angina pectoris of alignment degree and severe is not good enough；3. the high blood of severe The medication that generally needs on pressure patient clinical that 2 times a day, is easily caused bad kickback of using medicine (including postural hypotension, headache, head The symptoms such as portion's heating, edema).

Through patent retrieval, the formulation patent ublic specification of application relevant 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), benzenesulfonic acid ammonia chlorine ground Flat micro-balloon injection (CN101530396A) etc., 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 this 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 5～55g of element, preferably 20～40g, particularly preferably 30g；2～20g of crospolyvinylpyrrolidone, preferably 5g；Stearic acid 0.5～2.5g of magnesium, preferably 1.5g.

Chinese patent application prospectus CN101766582A provide a kind of tablet of Levamlodipine besylate and Its preparation method.The tablet is by the label with Levamlodipine besylate as active component and to be wrapped in outer membrane clothing group Become, wherein the diluent in label contains one or two in kieselguhr and differential silica gel, also containing pharmaceutically acceptable Other adjuvants, outer membrane clothing accounts for the 8%～12% of piece weight, can play a part of protection against the tide, lucifuge, obtains medicine stability Large increase.

Chinese patent application prospectus CN102846565A discloses a kind of system of Levamlodipine beaylate tablets Preparation Method, is mixed after Levamlodipine besylate, filler, disintegrating agent are pulverized and sieved, and adds lubricant granulation, pressure Piece.Levamlodipine beaylate tablets are prepared using the method for fluid-bed marumerization, reduces Levamlodipine besylate The relevant material of piece, improves stability, while simplifying preparation process, shortening the time, optimizing technological parameter, notable increasing The dissolution of product, improve product quality are added.

Chinese patent application prospectus CN101947210A discloses a kind of Levamlodipine besylate liposome Tablet, and its application in the medicine for preparing treatment essential hypertension.The Levamlodipine besylate liposome Tablet includes the material of following weight ratio：Levamlodipine besylate：Egg Yolk Lecithin (PC-98T)：Cholesterol：Poloxamer 188： Other pharmaceutically acceptable excipient=1：4-10:0.5-5:1-3:35-50.The liposome tablet of this invention greatly improves a benzenesulfonic acid left side The stability of rotation amlodipine and dissolution, 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, its formula is made up of Levamlodipine besylate, drop pill substrate, antioxidant, surfactant, coating material etc., Its preparation method is first Levamlodipine besylate to be prepared into the fine powder that fineness is more than 150 mesh.Take the base of formula ratio After matter heating melting, plus Levamlodipine besylate fine powder and relevant adjuvant, dispersion liquid is mixed into, is instilled in condensed fluid, drop Ball is made, makes coating or not coated drop pill.

Chinese patent application prospectus CN101530396A discloses a kind of preparation method of amlodipine microsphere, The medicine wrapped up by the microsphere for preparing is amlodipine and its organic salt, and the carrier material of the microsphere is polylactic acid (PLA), gathers The Biodegradable material such as lactic acid-hydroxyacetic acid copolymer (PLGA) or PLA-mPEG (PLA-mPEG), and Using surfactant solution, monosaccharide or polysaccharide solution, polyhydric alcohol solutions, cellulose solution, colloidal solution as disperse medium, lead to Emulsion solvent evaporation is crossed, under mechanical agitation or high speed shear effect, is prepared into amlodipine microsphere.The load of the patent application Medicine microsphere can subcutaneous injection use, in vivo with macromolecular material degraded and delay Slow release, rate of release is approximate Zero-order release profile, drug percutaneous undertissue absorbed into serum, the maintenance level of blood drug level long-time (2 weeks-March) can be maintained, Compared with common tablet, it is to avoid the blood drug level change that frequent oral medication brings, the generation of toxic and side effects is reduced, carry The drug safety of high patient.

In above-mentioned patent retrieval, the relevant report that has no with regard to Levamlodipine besylate oral slow-releasing preparation.Research Show, Levamlodipine removes dextrorotation composition, can reduce adverse reaction rate to a certain extent.But due to the high blood of kidney Pressure, often needs heavy dose for the treatment of, and patient is also easy to produce some side effect, the such as blood vessel such as flushed face, dizziness, headache, lower limbs edema Expansion reaction etc..And gerontal patient's dosage should start gradually to adjust dosage from low dose of when starting treatment, treat that patient can Therapeutic dose is gradually increased to during tolerance again.

It can be seen that, still have the following disadvantages during the ordinary preparation clinical application of Levamlodipine besylate：① Initial dose gradually should adjust dosage from the beginning of low dose, and loaded down with trivial details dose titration process brings certain to clinical application Inconvenience；2. the curative effect of the hypertension and patient with angina pectoris of alignment degree and severe is not good enough；3. on renal hypertension patient clinical generally Heavy dose for the treatment of is needed, and bad kickback of using medicine is easily caused (including diseases such as postural hypotension, headache, Head And Face heating, edema Shape), the fluctuation of blood drug level is larger.

For improving the clinical efficacy of Levamlodipine further, reduce hyperpietic (renal hypertension patient) medication Untoward reaction afterwards, increases the compliance of patient's medication, needs to carry out rational dosage form and Formulation, optimizes left-handed ammonia chlorine ground Flat release behavior, makes medicine while untoward reaction is reduced, plays maximum curative effect.

Accordingly, it is desirable to provide the slow releasing preparation of a kind of Levamlodipine or its salt, which is easy to use, curative effect of medication height, Take compliance good, untoward reaction is few, can quick acting, and long-time maintain steady effective blood drug concentration.

Content of the invention

In order to overcome above-mentioned shortcoming of the prior art, it is an object of the present invention to provide a kind of Levamlodipine Or the slow releasing preparation of its salt, which is easy to use, curative effect of medication height, takes that compliance is good, and untoward reaction is few, is suitable to large-scale promotion Application.

Another object of the present invention is to providing the slow releasing preparation of a kind of Levamlodipine or its salt, which quickly can rise Effect, and long-time maintains steady effective blood drug concentration, is suitable to large-scale promotion application.

Another object of the present invention is to providing the slow releasing preparation of a kind of Levamlodipine or its salt, its design is ingenious, Simple for structure, with good stability, it is suitable to large-scale promotion application.

Another object of the present invention is to a kind of preparation method of the slow releasing preparation of Levamlodipine or its salt is provided, its Design is ingenious, prepares simplicity, and the slow releasing preparation of obtained Levamlodipine or its salt is easy to use, curative effect of medication height, takes Compliance is good, and untoward reaction is few, is suitable to large-scale promotion application.

Another object of the present invention is to a kind of preparation method of the slow releasing preparation of Levamlodipine or its salt is provided, its Design is ingenious, prepare easy, the slow releasing preparation of obtained Levamlodipine or its salt can quick acting, and long-time remains flat Steady effective blood drug concentration, is suitable to large-scale promotion application.

