CN106420738B - A kind of sustained release preparation of levamlodipine or its salt and preparation method thereof - Google Patents

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

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CN106420738B
CN106420738B CN201610898040.1A CN201610898040A CN106420738B CN 106420738 B CN106420738 B CN 106420738B CN 201610898040 A CN201610898040 A CN 201610898040A CN 106420738 B CN106420738 B CN 106420738B
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release
sustained release
levamlodipine
sustained
medicine
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CN106420738A (en
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甘勇
朱春柳
杨彦玲
刘彦
朱全垒
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Shihuida Pharma Group (Jilin) Co., Ltd.
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杨彦玲
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings

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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 each 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 remainder 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 of sink conditions is met, more than 90% weight of active constituents of medicine discharged within the deenergized period of 6 hours to 14 hours.The sustained release preparation of the present invention can not include quick-release phase.Present invention also offers 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, suitable for large-scale promotion application.

Description

A kind of sustained release 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, in particular to one kind Sustained release preparation of levamlodipine or its salt and preparation method thereof.
Background technology
With the improvement of people's living standards, angiocardiopathy turns into the primary disease of China's cause of death, it is prestige Coerce " number one killer " of people's health and life.More than the 18 years old adult hypertension illness rate in China is up to 33.5%, and total number of persons surpasses 3.3 hundred million are crossed, death toll is up to 9,400,000 caused by hypertension and its complication every year in the whole world, 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 morbidity and mortality of hypertension still have year by year Elevated trend.
Although people achieve many progress in terms of the prevention, detection and 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 give drug therapy.Clinical test confirms that target control treatment can reduce cardiovascular danger, and be protected with kidney Shield acts on and reduced the danger of cerebrovascular events, and good drug therapy is for extending hyperpietic's life and life matter Amount has positive meaning.
Hypertension is both the common complication of CGN, be again cause glomerular capillary inner high voltage power and One of height filters and promotes glomerulosclerosis, further an important factor for infringement kidney.Therefore, reduce blood pressure, delay renal function Deteriorate, protection kidney patient renal function be treat chronic glomerulonephritis patients important step, the high blood of good treatment Pressure strategy should can stablize decompression and can and for kidney provide protective effect simultaneously, prevent because of hypertension and impaired renal function enters One step deteriorates.Therefore, find effectively decompression and improve the medicine of renal function as the focus of clinical research.
So far, clinical conventional drug for hypertension mainly has 6 major classes：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 evident in efficacy, and have the effect of resisting coronary heart disease angina pectoris, blood-fat and blood sugar is metabolized for it and Water-Electrolyte has no adverse effects, patient's clothes Medicine compliance is high, long-term use of still effective.Just because of calcium ion antagonist has treatment characteristic remarkable above, in recent years respectively Treatment Guidelines for Hypertension (such as JNC- VII,《Chinese hypertension prevention and control guide》) in 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, 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 leads to Road enters intracellular.In addition, this kind of medicine also has the advantages of prominent：Pressure reduction does not reduce the important vital organ such as the heart, brain, kidney CBF；The metabolins such as blood glucose, blood fat are had no adverse effects；Myocardial contractive power and Atrioventricular Conduction are influenceed small；Pair is made With less.Further, since its selection of height to petty action smooth muscle, has slight row's sodium profit to the adrenal gland of vein smooth muscle Urine acts on, and 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, it is the first chiral resolution optical voidness of China Medicine, 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 have and preferably applied.
Levamlodipine besylate absorbed following oral administration is complete, and 6-12 hour blood concentrations peak.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.Eliminated after absorption in a manner of two compartment model from blood plasma, inactive metabolin (90%) is metabolized as extensively in liver.Eventually It is 35 hours that end, which eliminates half-life period healthy person, 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 from urine by prototype, 60% in the form of metabolin, 20%- 25% discharges from bile or excrement.Levamlodipine besylate can not 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 length, and antihypertensive effect is slowly lasting, Bu Zhizao Hypertension rebound effect into after low blood pressure and drug withdrawal, 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, and it has higher affinity to blood vessel, and can significantly extend Ischemic Cardiomyopathy Run duration and the angina pectoris attacks time is moved to, reduce the consumption of anginal attack times and nitroglycerin.
At present, clinical conventional amlodipine formulation is conventional tablet, is used mainly for light, moderate hypertension patient. According to the literature, it is to study amlodipine to the therapeutic effect and its security of hypertension, have chosen 100 hyperpietics Research is included, 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 Fruit shows that total effective rate is up to 92% after treatment group's medication, higher than 74% (P of control group<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.
At present, conventional Levamlodipine besylate preparation is conventional tablet, is clinically widely used, main pin Light, moderate hypertension patient is used；During clinical application, Levamlodipine besylate ordinary preparation remain it is following not Foot part：1. the general initial dose of this product should gradually adjust dosage, cumbersome dosage adjustment process is to clinic since low dose Medication brings certain inconvenience；2. the effect of hypertension and patient with angina pectoris of alignment degree and severe, is not good enough；3. the high blood of severe Press and medication 2 times a day is usually required on patient clinical, be easily caused bad kickback of using medicine (including postural hypotension, headache, head The symptoms such as portion's heating, oedema).
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), 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 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 Element 5~55g, preferably 20~40g, particularly preferably 30g；2~20g of PVPP, 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 Its preparation method.The tablet be by using Levamlodipine besylate as active component label and be wrapped in outer membrane clothing group Into wherein the diluent in label contains one or both of diatomite and differential silica gel, also containing pharmaceutically acceptable Other auxiliary materials, outer membrane clothing account for the 8%~12% of piece weight, can play a part of moistureproof, lucifuge, obtain medicine stability Large increase.
Chinese patent application prospectus CN102846565A discloses a kind of system of Levamlodipine beaylate tablets Preparation Method, mixed after Levamlodipine besylate, filler, disintegrant are pulverized and sieved, add lubricant granulation, pressure Piece.Levamlodipine beaylate tablets are prepared using the method for fluid-bed marumerization, reduce Levamlodipine besylate The relevant material of piece, improves stability, while simplifies preparation process, shortens the time, optimizes technological parameter, significantly increases Add the dissolution rate of product, improve product quality.
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：Cholesterol：PLURONICS F87： Other pharmaceutically acceptable excipient=1：4-10:0.5-5:1-3:35-50.The liposome tablet of this 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, its formula are made up of Levamlodipine besylate, dripping pill matrix, antioxidant, surfactant, coating material etc., Its preparation method is that Levamlodipine besylate is prepared into fineness for fine powders more than 150 mesh first.Take the base of formula ratio After matter heating melting, add Levamlodipine besylate fine powder and relevant 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 medicine that the microballoon prepared is wrapped up is Amlodipine and its organic salt, and the carrier material of the microballoon is PLA (PLA), gathered The Biodegradable material such as lactic acid-hydroxyacetic acid copolymer (PLGA) or PLA-mPEG (PLA-mPEG), and Using surfactant solution, monose 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 Slow release with the degraded of high polymer material, and rate of release is approximation Zero-order release profile, drug percutaneous undertissue absorbed into serum, can maintain blood concentration for a long time (2 weeks-March) maintenance level, Compared with common tablet, the blood concentration change 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 on Levamlodipine besylate oral slow-releasing preparation is had no.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 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, treat that patient can Therapeutic dose is gradually increased to during tolerance again.
It can be seen that still had the following disadvantages 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 Inconvenience；2. the effect of 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, is easily caused bad kickback of using medicine (including the disease such as postural hypotension, headache, Head And Face heating, oedema Shape), the fluctuation of blood concentration is larger.
Further to improve the clinical efficacy of levamlodipine, hyperpietic (renal hypertension patient) medication is reduced Adverse reaction afterwards, the compliance of increase patient's medication is, it is necessary to carry out rational formulation and Formulation, with optimizing left-handed ammonia chlorine Flat release behavior, medicine is set to play the effect of maximum while adverse reaction is reduced.
Accordingly, it is desirable to provide the sustained release preparation of a kind of levamlodipine or its salt, its is easy to use, and 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.
The content of the invention
In order to overcome it is above-mentioned in the prior art the shortcomings that, it is an object of the present invention to provide a kind of levamlodipine Or the sustained release preparation of its salt, its is easy to use, and curative effect of medication is high, takes that compliance is good, and adverse reaction is few, suitable for large-scale promotion Using.
Another object of the present invention is to provide a kind of sustained release preparation of levamlodipine or its salt, it can quickly rise Effect, and steady effective blood drug concentration is maintained for a long time, suitable for large-scale promotion application.
Another object of the present invention is to provide a kind of sustained release preparation of levamlodipine or its salt, its is ingenious in design, It is simple for structure, there is good stability, suitable for large-scale promotion application.
Another object of the present invention is to provide a kind of preparation method of the sustained release preparation of levamlodipine or its salt, its It is ingenious in design, simplicity is prepared, the sustained release preparation of obtained levamlodipine or its salt is easy to use, and curative effect of medication is high, takes Compliance is good, and adverse reaction is few, suitable for large-scale promotion application.
Another object of the present invention is to provide a kind of preparation method of the sustained release preparation of levamlodipine or its salt, its It is ingenious in design, prepare it is easy, the sustained release preparation of obtained levamlodipine or its salt can quick acting, and maintain for a long time flat Steady effective blood drug concentration, suitable for large-scale promotion application.
Another object of the present invention is to provide a kind of preparation method of the sustained release preparation of levamlodipine or its salt, its It is ingenious in design, simplicity is prepared, the sustained release preparation of obtained levamlodipine or its salt is ingenious in design, simple for structure, has good Good stability, suitable for large-scale promotion application.
To achieve the above objectives, in the first aspect of the present invention, there is provided a kind of sustained release system of levamlodipine or its salt Agent, it is characterized in, including sustained release phase, the sustained release mutually contain active constituents of medicine, 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 the deenergized period of 6 hours to 12 hours.
The sustained release can be mutually suitably composed with any, it is preferred that the sustained release is mutually also containing sustained release phase carrier, institute Active constituents of medicine is stated to be 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 piece, sustained release ball, the sustained-release matrix in tablet, the slow release layer in double-layer tablets, the sustained release label of coating tablet and the sustained release of coated pellet At least one of 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 the second aspect of the present invention, there is provided a kind of preparation method of the sustained release preparation of levamlodipine or its salt, its Feature is, the sustained release preparation of described 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, described levamlodipine or its salt includes step：By institute Active constituents of medicine is stated to be included in the sustained release phase.