Another object of the present invention is to a kind of preparation method of the slow releasing preparation of Levamlodipine or its salt is provided, its Design is ingenious, prepares simplicity, and the slow releasing preparation design of obtained Levamlodipine or its salt is ingenious, simple for structure, with good Good stability, is suitable to large-scale promotion application.

For object above is reached, in a first aspect of the present invention, the slow release system of a kind of Levamlodipine or its salt is provided Agent, is characterized in, including slow release phase, the slow 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 is calculated as 2.5mg～20mg with the Levamlodipine, is meeting sink conditions In release medium, more than 90% weight of the active constituents of medicine discharge within the deenergized period of 6 hours to 12 hours.

The slow release mutually can be suitably composed with any, it is preferred that the slow release mutually also contains slow release phase carrier, institute State active constituents of medicine to be included in the slow release phase carrier.

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

The active constituents of medicine can be any suitable Levamlodipine or its salt, it is preferred that the medicine is lived Property composition be Levamlodipine, Levamlodipine besylate, maleic acid levo amido chloro diping.

In a second aspect of the present invention, a kind of preparation method of the slow releasing preparation of Levamlodipine or its salt is provided, its Feature is that the slow releasing preparation of described Levamlodipine or its salt is the left-handed ammonia chlorine ground of above-mentioned a first aspect of the present invention The slow releasing preparation of flat or its salt, the preparation method of the slow releasing preparation of described Levamlodipine or its salt includes step：By institute State active constituents of medicine to be included in the slow release phase.

The slow release mutually can be suitably composed with any, it is preferred that the slow release mutually also contains slow release phase carrier, In the step, the active constituents of medicine is included in the slow release phase carrier.

In a third aspect of the present invention, the slow releasing preparation of a kind of Levamlodipine or its salt is provided, is characterized in, including Mutually each independent or rapid release is mutually coated on the slow release phase for rapid release phase and slow release phase, the rapid release phase and the slow release Outward, a part of the rapid release containing active constituents of medicine, the slow release mutually contains its remaining part of the active constituents of medicine Point, the active constituents of medicine is Levamlodipine or its salt, and the active constituents of medicine is in terms of the Levamlodipine For 2.5mg～20mg, in the release medium of sink conditions is met, more than 90% weight of the active constituents of medicine little 6 Discharge within the deenergized period of 14 hours.

The active constituents of medicine can be included in the rapid release phase and the slow release phase with any suitable part by weight In, it is preferred that 0% weight of a part for described active constituents of medicine >=active constituents of medicine and the≤medicine is lived 50% weight of property composition, the active constituents of medicine of remainder >=50% weight of described active constituents of medicine and≤ 100% weight of the active constituents of medicine.

The active constituents of medicine can be included in the rapid release phase and the slow release phase with any suitable part by weight In, more preferably, 10% weight of a part >=active constituents of medicine of described active constituents of medicine and the≤medicine 45% weight of active component, the active constituents of medicine of remainder >=55% weight of described active constituents of medicine and The 90% weight of≤active constituents of medicine.

The active constituents of medicine can be included in the rapid release phase and the slow release phase with any suitable part by weight In, further, 15% weight of a part >=active constituents of medicine of described active constituents of medicine and≤described 40% weight of active constituents of medicine, the pharmaceutically active of remainder >=60% weight of described active constituents of medicine becomes Divide and the 85% weight of≤active constituents of medicine.

The a part >=active constituents of medicine of described active constituents of medicine 0% weight and the≤medicine is lived 50% weight of property composition, the active constituents of medicine of remainder >=50% weight of described active constituents of medicine and≤ In the case of 100% weight of the active constituents of medicine, in the release medium, in the rapid release phase and the slow release phase The active constituents of medicine can be with any suitable release behavior, more preferably, in the release medium, the rapid release More than 90% weight of the active constituents of medicine in phase discharge within the deenergized period of 30 minutes, the institute in the slow release phase State more than 90% weight of active constituents of medicine to discharge within the deenergized period of 6 hours to 14 hours.

In the release medium, the active constituents of medicine in the rapid release phase and the slow release phase can have appoints What suitable release behavior, further, in the release medium, the active constituents of medicine in the rapid release phase More than 90% weight discharge within the deenergized period of 15 minutes, 90% weight of the active constituents of medicine in the slow release phase Discharge within the deenergized period of 6 hours to 12 hours above.

The rapid release phase and the slow release mutually can be suitably composed with any, it is preferred that the rapid release mutually also contains Rapid release phase carrier, a part for described active constituents of medicine is included in the rapid release phase carrier, and the slow release mutually also contains Slow release phase carrier, the remainder of described active constituents of medicine is included in the slow release phase carrier, the rapid release phase carrier Each independent with the slow release phase carrier or the rapid release phase carrier is coated on outside the slow release phase carrier.

The rapid release phase carrier can be any suitable rapid release phase carrier, and more preferably, the rapid release phase carrier is selected from speed Release the rapid release coatings of piece, rapid release ball, rapid release substrate, the release layer in double-layer tablet and coated tablet or coated pill in tablet In at least one.

In a fourth aspect of the present invention, a kind of preparation method of the slow releasing preparation of Levamlodipine or its salt is provided, its It is characterised by, the slow releasing preparation of described Levamlodipine or its salt is the left-handed ammonia chlorine of above-mentioned a third aspect of the present invention Horizon or the slow releasing preparation of its salt, the preparation method of the slow releasing preparation of described Levamlodipine or its salt includes following step Suddenly：

(1) part for described active constituents of medicine is included in the rapid release phase, described pharmaceutically active is become The remainder for dividing is included in the slow release phase；

(2) make the rapid release phase mutually each independent with the slow release, or the rapid release is mutually coated on the slow release phase Outward.

The rapid release phase and the slow release mutually can be suitably composed with any, it is preferred that the rapid release mutually also contains Rapid release phase carrier, the slow release mutually also contains slow release phase carrier, in the step (1), by described active constituents of medicine A part is included in the rapid release phase carrier, the remainder of described active constituents of medicine is included in the slow release and is mutually carried In body；In the step (2), make the rapid release phase carrier and the slow release phase carrier each independent, or by the rapid release Phase carrier is coated on outside the slow release phase carrier.

Beneficial effects of the present invention are essentially consisted in：

1st, the Levamlodipine of the present invention or the slow releasing preparation of its salt include slow release phase, and slow release becomes containing pharmaceutically active Point, active constituents of medicine be Levamlodipine or its salt, active constituents of medicine with Levamlodipine be calculated as 2.5mg～ 20mg, in the release medium of sink conditions is met, more than 90% weight of active constituents of medicine in 6 hours to 12 hours release Release in the cycle is put, therefore, easy to use, curative effect of medication height, take that compliance is good, untoward reaction is few, is suitable to large-scale promotion Application.