The sustained release can be mutually suitably composed with any, it is preferred that 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, there is provided a kind of sustained release preparation of levamlodipine or its salt, it is characterized in, including Mutually 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 of sink conditions is met for 2.5mg~20mg Discharged up in the deenergized period of 14 hours.
The active constituents of medicine can be included in the quick-release phase and the sustained 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 the weight of the remainder of described 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 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 the weight of the remainder of described 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 part by weight In, further, 15% weight of a part >=active constituents of medicine of described active constituents of medicine and≤it is described 40% weight of active constituents of medicine, the pharmaceutical activity of the weight of the remainder of described active constituents of medicine >=60% into Point and the 85% weight of≤active constituents of medicine.
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 the weight of the remainder of described 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 More than 90% weight of the active constituents of medicine in phase discharged within the deenergized period of 30 minutes, the institute in the sustained release phase State and more than 90% weight of active constituents of medicine discharged within the deenergized period of 6 hours to 14 hours.
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 More than 90% weight discharged within the deenergized period of 15 minutes, 90% weight of the active constituents of medicine in the sustained release phase Discharged above within the deenergized period of 6 hours to 12 hours.
The quick-release phase and the sustained release can be mutually suitably composed with any, it is preferred that the quick-release mutually also contains Quick-release phase carrier, a part for described active constituents of medicine are included in the quick-release phase carrier, and the sustained release mutually also contains Phase carrier is sustained, the remainder of described active constituents of medicine is included in the sustained release phase carrier, the quick-release phase carrier It is each independent or the quick-release phase carrier is coated on described be sustained outside 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.
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 piece, sustained release ball, the sustained-release matrix in tablet, the slow release layer in double-layer tablets, the sustained release label of coating tablet and the sustained release of coated pellet At least one of 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 the fourth aspect of the present invention, there is provided a kind of preparation method of the sustained release preparation of levamlodipine or its salt, its It is characterised by, the sustained release preparation of described 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, described levamlodipine or its salt includes following step Suddenly：
(1) by a part for described active constituents of medicine be included in the quick-release phase in, by described pharmaceutical activity into The remainder divided is included in the sustained release phase；
(2) make the quick-release phase mutually each 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 be mutually suitably composed with any, it is preferred that the quick-release mutually also contains Quick-release phase carrier, the sustained release is mutually also containing sustained release phase carrier, in the step (1), by described active constituents of medicine A part is included in the quick-release phase carrier, and the remainder of described active constituents of medicine is included in into the sustained release mutually carries In body；In the step (2), make the quick-release phase carrier and the sustained release phase carrier each 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：
1st, the sustained release preparation of levamlodipine of the invention or its salt includes sustained release phase, sustained release mutually containing pharmaceutical activity into Point, active constituents of medicine is levamlodipine or its salt, active constituents of medicine with levamlodipine be calculated as 2.5mg~ 20mg, in the dissolution medium of sink conditions is met, more than 90% weight of active constituents of medicine released at 6 hours to 12 hours Put in the cycle and discharge, therefore, easy to use, curative effect of medication is high, takes that compliance is good, and adverse reaction is few, suitable for large-scale promotion Using.
2nd, 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 each 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 remainder 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 of sink conditions is met, it is more than 90% weight of active constituents of medicine Discharged in the deenergized period of 6 hours to 14 hours, therefore, can quick acting, and for a long time maintain steady effective blood drug concentration, fit In large-scale promotion application.
3rd, 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 each 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 remainder 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 of sink conditions is met, it is more than 90% weight of active constituents of medicine Discharged in the deenergized period of 6 hours to 14 hours, it is therefore, ingenious in design, it is simple for structure, there is good stability, suitable for big rule Mould popularization and application.
4th, the preparation method of the sustained release preparation of levamlodipine of the invention or its salt includes step：By pharmaceutical activity into 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 2.5mg~20mg is calculated as, so as to which the sustained release preparation of levamlodipine or its salt be made, is meeting the dissolution medium of sink conditions In, more than 90% weight of active constituents of medicine discharged within the deenergized period of 6 hours to 12 hours, therefore, ingenious in design, system Standby easy, the sustained release preparation of obtained levamlodipine or its salt is easy to use, and curative effect of medication is high, and it is good to take compliance, no Good reaction is few, suitable for large-scale promotion application.
5th, the preparation method of the sustained release preparation of levamlodipine of the invention or its salt comprises the following steps：(1) by institute A part for the active constituents of medicine stated is included in the quick-release phase, and the remainder of described active constituents of medicine is included In the sustained release phase；(2) make the quick-release phase mutually each independent with the sustained release, 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, so as to which the sustained release preparation of levamlodipine or its salt be made, in the dissolution medium of sink conditions is met, More than 90% weight of active constituents of medicine discharged within the deenergized period of 6 hours to 14 hours, it is therefore, ingenious in design, prepare Simplicity, the sustained release preparation of obtained levamlodipine or its salt can quick acting, and maintain steady effectively blood medicine dense for a long time Degree, suitable for large-scale promotion application.
6th, the preparation method of the sustained release preparation of levamlodipine of the invention or its salt comprises the following steps：(1) by institute A part for the active constituents of medicine stated is included in the quick-release phase, and the remainder of described active constituents of medicine is included In the sustained release phase；(2) make the quick-release phase mutually each independent with the sustained release, 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, so as to which the sustained release preparation of levamlodipine or its salt be made, in the dissolution medium of sink conditions is met, More than 90% weight of active constituents of medicine discharged within the deenergized period of 6 hours to 14 hours, it is therefore, ingenious in design, prepare Simplicity, the sustained release preparation of obtained levamlodipine or its salt is ingenious in design, simple for structure, has good stability, is suitable to 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 combinations thereof specially pointed out in appended claims.
Brief description of the drawings
Fig. 1 be the present invention levamlodipine or its salt sustained release preparation the first specific embodiment main view perspective show It is intended to, for the capsule containing quick-release ball 1 and sustained release ball 2.
Fig. 2 be the present invention levamlodipine or its salt sustained release preparation the second specific embodiment main view perspective show It is intended to, for the capsule containing fast-release tablet 3 and sustained release tablets 4.
Fig. 3 be the present invention levamlodipine or its salt sustained release preparation the 3rd specific embodiment main view perspective show It is intended to, to contain the outside capsule with the coated pellet of quick-release coatings 5, inside with sustained release capsule core 6.
Fig. 4 be the present invention levamlodipine or its salt sustained release preparation the 4th specific embodiment main view perspective show It is intended to, is the tablet that sustained release ball 2 is enclosed with quick-release matrix 7.
Fig. 5 be the present invention levamlodipine or its salt sustained release preparation the 5th specific embodiment main view perspective show It is intended to, for the bilayer tablet that quick-release matrix 8 is contained on upper strata, sustained-release matrix 9 is contained in lower floor.
Fig. 6 be the present invention levamlodipine or its salt sustained release preparation the 6th specific embodiment main view perspective show It is intended to, is that outside has sustained-release coating layer 10, the coating tablet that internal lower floor is boosting layer 11, internal upper strata is medicine-containing particle 12.
Fig. 7 be the present invention levamlodipine or its salt sustained release preparation the 7th specific embodiment main view perspective show It is intended to, is that outside has quick-release coatings 13, the coating tablet that inside is sustained release tablets 4.
Fig. 8 is that the levamlodipine of the present invention or the sustained release preparation of its salt have the tablets in vitro of single-phase drug release behavior bent Line.
Fig. 9 is that the levamlodipine of the present invention or the spansule of its salt have 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 blood medicine after the levamlodipine of the oral present invention of beasle dog or the sustained-release tablet and reference preparation of its salt Concentration time curve；
Embodiment
The invention provides a kind of levamlodipine or the sustained release preparation of its salt, containing sustained release mutually or containing quick-release phase and Phase is sustained, in the dissolution medium of sink conditions is met, within the deenergized period of 6 hours to 14 hours, is had more than 90% weight 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 its 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 medicine The sustained release preparation of specification and the demand for the treatment of, levamlodipine of the invention or its salt, quick-release phase pharmaceutical active composition account for 0wt%~50wt% of active constituents of medicine total amount, preferably 10wt%~45wt%, more preferably 15wt%~40wt%； Sustained 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 sustained release preparation of its salt, the design of quick-release phase can To ensure the rapid release of medicine well, meet the needs of medicine rapid-onset, be rapidly achieved treatment concentration；Sustained release phase is set Meter can ensure the steady release of active component, it is ensured that on blood pressure level higher daytime, active component sustained release, make hypertension The blood pressure held stationary of patient, and can be adjusted correspondingly in blood pressure level relatively low night, plasma drug level.
The levamlodipine of the present invention or the sustained release preparation of its salt, when the quick-release phase pharmaceutical active composition is 0wt%, sustained release phase pharmaceutical active composition is when be 100wt%, that is, only containing phase is sustained when, according to Chinese Pharmacopoeia 2015 editions The requirement of drug release determination, in the dissolution medium of sink conditions is met, active constituents of medicine discharges more than 90wt% time 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 composition is 0wt%~50wt%, when sustained release phase pharmaceutical active composition is 50wt%~100wt%, according to 2015 editions releases of Chinese Pharmacopoeia The requirement of measure is spent, in the dissolution medium of sink conditions is met, in the quick-release phase pharmaceutical active composition preferably 30 minutes There is more than 90wt% to discharge, there is more than 90wt% to discharge in more preferably 15 minutes；The sustained release phase pharmaceutical active composition release More than 90wt% time 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 phase is sustained 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 mutually carries 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 Carrier is released to be preferably but not limited to sustained release tablets, be sustained ball, the sustained release base for being formulated as the sustained release tablets of several units or being 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 can use capsule, tablet, double-layer tablets, coating tablet, The form of coated pellet, realize drug release behavior of the present invention.
1st, capsule
The levamlodipine of the present invention or the capsule of one of the formulation 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. Prepared etc. conventional method well-known to those skilled in the art；Medicine can also be lived by way of fluidized bed coating carries medicine Property composition, 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 by the conventional method well-known to those skilled in the art such as wet granulation, extrusion spheronization and is sustained Ball；Active constituents of medicine can also be disperseed by way of fluidized bed coating carries medicine or contained to carry medicine in formation in blank capsule core Capsule core, then 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 well mixed, it is filling then to carry out capsule.