2nd, the Levamlodipine of the present invention or the slow releasing preparation of its salt include rapid release phase and slow release phase, rapid release phase and slow release Mutually each independence or rapid release are mutually coated on outside slow release phase, a part of the rapid release containing active constituents of medicine, and slow release mutually contains The remainder of active constituents of medicine, active constituents of medicine is Levamlodipine or its salt, and active constituents of medicine is with left-handed ammonia Flordipine is calculated as 2.5mg～20mg, in the release medium of sink conditions is met, more than 90% weight of active constituents of medicine In the deenergized period of 6 hours to 14 hours discharge, therefore, can quick acting, and long-time maintain steady effective blood drug concentration, fit In large-scale promotion application.

3rd, the Levamlodipine of the present invention or the slow releasing preparation of its salt include rapid release phase and slow release phase, rapid release phase and slow release Mutually each independence or rapid release are mutually coated on outside slow release phase, a part of the rapid release containing active constituents of medicine, and slow release mutually contains The remainder of active constituents of medicine, active constituents of medicine is Levamlodipine or its salt, and active constituents of medicine is with left-handed ammonia Flordipine is calculated as 2.5mg～20mg, in the release medium of sink conditions is met, more than 90% weight of active constituents of medicine Discharge in the deenergized period of 6 hours to 14 hours, therefore, design is ingenious, simple for structure, with good stability, is suitable to big rule Mould popularization and application.

4th, the preparation method of the slow releasing preparation of the Levamlodipine of the present invention or its salt includes step：Pharmaceutically active is become Subpackage is contained in slow release phase, and active constituents of medicine is Levamlodipine or its salt, and active constituents of medicine is with Levamlodipine 2.5mg～20mg is calculated as, so as to the slow releasing preparation of Levamlodipine or its salt is obtained, is meeting the release medium of sink conditions In, more than 90% weight of active constituents of medicine discharge within the deenergized period of 6 hours to 12 hours, therefore, design ingenious, system Standby easy, the slow releasing preparation of obtained Levamlodipine or its salt is easy to use, curative effect of medication height, and it is good to take compliance, no Good reaction is few, is suitable to large-scale promotion application.

5th, the preparation method of the slow releasing preparation of the Levamlodipine of the present invention or its salt is comprised the following steps：(1) by institute A part for the active constituents of medicine that states is included in the rapid release phase, and the remainder of described active constituents of medicine is included In the slow release phase；(2) make the rapid release phase mutually each independent with the slow release, or the rapid release is mutually coated on described Outside slow release phase, wherein active constituents of medicine is Levamlodipine or its salt, and active constituents of medicine is calculated as with Levamlodipine 2.5mg～20mg, so as to the slow releasing preparation of Levamlodipine or its salt is obtained, in the release medium of sink conditions is met, More than 90% weight of active constituents of medicine discharge within the deenergized period of 6 hours to 14 hours, therefore, design ingenious, preparation Simplicity, the slow releasing preparation of obtained Levamlodipine or its salt can quick acting, and long-time maintains steadily effectively blood medicine dense Degree, is suitable to large-scale promotion application.

6th, the preparation method of the slow releasing preparation of the Levamlodipine of the present invention or its salt is comprised the following steps：(1) by institute A part for the active constituents of medicine that states is included in the rapid release phase, and the remainder of described active constituents of medicine is included In the slow release phase；(2) make the rapid release phase mutually each independent with the slow release, or the rapid release is mutually coated on described Outside slow release phase, wherein active constituents of medicine is Levamlodipine or its salt, and active constituents of medicine is calculated as with Levamlodipine 2.5mg～20mg, so as to the slow releasing preparation of Levamlodipine or its salt is obtained, in the release medium of sink conditions is met, More than 90% weight of active constituents of medicine discharge within the deenergized period of 6 hours to 14 hours, therefore, design ingenious, preparation Simplicity, the slow releasing preparation design of obtained Levamlodipine or its salt is ingenious, simple for structure, with good stability, is suitable to Large-scale promotion application.

The these and other objects, feature of the present invention and advantage, by following detailed descriptions, drawings and claims are obtained To fully demonstrate, and means, device and the combinations thereof that can pass through specially to point out in claims are achieved.

Description of the drawings

Fig. 1 is that the main view perspective of the first specific embodiment of the slow releasing preparation of the Levamlodipine of the present invention or its salt is shown It is intended to, is the capsule containing rapid release ball 1 and slow release ball 2.

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

Fig. 3 is that the main view perspective of the 3rd specific embodiment of the slow releasing preparation of the Levamlodipine of the present invention or its salt is shown It is intended to, is, containing outside, there is the capsule that rapid release coatings 5, inside have the coated pill of slow release capsule core 6.

Fig. 4 is that the main view perspective of the 4th specific embodiment of the slow releasing preparation of the Levamlodipine of the present invention or its salt is shown Being intended to, is the tablet that slow release ball 2 is enclosed with rapid release substrate 7.

Fig. 5 is that the main view perspective of the 5th specific embodiment of the slow releasing preparation of the Levamlodipine of the present invention or its salt is shown It is intended to, is bilayer tablet that upper strata contains that rapid release substrate 8, lower floor contains sustained-release matrix 9.

Fig. 6 is that the main view perspective of the 6th specific embodiment of the slow releasing preparation of the Levamlodipine of the present invention or its salt is shown Be intended to, be outside have sustained-release coating layer 10, internal lower floor be boosting layer 11, internal upper strata for medicine-containing particle 12 coated tablet.

Fig. 7 is that the main view perspective of the 7th specific embodiment of the slow releasing preparation of the Levamlodipine of the present invention or its salt is shown It is intended to, is outside with rapid release coatings 13, the internal coated tablet for slow releasing tablet 4.

Fig. 8 is the tablets in vitro song that the Levamlodipine of the present invention or the slow releasing preparation of its salt have single-phase drug release behavior Line.

Fig. 9 is the tablets in vitro song that the Levamlodipine of the present invention or the slow releasing capsule of its salt have two-phase drug release behavior Line.

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

Figure 11 is that beasle dog is administered orally blood medicine after the slow releasing tablet of the Levamlodipine of the present invention or its salt and reference preparation Concentration-time curve；

Specific embodiment

The invention provides the slow releasing preparation of a kind of Levamlodipine or its salt, containing slow release phase or containing rapid release phase and Slow release phase, in the release medium of sink conditions is met, within the deenergized period of 6 hours to 14 hours, has more than 90% weight Active constituents of medicine release, active constituents of medicine here is Levamlodipine or its salt.

For reaching the release purpose of rapid-onset, preferably rapid release phase is mutually combined with slow release, and its release behavior is according to biphase Release profile, first is mutually rapid release phase, and second is mutually slow release phase.

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

The Levamlodipine that the present invention is provided or the slow releasing preparation of its salt contain 2.5mg～20mg (with left-handed ammonia chlorine ground Flat meter) active constituents of medicine Levamlodipine and its pharmaceutically acceptable salt, preferably Levamlodipine besylate.