(2) (referred to as it is coated containing the outside coated pellet with sustained release capsule core 6 with quick-release coatings 5, inside containing quick-release 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 that is sustained capsule core 6, can be by will be upper The sustained release ball 2 stated in (1) carries out the operation preparation of subsequent packet quick-release coatings 5 as sustained release capsule core 6.Specifically, can be by institute The sustained release ball 2 stated, by way of fluidized bed coating carries medicine, active constituents of medicine and suitable amount of adhesive are dispersed or dissolved in bag In clothing solvent, contain in being sustained on ball 2, form described outside with quick-release coatings 5, the internal bag with sustained release capsule core 6 Clothing ball；It is finally that described 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 the way that the mixture of active constituents of medicine, diluent and other auxiliary materials be directly pressed It is prepared by piece.Any technical staff known selection to these functional excipients and diluent in this area.Or 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 dried, and adds lubricant, 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 area staff such as fluid bed, high-efficiency coating pot can also be passed through Well known coating mode, is coated to the fast-release tablet containing active constituents of medicine, in label expoeridium extended release coatings membrane material shape Into.
Finally, by the fast-release tablet 3 and sustained release tablets 4, according to required active component dosage strengths, it is filling to carry out capsule.
2. tablet
The tablet of the levamlodipine of the present invention or one of the sustained release preparation formulation of its salt, as shown in Figure 4, can pass through The tablet being made up 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 0wt%~50wt% active constituents of medicine, the sustained release mutually active constituents of medicine containing 50wt%~100wt% are described Active constituents of medicine gross weight is counted as 2.5mg~20mg using levamlodipine.
The tablet that described 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 pass through being sufficiently mixed active constituents of medicine, diluent and other auxiliary materials or by wet method system 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, 50wt%~95wt% diluent, and 1wt%~45wt% other auxiliary materials.
It is described 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 delayed Release ball；Active constituents of medicine can also be disperseed by way of fluidized bed coating carries medicine or contained to carry in formation in blank capsule core Pill core, then 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 1wt%~25wt% active constituents of medicine, 10wt%~70wt% extended release coatings membrane materials, 1wt%~3wt% antiplastering aid, 0wt%~70wt% diluent, and 0wt%~10wt% other auxiliary materials.
Finally, by quick-release matrix 7 and sustained release ball 2, it is well mixed according to the specification ratio of active component, then by with spy The tablet press machine of different agitating function, it is tabletted.
3. double-layer tablets
The double-layer tablets of the levamlodipine of the present invention or one of the formulation of sustained release preparation of its salt can be by with lower section Formula, realize 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 is mutually slow release layer；Gross weight based on active constituents of medicine is 100% weight meter, and the quick-release mutually contains 0wt% ~50wt% active constituents of medicine, the sustained release mutually live by the active constituents of medicine containing 50wt%~100wt%, the medicine Property composition counts gross weight as 2.5mg~20mg using levamlodipine.
The double-layer tablets of the sustained release preparation of the described levamlodipine with two-phase drug release behavior or its salt, are shown in Fig. 5 institutes Show, comprising 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 0wt%~10wt% active constituents of medicine, 50wt%~ 95wt% diluent, and 1wt%~45wt% other auxiliary materials.
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 5wt%~10wt% active constituents of medicine, 10wt%~75wt% sustained-release matrix matrix, 20wt%~60wt% diluent, 0.1wt%~20wt% other auxiliary materials.
Finally, by quick-release matrix 8 and sustained-release matrix 9, it is separately added into the hopper of tablet press machine, is pressed into double-layer tablets.
4. coating tablet
The levamlodipine of the present invention or the coating tablet of one of the formulation of sustained release preparation of its salt can be by with lower sections Formula, realize drug release behavior of the present invention.
When the quick-release phase pharmaceutical active composition is 0wt%, and sustained release phase pharmaceutical active composition is 100wt%, i.e., The quick-release mutually be not present when, as shown in Figure 6, can by by active constituents of medicine, hydrophilic polymers, osmotic pressure accelerator with And other auxiliary materials etc., pelletized after being well mixed by conventional method well-known to those skilled in the art, obtain medicine-containing particle；Will Promote osmopolymer, osmotic pressure accelerator and other auxiliary materials etc., mixed by conventional method well-known to those skilled in the art Pelletized after uniformly, obtain boosting layer particle；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 forms levamlodipine or the sustained release coating piece of its salt.
When the quick-release phase pharmaceutical active composition is 0wt%~50wt%, being sustained phase pharmaceutical active composition is During 50wt%~100%, can by by active constituents of medicine, sustained-release matrix matrix, hydrophilic polymers, diluent and other Auxiliary material etc., direct tablet compressing system is used by tabletting after conventional method well-known to those skilled in the art granulation or after being well mixed 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 the 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, PVP, 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 Change the 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, PVP, is total to PVP, 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 carboxymethylcellulose, sodium carboxymethyl starch, PVP In one or more.
Blank capsule core of the present invention is selected from sucrose capsule core, starch capsule core, microcrystalline cellulose capsule core, silica ball One kind in core, hydroxypropyl cellulose capsule core.
Other auxiliary materials of the present invention, including the one or more in lubricant, colouring agent, adhesive；
Lubricant of the present invention is selected from magnesium stearate, stearic acid, sodium stearyl fumarate, talcum powder and superfine silica gel powder In one or more；
Colouring agent of the present invention is selected from iron oxide red, iron oxide yellow, iron oxide purple, iron oxide black, titanium dioxide In one or more.
Adhesive of the present invention be selected from hydroxypropyl methyl cellulose, PVP, 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, described in detail especially exemplified by following examples.All hundred Divide and be weight percentage than, unless otherwise specified.
Embodiment 1：Capsule containing sustained release ball
I pill core) is carried
II) bag barrier gown
III) bag extended release coatings
1.1 carry the preparation of medicine coating solution
Weigh adhesive (hydroxypropyl cellulose, copolyvidone or PVP) in right amount, be scattered in 95% ethanol solution, The coating solution that solid content is 10% is configured to, is sufficiently mixed uniformly；The levamlodipine of recipe quantity is weighed again, is uniformly dispersed It is standby as the load medicine coating solution of sustained release phase in above-mentioned coating solution.
1.2 carry medicine
Blank capsule core (microcrystalline cellulose capsule core or sucrose capsule core) is added into fluid bed, regulation intake, EAT, mist Change the operating parameters such as pressure, spray into the sustained release prepared 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) adds the appropriate aqueous solution and is diluted to the sustained release clothing film coating that solid content is 15% Liquid, by the way of the spray coating of fluid bed bottom, it is injected to and carries on pill core, sustained release ball is made.
Capsule is filling：The sustained release ball that above-mentioned preparation is completed, it is filling to carry out capsule.
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 is dissolution medium, and rotating speed is 75 turns per minute, is operated 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 supplement mutually synthermal, same volume Long-pending dissolution medium, supernatant is taken as need testing solution；Separately take levamlodipine reference substance appropriate, accurately weighed, solubilization It is diluted to after agent dissolving with dissolution medium in every 1mL containing about the μ g of levamlodipine 20, as reference substance solution.Take above two Solution, by UV-VIS spectrophotometry (four general rules 0401 of Chinese Pharmacopoeia version in 2015), determined at 237nm wavelength Absorbance, calculate the stripping quantity of every.
Wherein, the releasing result of prescription 2 is shown in Fig. 8, and insoluble 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), using equivalent progressively increase method it is well mixed after, add fluid bed；Using 80% ethanol solution as viscous Mixture is pelletized；Dry to moisture and be less than 5%, cross 20 mesh sieve whole grains, then add magnesium stearate, mix, as benzene sulfonic acid Levamlodipine slow-releasing granules；According to recipe quantity, the suitable sustained release tablets of hardness are pressed into.
Capsule is filling：The sustained release tablets that above-mentioned preparation is completed, it is filling to carry out capsule.
Drug release determination method is the same as embodiment 1；
Wherein, the releasing result of prescription 4 is shown in Fig. 8, and insoluble 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. moistureproof clothing film
Preparation method is as follows：
The preparation of medicated layer：By maleic acid levo amido chloro diping and hydrophilic polymer (PVP, copolyvidone), oxidation Iron oxide yellow, using equivalent progressively increase method it is well mixed after, add fluid bed；Spray into 95% ethanol-water solution granulation；Dry to water Divide content to be less than 5%, cross 20 mesh sieves, whole grain, obtain medicine-containing particle, then add magnesium stearate, mix, it is standby；
The preparation of boosting layer：By sodium carboxymethyl starch, hydroxypropyl methyl cellulose K15M, sodium chloride, copolyvidone S630 And iron oxide red, after being well mixed, fluid bed is added, sprays into 95% ethanol-water solution granulation；Dry to moisture and be less than 5%, 20 mesh sieves are crossed, whole grain, obtain boosting layer particle, then, magnesium stearate is added, mixes, it is standby；
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；
Bag extended release coatings：Cellulose acetate is dissolved in acetone soln, Macrogol 4000 is dissolved in the aqueous solution, two kinds molten Liquid is hybridly prepared into pellicle coating solution；Above-mentioned inspection qualified double-deck core is put in high-efficiency coating pot, using pellicle bag Clothing liquid is coated；Product after coating is dried 12 hours under the conditions of 45 DEG C, removes unnecessary 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 moistureproof clothing：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, produce.
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 is dissolution medium, and rotating speed is 75 turns per minute, is operated 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 supplement mutually synthermal, same volume Long-pending dissolution medium, supernatant is taken as need testing solution；Separately take maleic acid levo amido chloro diping reference substance appropriate, precision claims It is fixed, it is diluted to after solubilizer dissolving with dissolution medium in every 1mL containing about the μ g of maleic acid levo amido chloro diping 20, it is molten as reference substance Liquid.Above two solution is taken, according to UV-VIS spectrophotometry (four general rules 0401 of Chinese Pharmacopoeia version in 2015), Absorbance is determined at 237nm wavelength, calculates the stripping quantity of every.
Wherein, the releasing result of prescription 9 is shown in Fig. 8, and insoluble 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. it is sustained ball
I pill core) is carried
II) bag barrier gown
III) bag 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 capsule core or sucrose capsule core) add fluid bed, adjust into The operating parameters such as air quantity, EAT, bed temperature, flow velocity, atomizing pressure, spray into the quick-release prepared and mutually carry medicine coating solution, as Quick-release ball.
It is sustained ball：
1.1 carry the preparation of medicine coating solution
Weigh adhesive (copolyvidone or PVP) in right amount, be scattered in 95% ethanol solution, be configured to solid content For the coating solution of 10% PVP, it is sufficiently mixed uniformly；The levamlodipine of recipe quantity is weighed again, is evenly dispersed in above-mentioned It is standby as the load medicine coating solution of sustained release phase in coating solution.