The active constituents of medicine total amount of the slow releasing preparation of Levamlodipine or its salt based on the present invention, according to medicine Specification and the demand for the treatment of, the slow releasing preparation of the Levamlodipine of the present invention or its salt, rapid release phase pharmaceutical active composition is accounted for 0wt%～the 50wt% of active constituents of medicine total amount, preferably 10wt%～45wt%, more preferably 15wt%～40wt%； Slow release phase pharmaceutical active composition accounts for 50wt%～100wt%, the preferably 55wt%～90wt% of active constituents of medicine total amount, More preferably 60wt%～85wt%.

The Levamlodipine with two-phase drug release behavior of the present invention or the slow releasing preparation of its salt, the design of rapid release phase can To ensure the rapid release of medicine well, meet the demand of medicine rapid-onset, be rapidly achieved treatment concentration；The setting of slow release phase Meter can ensure the steady release of active component, it is ensured that in blood pressure level higher daytime, active component sustained release, make hypertension The blood pressure held stationary of patient, and at blood pressure level relatively low night, plasma drug level can be adjusted correspondingly.

The Levamlodipine of the present invention or the slow releasing preparation of its salt, when the rapid release phase pharmaceutical active composition is 0wt%, when slow release phase pharmaceutical active composition is 100wt%, that is, during only containing slow release phase, according to Chinese Pharmacopoeia 2015 editions The requirement of drug release determination, in the release medium of sink conditions is met, active constituents of medicine discharges the time of more than 90wt% Preferably 6 hours to 12 hours.

The Levamlodipine of the present invention or the slow releasing preparation of its salt, when the rapid release phase pharmaceutical active composition is 0wt%～50wt%, when slow release phase pharmaceutical active composition is 50wt%～100wt%, according to 2015 editions releases of Chinese Pharmacopoeia The requirement that degree is determined, in the release medium of sink conditions is met, in the rapid release phase pharmaceutical active composition preferably 30 minutes There is more than 90wt% to discharge, in more preferably 15 minutes, have more than 90wt% to discharge；The slow release phase pharmaceutical active composition release Preferably 6 hours to the 14 hours time of more than 90wt%, more preferably 6 hours to 12 hours.

The slow releasing preparation of the Levamlodipine of the present invention or its salt is comprising rapid release phase carrier and slow release phase carrier；Rapid release phase In active constituents of medicine to be discharged be included in rapid release phase carrier, and active constituents of medicine to be discharged in slow release phase includes In slow release phase carrier.

In the slow releasing preparation of the Levamlodipine of the present invention or its salt, the rapid release phase carrier is mutually carried with the slow release Body, preferably capsule, tablet, double-layer tablet, coated tablet and its any form of combination.

Specifically, the rapid release phase carrier in the present invention is preferably but not limited to fast-release tablet or rapid release ball, the rapid release in tablet Substrate, the release layer in double-layer tablet, the rapid release coatings of coated tablet or coated pill；Slow release phase carrier in the present invention is preferably but not It is limited to slow releasing tablet or slow release ball, the sustained-release matrix in tablet, the slow release layer in double-layer tablet, the slow releasing tablet in coated tablet or coated pill Core or slow release capsule core.

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

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

The slow releasing preparation of the Levamlodipine of the present invention or its salt can adopt capsule, tablet, double-layer tablet, coated tablet, The form of coated pill, realizes drug release behavior of the present invention.

1st, capsule

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

(1) capsule containing rapid release ball 1 and slow release ball 2, as shown in Figure 1

Rapid release ball 1 can pass through for active constituents of medicine, diluent and other adjuvants etc. to pass through wet granulation, extrusion spheronization Prepare etc. conventional method well-known to those skilled in the art；By way of fluidized bed coating carries medicine, medicine can also be lived Property composition, binding agent, diluent be dispersed or dissolved in coating solvent, contain and formed on celphere.

Slow release ball 2 can pass through by active constituents of medicine, sustained-release matrix substrate, hydrophilic polymers, diluent and its His adjuvant etc. prepares matrix type slow 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 or contain to be formed on celphere to carry medicine by way of fluidized bed coating carries medicine Capsule core, then forms in load pill core one layer of extended release coatings membrane material of outsourcing.

Above-mentioned rapid release ball and slow release ball proportionally weighed, mix homogeneously, then carry out capsule fill.

(2) (referred to as contain rapid release coating containing the outside coated pill that there is rapid release coatings 5, inside with slow release capsule core 6 Layer 5 coated pill) capsule, as shown in Figure 3

Outside of the present invention has rapid release coatings 5, the internal coated pill with slow release capsule core 6, and can pass through will be upper The slow release ball 2 that states in (1) carries out 5 operation preparation of subsequent packet rapid release coatings as slow release capsule core 6.Specifically, can be by institute The slow release ball 2 that states, by way of fluidized bed coating carries medicine, active constituents of medicine and suitable amount of adhesive is dispersed or dissolved in bag In clothing solvent, contain on slow release ball 2, form described outside and there is rapid release coatings 5, the internal bag with slow release capsule core 6 Clothing ball；Finally described outside being had rapid release coatings 5, the internal coated pill with slow release capsule core 6 carries out capsule fill.

(3) capsule containing fast-release tablet 3 and slow releasing tablet 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 adjuvants Prepared by piece.Any technical staff in this area all knows the selection to these functional excipients and diluent.Or, rapid release Piece 3 can pass through the mixture of active constituents of medicine, diluent and other adjuvants, be pelletized by the way of wet granulation, whole Grain simultaneously dries, and adds lubricant, then carries out tabletting preparation.

The slow releasing tablet 4 of the present invention can pass through active constituents of medicine, sustained-release matrix substrate, hydrophilic polymers, diluent And other adjuvants etc., tabletting or mixing are equal after the conventional method granulation well-known to those skilled in the art such as wet granulation After even, matrix sustained release tablet is prepared using direct compression；This area staff such as fluid bed, high-efficiency coating pot can also be passed through Known to coating mode, the fast-release tablet containing active constituents of medicine is coated, in label expoeridium extended release coatings membrane material shape Become.

Finally, by the fast-release tablet 3 and slow releasing tablet 4, according to required active component dosage strengths, capsule fill is carried out.

2. tablet

The tablet of one of the slow releasing preparation dosage form of the Levamlodipine of the present invention or its salt, as shown in Figure 4, can pass through The tablet being made up of rapid release substrate 7 and slow release ball 2, realizes drug release behavior of the present invention.

In the slow releasing preparation of the Levamlodipine of the present invention or its salt, the rapid release is mutually rapid release in the present embodiment Substrate, the slow release is mutually slow release ball；Gross weight based on active constituents of medicine is 100% weight meter, and the rapid release mutually contains The active constituents of medicine of 0wt%～50wt%, active constituents of medicine of the slow release containing 50wt%～100wt%, described Active constituents of medicine with Levamlodipine count gross weight as 2.5mg～20mg.

The tablet that described rapid release substrate 7 and slow release ball 2 constitute, includes rapid release substrate 7 and slow release ball in structure composition 2；The rapid release substrate 7 can pass through being sufficiently mixed active constituents of medicine, diluent and other adjuvants or through wet method system Grain is prepared from.Wherein, the gross weight based on rapid release substrate is that 100% weight meter, the rapid release substrate includes 0wt%～5wt% Active constituents of medicine, the diluent of 50wt%～95wt%, and other adjuvants of 1wt%～45wt%.

The slow release ball 2 can pass through by active constituents of medicine, sustained-release matrix substrate, hydrophilic polymers, diluent with And other adjuvants 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 or contain to be formed on celphere to carry by way of fluidized bed coating carries medicine Pill core, then forms in load pill core one layer of extended release coatings membrane material of outsourcing.Gross weight based on sustained-release coating layer is 100% weight Meter, active constituents of medicine of the sustained-release coating layer comprising 1wt%～25wt%, 10wt%～70wt% extended release coatings membrane material, Other adjuvants of the antiplastering aid of 1wt%～3wt%, the diluent of 0wt%～70wt%, and 0wt%～10wt%.

Finally, by rapid release substrate 7 and slow release ball 2, according to the specification ratio mix homogeneously of active component, then by with spy The tablet machine of different agitating function, tabletted.

3. double-layer tablet

The double-layer tablet of one of the dosage form of slow releasing preparation of the Levamlodipine of the present invention or its salt can pass through with lower section Formula, realizes drug release behavior of the present invention.

In the slow releasing preparation of the Levamlodipine of the present invention or its salt, the rapid release is mutually rapid release in the present embodiment Layer, the slow release is mutually slow release layer；Gross weight based on active constituents of medicine is 100% weight meter, and the rapid release mutually contains 0wt% The active constituents of medicine of～50wt%, active constituents of medicine of the slow release containing 50wt%～100wt%, the medicine is lived Property composition with Levamlodipine count gross weight as 2.5mg～20mg.

The double-layer tablet of the slow releasing preparation of the described Levamlodipine with two-phase drug release behavior or its salt, is shown in Fig. 5 institute Show, comprising rapid release substrate 8 and sustained-release matrix 9, respectively as the release layer in double-layer tablet and slow release layer；Wherein rapid release substrate 8 can By active constituents of medicine, diluent and other adjuvants being sufficiently mixed or being prepared from through wet granulation；Wherein, it is based on The gross weight of release layer is 100% weight meter, active constituents of medicine of the release layer comprising 0wt%～10wt%, 50wt%～ The diluent of 95wt%, and other adjuvants of 1wt%～45wt%.

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

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

4. coated tablet

The coated tablet of one of the dosage form of slow releasing preparation of the Levamlodipine of the present invention or its salt can pass through with lower section Formula, realizes drug release behavior of the present invention.

When the rapid release phase pharmaceutical active composition is that 0wt%, slow release phase pharmaceutical active composition is 100wt%, i.e., When the rapid release is not mutually present, as shown in Figure 6, can pass through by active constituents of medicine, hydrophilic polymers, osmotic pressure accelerator with And other adjuvants etc., pelletized after conventional method mix homogeneously well-known to those skilled in the art, obtain medicine-containing particle；Will Promote osmopolymer, osmotic pressure accelerator and other adjuvants etc., mixed by conventional method well-known to those skilled in the art Pelletize after uniform, obtain boosting layer granule；Medicine-containing particle and boosting layer granule are separately added into bi-layer tablet press, suppress double-layer tablet 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 forms the sustained release coating piece of Levamlodipine or its salt.

When the rapid release phase pharmaceutical active composition is that 0wt%～50wt%, slow release phase pharmaceutical active composition is During 50wt%～100%, can pass through by active constituents of medicine, sustained-release matrix substrate, hydrophilic polymers, diluent and other Adjuvant etc., adopts direct compression system after tabletting or mix homogeneously after conventional method well-known to those skilled in the art is pelletized Standby slow releasing tablet (slow release phase)；Then pass through to the method using above-mentioned slow releasing tablet (slow release phase) expoeridium rapid release clothing layer (rapid release phase) The sustained release coating piece of Levamlodipine or its salt of the preparation with two-phase drug release behavior.

In the slow releasing preparation of the Levamlodipine of the present invention or 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 One or more in change starch, sucrose, Mannitol, sorbitol, sucrose, starch, carboxymethyl starch sodium.

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

Osmotic pressure accelerator of the present invention includes following material well-known to those skilled in the art, Sodium Chloride, chlorine One or more in change potassium, Lactose, Mannitol, sorbitol, glucose, sucrose, Fructose.

Hydrophilic polymer of the present invention includes following material well-known to those skilled in the art, polyvidone, altogether Polyvidone, polyoxyethylene, Carbomer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium alginate, Huang 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 carboxymethyl cellulose, carboxymethyl starch sodium, polyvidone In one or more.

Celphere of the present invention is selected from sucrose capsule core, starch capsule core, Microcrystalline Cellulose capsule core, silicon dioxide ball One kind in core, hydroxypropyl cellulose capsule core.

Other adjuvants of the present invention, including one or more in lubricant, coloring agent, binding agent；

Lubricant of the present invention be selected from magnesium stearate, stearic acid, Sodium Stearyl Fumarate, Pulvis Talci and micropowder silica gel In one or more；

Coloring agent of the present invention be selected from iron oxide red, iron oxide yellow, iron oxide purple, iron oxide black, titanium dioxide In one or more.

Binding agent of the present invention selected from hydroxypropyl methyl cellulose, polyvidone, Copolyvidone, hydroxyethyl cellulose, One or more in methylcellulose, hydroxypropyl cellulose, and their mixture.

In order to be more clearly understood that the technology contents of the present invention, describe in detail especially exemplified by following examples.All of hundred Divide and be weight percentage than all, unless otherwise specified.

Embodiment 1：Capsule containing slow release ball

I) pill core is carried

II) bag contagion gown

III) bag extended release coatings

1.1 preparations for carrying medicine coating solution

Weigh binding agent (hydroxypropyl cellulose, Copolyvidone or polyvidone) appropriate, be scattered in 95% ethanol solution, The coating solution that solid content is 10% is configured to, is sufficiently mixed uniform；Weigh the Levamlodipine of recipe quantity again, be uniformly dispersed In above-mentioned coating solution, as the load medicine coating solution of slow release phase, standby.