1.2 carry medicine
Blank capsule core (microcrystalline cellulose capsule core or sucrose capsule core) is added into fluid bed, regulation intake, EAT, mist Change the operating parameters such as pressure, spray into the sustained release prepared and mutually carry medicine coating solution, carry out load medicine, as load pill core；Sustained release is wrapped Clothing liquid aqueous dispersion (Sulisi, Utech) adds the appropriate aqueous solution and is diluted to the sustained release clothing film coating that solid content is 15% Liquid, by the way of fluidized bed coating, it is injected to and carries on pill core, sustained release ball is made.
Capsule is filling：The quick-release ball and sustained release ball that above-mentioned preparation is completed, after fully being mixed according to prescription ratio, carry out glue Capsule is filling.
Drug release determination method is the same as embodiment 1；
Wherein, the releasing result of prescription 10 is shown in Fig. 9, and insoluble 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 With equivalent progressively increase method it is well mixed after, add fluid bed；Pelletized using the aqueous solution as adhesive；Dry to moisture and be less than 5%, 20 mesh sieve whole grains are crossed, then add magnesium stearate, are mixed, as Levamlodipine besylate immediate-release granules；According to place Fang Liang, it 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, PVP, carbomer or polyoxyethylene), using equivalent progressively increase method it is well mixed after, add fluid bed；It is molten with 80% ethanol Liquid is pelletized as adhesive；Dry to moisture and be less than 5%, cross 20 mesh sieve whole grains, then add magnesium stearate, mix, make For Levamlodipine besylate slow-releasing granules；According to recipe quantity, the suitable sustained release tablets of hardness are pressed into.
Capsule is filling：The fast-release tablet and sustained release tablets that above-mentioned preparation is completed, combine and mix according to prescription ratio, carry out capsule It is filling.
Drug release determination method is the same as embodiment 1；
Wherein, the releasing result of prescription 13 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 Release mutually drug release amount and reach the 90% of sustained-release dosage, 8 hours drug release amounts of insoluble 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) bag barrier gown
III) bag extended release coatings
IV) bag 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, sprays into recipe quantity Blank capsule core (microcrystalline cellulose or sucrose capsule core) on, as carry pill core；
Bag extended release coatings：Sustained release coating liquid aqueous dispersion is added into the appropriate aqueous solution to dilute, mixed, as sustained release clothing film bag Clothing liquid, by the way of fluidized bed coating, it is injected to and carries on pill core, sustained release ball is made.
Bag quick-release clothing：Maleic acid levo amido chloro diping and adhesive are scattered in 95% ethanol solution, mixed, made For quick-release clothing coating solution, by the way of fluidized bed coating, it is injected on sustained release ball, 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, capsule filling is carried out according to recipe quantity Dress.
Drug release determination method is the same as embodiment 1；
Wherein, the releasing result of prescription 18 is shown in Fig. 9, and insoluble 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 up of quick-release matrix and sustained release ball
1. quick-release matrix (1000)
2. it is sustained ball
I pill core) is carried
II) bag 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 increase method it is well mixed after, add fluid bed；Spray into the granulation of the 10% PVP aqueous solution；Dry to moisture and be less than 5%, 20 mesh sieves are crossed, whole grain, then add magnesium stearate, are mixed, as levamlodipine quick-release matrix.
It is sustained ball：First, by levamlodipine and adhesive (hydroxypropyl cellulose, PVP), it is dissolved or dispersed in In the aqueous solution, it is configured to carry drug solns, by the way of fluidized bed coating, sprays into the blank capsule core (microcrystalline cellulose of recipe quantity Or sucrose capsule core) on, as load pill core；Extended release coatings membrane material (ethyl cellulose or acrylic resin), talcum powder are distinguished It is scattered in appropriate ethanol solution, mixes, as sustained release clothing film coating liquid, by the way of fluidized bed coating, is injected to load On pill core, sustained release ball is made.
Tabletting：Quick-release matrix that above-mentioned preparation is completed, sustained release ball are well 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, the releasing result of prescription 20 is shown in Figure 10, and insoluble 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：Levamlodipine besylate and diluent is (microcrystalline cellulose, pregelatinized starch, mannitol, poly- Tie up ketone), using equivalent progressively increase method it is well mixed after, add fluid bed；Pelletized using the aqueous solution as adhesive；Dry to moisture and contain Amount is less than 5%, crosses 20 mesh sieves, whole grain, then adds magnesium stearate, mixes, as Levamlodipine besylate quick-release matrix.