1.2 carry medicine

Celphere (Microcrystalline Cellulose capsule core or sucrose capsule core) is added fluid bed, adjusts intake, inlet temperature, mist Change the operating parameters such as pressure, spray into the slow release for preparing and medicine coating solution is mutually carried, load medicine is carried out, as load pill core；By slow release bag Clothing liquid aqueous dispersion (Sulisi or Eudragit RS 100) adds appropriate aqueous solution to be diluted to the slow release clothing film coating that solid content is 15% Liquid, by the way of fluid bed bottom spray coating, is injected on load pill core, makes slow release ball.

Capsule fill：The slow release ball that above-mentioned preparation is completed, carries out capsule fill.

Drug release determination (Rotating shaker)

This product is taken, according to dissolution method (Chinese Pharmacopoeia four 0,931 first methods of 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, be centrifuged (8000rpm, 15min), while supplementing mutually synthermal, same volume The release medium of product, takes supernatant as need testing solution；Levamlodipine reference substance is separately taken appropriate, accurately weighed, solubilization It is diluted in every 1mL containing about 20 μ g of Levamlodipine, as reference substance solution with dissolution medium after agent dissolving.Take above two Solution, by ultraviolet visible spectrophotometry (Chinese Pharmacopoeia four general rules 0401 of version in 2015), determines at the wavelength of 237nm Absorbance, calculates the stripping quantity of per.

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

Embodiment 2：Capsule containing slow releasing tablet

Preparation method is as follows：

By Levamlodipine besylate and diluent (Mannitol), sustained-release matrix substrate (hydroxypropyl cellulose, poly- dimension Ketone, Carbomer or polyoxyethylene), progressively increased after method mix homogeneously using equivalent, add fluid bed；Using 80% ethanol solution as viscous Mixture is pelletized；Dry to moisture and 5% is less than, 20 mesh sieve granulate are crossed, magnesium stearate is subsequently adding, mix, as benzenesulfonic acid Levamlodipine slow-releasing granules；According to recipe quantity, the suitable slow releasing tablet of hardness is pressed into.

Capsule fill：The slow releasing tablet that above-mentioned preparation is completed, carries out capsule fill.

Drug release determination method is with embodiment 1；

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

Embodiment 3：Sustained release coating piece containing boosting layer

1. medicated layer

2. boosting layer

3. semi-transparent clothing film

4. moistureproof clothing film

Preparation method is as follows：

The preparation of medicated layer：By maleic acid levo amido chloro diping and hydrophilic polymer (polyvidone, Copolyvidone), oxidation Iron oxide yellow, is progressively increased after method mix homogeneously using equivalent, adds fluid bed；Spray into 95% ethanol-water solution granulation；Dry to water Content is divided to be less than 5%, 20 mesh sieves, granulate, obtain medicine-containing particle, be subsequently adding magnesium stearate excessively, mix, standby；

The preparation of boosting layer：By carboxymethyl starch sodium, hydroxypropyl methyl cellulose K15M, Sodium Chloride, Copolyvidone S630 And iron oxide red, after mix homogeneously, fluid bed is added, spray into 95% ethanol-water solution granulation；Dry to moisture and be less than 5%, 20 mesh sieves, granulate, obtain boosting layer granule excessively, subsequently, add magnesium stearate, mix, standby；

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

Bag 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 semipermeable membrane coating solution；Put in high-efficiency coating pot, double-deck core qualified for above-mentioned inspection using semipermeable membrane bag Clothing liquid is coated；Product after coating is dry 12 hours under the conditions of 45 DEG C, removes unnecessary organic solvent and moisture；

The punching of coated tablet：By the way of laser boring, an a diameter of 0.9mm is broken in the pastille layer surface of tablet Drug release hole；

The moistureproof clothing of bag：By OPADRY coating powder, it is dissolved in and is dispersed in water, is configured to moistureproof clothing Coating Solution；Then will beat Controlled release tablet behind hole is coated using moistureproof clothing Coating Solution；Under the conditions of 45 DEG C, dry 12 hours, obtain final product.

Drug release determination (paddle method)

This product is taken, according to dissolution method (Chinese Pharmacopoeia four 0,931 second methods of 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, be centrifuged (8000rpm, 15min), while supplementing mutually synthermal, same volume The release medium of product, takes supernatant as need testing solution；Maleic acid levo amido chloro diping reference substance is separately taken appropriate, accurate title 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, molten as reference substance Liquid.Above two solution is taken, according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia four general rules 0401 of version in 2015), Mensuration absorbance at the wavelength of 237nm, calculates the stripping quantity of per.

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

Embodiment 4：Capsule containing rapid release ball and slow release ball

1. rapid release ball

2. slow release ball

I) pill core is carried

II) bag contagion gown

III) bag extended release coatings

Preparation method is as follows：

Rapid release ball：Levamlodipine and binding agent (Copolyvidone) is dissolved or dispersed in 95% ethanol solution, It is made the load medicine coating solution of rapid release phase；By celphere (Microcrystalline Cellulose capsule core or sucrose capsule core) add fluid bed, adjust into The operating parameters such as air quantity, inlet temperature, bed temperature, flow velocity, atomizing pressure, spray into the rapid release for preparing and mutually carry medicine coating solution, as Rapid release ball.

Slow release ball：

1.1 preparations for carrying medicine coating solution

Weigh binding agent (Copolyvidone or polyvidone) appropriate, be scattered in 95% ethanol solution, be configured to solid content For the coating solution of 10% polyvidone, it is sufficiently mixed uniform；Weigh the Levamlodipine of recipe quantity again, be evenly dispersed in above-mentioned In coating solution, as the load medicine coating solution of slow release phase, standby.

1.2 carry medicine

Celphere (Microcrystalline Cellulose capsule core or sucrose capsule core) is added fluid bed, adjusts intake, inlet temperature, mist Change the operating parameters such as pressure, spray into the slow release for preparing and medicine coating solution is mutually carried, load medicine is carried out, as load pill core；By slow release bag Clothing liquid aqueous dispersion (Sulisi, Eudragit RS 100) adds appropriate aqueous solution to be diluted to the slow release clothing film coating that solid content is 15% Liquid, by the way of fluidized bed coating, is injected on load pill core, makes slow release ball.

Capsule fill：The rapid release ball that above-mentioned preparation is completed and slow release ball, after fully mixing according to prescription ratio, carry out glue Capsule fill.

Drug release determination method is with embodiment 1；

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

Embodiment 5：Containing the capsule that fast-release tablet and slow releasing tablet constitute

1. fast-release tablet

2. slow releasing tablet

Preparation method is as follows：

Fast-release tablet：By Levamlodipine besylate and diluent (Microcrystalline Cellulose, pregelatinized Starch or Mannitol), adopt Progressively increased after method mix homogeneously with equivalent, add fluid bed；Pelletized using aqueous solution as binding agent；Dry to moisture and be less than 5%, 20 mesh sieve granulate are crossed, magnesium stearate is subsequently adding, mix, as Levamlodipine besylate immediate-release granules；According to place Fang Liang, is pressed into the suitable fast-release tablet of hardness.