Sustained-release matrix：By Levamlodipine besylate and diluent (mannitol, copolyvidone), sustained-release matrix matrix (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose), using equivalent progressively increase method it is well mixed after, add stream Change bed；Pelletized using 95% ethanol solution as adhesive；Dry to moisture and be less than 5%, cross 20 mesh sieves, whole grain, Ran Houjia Enter magnesium stearate, mix, 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, the releasing result of prescription 22 is shown in Figure 10, and insoluble 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. bag 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), using equivalent progressively increase method it is well mixed after, add fluid bed；Spray into 85% ethanol The aqueous solution is pelletized；Dry to moisture and be less than 5%, cross 20 mesh sieves, whole grain, then add magnesium stearate, mix, then suppress The sustained release tablets label suitable into hardness；
Bag quick-release clothing：Quick-release clothing coating solution is prepared according to quick-release clothing prescription, above-mentioned sustained release tablets are 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 the same as embodiment 3；
Wherein, the releasing result of prescription 25 is shown in Figure 10, and insoluble 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 dogs 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, puts in heparinised tubes, centrifuges (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 quick-release phase can ensure that primary drugs are fast well Quick-release is put, and meets the needs of medicine rapid-onset；Phase release time maintenance about 6 hours to 14 hours is sustained, is maintained more stable Blood concentration, blood pressure fluctuation of concentration is avoided, it is safer effective；This product can improve the single-dose of levamlodipine Dosage, strengthen therapeutic effect on the basis of, there is provided a kind of compliance is good, adverse reaction is few, can quick acting, for a long time maintain have 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 sustained release preparation of levamlodipine or its salt, Have the following advantages that：
Compared with common quick release preparation
1. the long-acting release of medicine can be realized, lasting medicine, the fluctuation of 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, be sustained pellet also have can dose fractionation the advantages of, 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, can be (white in the physiological period of needs My god) sustained release, reduce blood pressure, and can be adjusted correspondingly in activity level relatively low night, plasma drug level, subtract 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 component, keeps the blood concentration of relative constancy, reduce due to Adverse reaction caused by blood concentration is too high；
3. need to only take once daily, it is more suitable for the hypertension and patient with angina pectoris long-term prescription of moderate and severe；
Therefore, the beneficial effect of this preparation is the drug release of the sustained release preparation based on levamlodipine or its salt of the invention What behavior advantage embodied, it is embodied in：
(1) there is the sustained release preparation of two-phase drug release behavior, the design of quick-release phase, it is ensured that risen rapidly after drug administration Effect；The design of phase is sustained, then can make medicine (daytime) sustained release in the physiological period of needs, reduce blood pressure, and in activity Horizontal relatively low night, plasma drug level can be adjusted correspondingly；
(2) dosage can be improved, the complicated processes of dosage adjustment is eliminated, need to only take once daily, gastrointestinal irritation 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 prescription.
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, suitable for large-scale promotion application.
As can be seen here, the purpose of the present invention is achieved completely and effectively.The function and structural principle of the present invention Shown and illustrated in embodiment, under without departing substantially from the principle, embodiment can make any modification.So this hair The bright all variant embodiments included based on claim spirit and right.

Claims (5)

1. the sustained release preparation of a kind of levamlodipine or its salt, it is characterised in that the sustained release preparation is containing sustained release tablets Capsule, the sustained release tablets include Levamlodipine besylate, mannitol, sustained-release matrix matrix and magnesium stearate, wherein, institute State sustained-release matrix matrix and be selected from hydroxypropyl cellulose GXF, 30 POVIDONE K 30 BP/USP 90, PVP K30, carbomer and/or polyoxyethylene；Institute The active constituents of medicine stated in sustained release preparation is Levamlodipine besylate, and the active constituents of medicine is with levamlodipine 2.5mg~20mg is calculated as, in the dissolution medium of sink conditions is met, more than 90% weight of the active constituents of medicine 6 Discharged in hour to the deenergized period of 12 hours.
2. the sustained release preparation of levamlodipine as claimed in claim 1 or its salt, it is characterised in that with 1000 capsules Meter, the sustained release preparation contain 14 grams Levamlodipine besylate, 40 grams of mannitol, 2 grams of magnesium stearate and by The sustained-release matrix matrix of the carbomer of 57 grams of 90,40 grams of 30 POVIDONE K 30 BP/USP and 5 grams of PVP K30 composition.
3. the sustained release preparation of levamlodipine as claimed in claim 1 or its salt, it is characterised in that with 1000 capsules Meter, the sustained release preparation contain 7 grams of Levamlodipine besylate, 35 grams of mannitol, 2 grams of magnesium stearate and by 47 Gram hydroxypropyl cellulose, 20 grams of carbomer and 5 grams PVP K30 composition sustained-release matrix matrix.
4. the sustained release preparation of levamlodipine as claimed in claim 1 or its salt, it is characterised in that with 1000 capsules Meter, the sustained release preparation contain 28 grams Levamlodipine besylate, 30 grams of mannitol, 2 grams of magnesium stearate and by The sustained-release matrix matrix of 57 grams of polyoxyethylene, 10 grams of carbomer and 5 grams of PVP K30 composition.
A kind of 5. preparation method of the sustained release preparation of levamlodipine or its salt, it is characterised in that described left-handed ammonia chlorine Flat or its salt sustained release preparation is the sustained release preparation of the levamlodipine or its salt as any one of Claims 1-4, The preparation method of the sustained release preparation of described levamlodipine or its salt includes step：
By Levamlodipine besylate and mannitol, sustained-release matrix matrix, using equivalent progressively increase method it is well mixed after, add stream Change bed；
Pelletized using 80% ethanol solution as adhesive；
Dry to moisture and be less than 5%, cross 20 mesh sieve whole grains, then add magnesium stearate, mix, as the left-handed ammonia of benzene sulfonic acid Flordipine slow-releasing granules；
According to recipe quantity, the suitable sustained release tablets of hardness are pressed into；
The sustained release tablets that above-mentioned preparation is completed, it is filling to carry out capsule.
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