Slow releasing tablet：By Levamlodipine besylate and diluent (Mannitol), sustained-release matrix substrate (hydroxy propyl cellulose Element, polyvidone, Carbomer or polyoxyethylene), progressively increased after method mix homogeneously using equivalent, add fluid bed；Molten with 80% ethanol Liquid is pelletized as binding agent；Dry to moisture and 5% is less than, 20 mesh sieve granulate are crossed, magnesium stearate is subsequently adding, mix, make For Levamlodipine besylate slow-releasing granules；According to recipe quantity, the suitable slow releasing tablet of hardness is pressed into.

Capsule fill：The fast-release tablet that above-mentioned preparation is completed and slow releasing tablet, mix according to the combination of prescription ratio, carry out capsule Fill.

Drug release determination method is with 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 for 15 minutes rapid releases, delays within 8 hours Release mutually drug release amount and the 90% of sustained-release dosage is reached, 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 pill containing rapid release coatings

I) pill core is carried

II) bag contagion gown

III) bag extended release coatings

IV) bag rapid release clothing

Preparation method is as follows：

Carry medicine：First, by maleic acid levo amido chloro diping and binding agent (hydroxypropyl cellulose, Copolyvidone or poly- dimension Ketone), it is dissolved or dispersed in 95% ethanol solution, is configured to drug solns are carried, by the way of fluidized bed coating, sprays into recipe quantity Celphere (Microcrystalline Cellulose or sucrose capsule core) on, as carry pill core；

Bag extended release coatings：Sustained release coating liquid aqueous dispersion is added appropriate aqueous solution dilution, is mixed, as slow release clothing film bag Clothing liquid, by the way of fluidized bed coating, is injected on load pill core, makes slow release ball.

Bag rapid release clothing：Maleic acid levo amido chloro diping and binding agent being scattered in 95% ethanol solution, mix, makees For rapid release clothing coating solution, by the way of fluidized bed coating, it is injected on slow release ball, makes the coating containing rapid release coatings Ball.

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

Drug release determination method is with embodiment 1；

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

Embodiment 7：The tablet being made up of rapid release substrate and slow release ball

1. rapid release substrate (1000)

2. slow release ball

I) pill core is carried

II) bag extended release coatings

Preparation method is as follows：

Rapid release substrate：By Levamlodipine and diluent (pregelatinized Starch, Mannitol or Microcrystalline Cellulose), adopt etc. Amount is progressively increased after method mix homogeneously, adds fluid bed；Spray into the granulation of 10% polyvidone aqueous solution；Dry to moisture and 5% be less than, Cross 20 mesh sieves, granulate, magnesium stearate is subsequently adding, is mixed, as Levamlodipine rapid release substrate.

Slow release ball：First, by Levamlodipine and binding agent (hydroxypropyl cellulose, polyvidone), it is dissolved or dispersed in In aqueous solution, it is configured to drug solns are carried, by the way of fluidized bed coating, sprays into the celphere (Microcrystalline Cellulose of recipe quantity Or sucrose capsule core) on, as load pill core；By extended release coatings membrane material (ethyl cellulose or acrylic resin), Pulvis Talci respectively It is scattered in appropriate ethanol solution, mixes, as slow release clothing film coating liquid, by the way of fluidized bed coating, be injected to load On pill core, slow release ball is made.

Tabletting：Rapid release substrate that above-mentioned preparation is completed, slow release ball are pressed into hardness suitable according to recipe quantity mix homogeneously Tablet.

Drug release determination method is with embodiment 3；

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

Embodiment 8：Rapid release substrate and the substrate composed double-layer tablet of slow release

1. rapid release substrate (1000)

2. sustained-release matrix

Preparation method is as follows：

Rapid release substrate：Levamlodipine besylate and diluent is (Microcrystalline Cellulose, pregelatinized Starch, Mannitol, poly- Dimension ketone), progressively increased after method mix homogeneously using equivalent, add fluid bed；Pelletized using aqueous solution as binding agent；Dry to moisture and contain Amount is less than 5%, and 20 mesh sieves, granulate, are subsequently adding magnesium stearate excessively, mixes, as Levamlodipine besylate rapid release substrate.

Sustained-release matrix：By Levamlodipine besylate and diluent (Mannitol, Copolyvidone), sustained-release matrix substrate (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose), is progressively increased after method mix homogeneously using equivalent, adds stream Change bed；Pelletized using 95% ethanol solution as binding agent；Dry to moisture and 5% is less than, cross 20 mesh sieves, granulate, Ran Houjia Enter magnesium stearate, mix, as Levamlodipine besylate sustained-release matrix.

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

Drug release determination method is with embodiment 3；

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

Embodiment 9：Sustained release coating piece containing rapid release coatings

1. the preparation (1000) of slow releasing tablet

2. bag rapid release clothing

Preparation method is as follows：

The preparation of maleic acid levo amido chloro diping slow releasing tablet：By maleic acid levo amido chloro diping and sustained-release matrix substrate (hydroxyl Propyl cellulose), binding agent (Copolyvidone), progressively increased after method mix homogeneously using equivalent, add fluid bed；Spray into 85% ethanol Aqueous solution is pelletized；Drying to moisture is less than 5%, and 20 mesh sieves, granulate, are subsequently adding magnesium stearate excessively, mixes, then suppresses The slow releasing tablet label for becoming hardness suitable；

Bag rapid release clothing：Rapid release clothing coating solution is prepared according to rapid release clothing prescription, above-mentioned slow releasing tablet is put in high-efficiency coating pot Scanning frequency releases clothing coating；Under the conditions of 45 DEG C, dry 12 hours, remove unnecessary organic solvent and moisture；

Drug release determination method is with embodiment 3；

Wherein, 25 releasing result of prescription is shown in Figure 10, drug release, and mutually drug release amount reaches immediate release dose for 30 minutes rapid releases 90%, mutually drug release amount reaches the 90% of sustained-release dosage for 14 hours slow release, 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 dog 6, male 3, female 3,8～10kg of weight range, be randomly divided into two groups, per 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/ piece, totally 2) and benzenesulfonic acid left-handed Amlodipine slow releasing tablet (makes tablet recipe 20,22,25, specification by oneself in embodiment 7,8,9：10mg/ piece, totally 1), per only Beagle Dog before medication (0h), medication after take in dog side foreleg vein within 0.5,1,2,3,4,5,6,8,10,12,16,24 and 50 hours Blood 2mL, puts in heparinised tubes, is centrifuged (5000rpm, 10min), isolates blood plasma, frozen in -80 DEG C, stand-by；

Using the concentration of Levamlodipine besylate in LC-MS/MS blood plasma, internal blood medicine is dense Degree-time graph result is shown in Figure 11.As a result show, the Levamlodipine in rapid release phase can ensure that primary drugs are fast well Rapid release is put, and meets the demand of medicine rapid-onset；Slow release phase is maintained about 6 hours to 14 hours release time, is maintained more stable Blood drug level, it is to avoid blood pressure fluctuation of concentration, safer effectively；This product can be in the single-dose for improving Levamlodipine Dosage, on the basis of strengthening therapeutic effect, provides that a kind of compliance is good, untoward reaction is few, can quick acting, long-time is maintained to be had The new sustained release preparation of effect blood drug level.

The present inventor by the research of physicochemical property, stability and biological property to Levamlodipine, according to facing The treatment of bed needs the demand with the compliance of patient medication, devises the slow releasing preparation of a kind of Levamlodipine or its salt, Have the advantage that：

Compared with common quick release preparation

1. can achieve medicine long-acting release, lasting medicine, the fluctuation of blood drug level is little, reduces the bad of patient medication Reaction；

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

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

Compared with common slow releasing preparation

1. there is slow drug release behavior, the principle of chronopharmacology is conformed better to, can be (white in the physiological period for needing My god) sustained release, reduce blood pressure, and at level of activation relatively low night, plasma drug level can be adjusted correspondingly, and subtract The generation of few drug resistance；

2. treatment can be reached dense with rapid-onset after the rapid release with two-phase drug release behavior mutually designs guarantee drug administration Degree, the design of slow release phase ensures that the steady release of later stage active component, keeps the blood drug level of relative constancy, minimizing due to The too high untoward reaction for causing of blood drug level；

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

Therefore, the beneficial effect of this preparation is the drug release of the slow releasing preparation of Levamlodipine based on the present invention or its salt Behavior advantage embodies, and is embodied in：

(1) slow releasing preparation with two-phase drug release behavior, the design of rapid release phase, it is ensured that risen after drug administration rapidly Effect；The design of slow release phase, then can make medicine (daytime) sustained release in the physiological period for needing, reduce blood pressure, and in activity At level relatively low night, plasma drug level can be adjusted correspondingly；

(2) dosage can be improved, the complicated processes of dose titration is eliminated, only need to take once daily, gastrointestinal irritation Little, the good patient compliance of property；

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

To sum up, the Levamlodipine of the present invention or the slow releasing preparation of its salt are easy to use, curative effect of medication height, take and comply with Property good, untoward reaction is few, can quick acting, and long-time maintains steady effective blood drug concentration, designs ingenious, simple for structure, tool There is good stability, be suitable to large-scale promotion application.

As can be seen here, the purpose of the present invention has been achieved completely and effectively.The function of the present invention and structural principle Shown in an embodiment and illustrated, without departing substantially under the principle, embodiment can be made any modification.So, this The bright all variant embodiment for including based on claim spirit and right.

Claims

1. the slow releasing preparation of a kind of Levamlodipine or its salt, it is characterised in that including slow release phase, the slow release mutually contains medicine Thing active component, the active constituents of medicine is Levamlodipine or its salt, and the active constituents of medicine is with the left-handed ammonia Flordipine is calculated as 2.5mg-20mg, in the release medium of sink conditions is met, 90% weight of the active constituents of medicine with On discharge within the deenergized period of 6 hours to 12 hours.

2. the slow releasing preparation of Levamlodipine as claimed in claim 1 or its salt, it is characterised in that the slow release mutually also contains There is slow release phase carrier, the active constituents of medicine is included in the slow release phase carrier.

3. a kind of preparation method of the slow releasing preparation of Levamlodipine or its salt, it is characterised in that described left-handed ammonia chlorine ground The slow releasing preparation of flat or its salt is the slow releasing preparation of Levamlodipine as claimed in claim 1 or its salt, and described is left-handed The preparation method of the slow releasing preparation of amlodipine or its salt includes step：The active constituents of medicine is included in the slow release phase In.

4. the preparation method of the slow releasing preparation of Levamlodipine as claimed in claim 3 or its salt, it is characterised in that described Slow release mutually also contains slow release phase carrier, in the step, the active constituents of medicine is included in the slow release phase carrier.

5. the slow releasing preparation of a kind of Levamlodipine or its salt, it is characterised in that including rapid release phase and slow release phase, the rapid release Mutually and the slow release mutually each independent or rapid release is mutually coated on outside the slow release phase, the rapid release mutually contains pharmaceutically active A part for composition, the slow release mutually contains the remainder of the active constituents of medicine, and the active constituents of medicine is left-handed Amlodipine or its salt, the active constituents of medicine is calculated as 2.5mg-20mg with the Levamlodipine, is meeting bakie bar In the release medium of part, more than 90% weight of the active constituents of medicine discharge within the deenergized period of 6 hours to 14 hours.

6. the slow releasing preparation of Levamlodipine as claimed in claim 5 or its salt, it is characterised in that described pharmaceutically active 0% weight of a part for composition >=active constituents of medicine and the 50% weight of≤active constituents of medicine, described The active constituents of medicine of remainder >=50% weight of active constituents of medicine and the 100% of the≤active constituents of medicine Weight.

7. the slow releasing preparation of Levamlodipine as claimed in claim 6 or its salt, it is characterised in that in the release medium In, more than 90% weight of the active constituents of medicine in the rapid release phase discharge within the deenergized period of 30 minutes, described More than 90% weight of the active constituents of medicine in slow release phase discharge within the deenergized period of 6 hours to 14 hours.

8. the slow releasing preparation of Levamlodipine as claimed in claim 5 or its salt, it is characterised in that the rapid release mutually also contains The part for having rapid release phase carrier, described active constituents of medicine is included in the rapid release phase carrier, and the slow release mutually also contains The remainder for having slow release phase carrier, described active constituents of medicine is included in the slow release phase carrier, and the rapid release is mutually carried Body and the slow release phase carrier are each independent or the rapid release phase carrier is coated on outside the slow release phase carrier.

9. a kind of preparation method of the slow releasing preparation of Levamlodipine or its salt, it is characterised in that described left-handed ammonia chlorine ground The slow releasing preparation of flat or its salt is the slow releasing preparation of Levamlodipine as claimed in claim 7 or its salt, and described is left-handed The preparation method of the slow releasing preparation of amlodipine or its salt is comprised the following steps：

(1) part for described active constituents of medicine is included in the rapid release phase, by described active constituents of medicine Remainder is included in the slow release phase；

(2) make the rapid release phase mutually each independent with the slow release, or the rapid release is mutually coated on outside the slow release phase.

10. the preparation method of the slow releasing preparation of Levamlodipine as claimed in claim 9 or its salt, it is characterised in that institute Rapid release is stated mutually also containing rapid release phase carrier, the slow release mutually also contains slow release phase carrier, in the step (1), will be described A part for active constituents of medicine is included in the rapid release phase carrier, and the remainder of described active constituents of medicine is included In the slow release phase carrier；In the step (2), make the rapid release phase carrier and the slow release phase carrier each independent, Or the rapid release phase carrier is coated on outside the slow release phase carrier.