CN102247366B - Medicinal compositionslow-releaseformulation containing Enalapril and Felodipine - Google Patents
Medicinal compositionslow-releaseformulation containing Enalapril and Felodipine Download PDFInfo
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- CN102247366B CN102247366B CN201010181402.8A CN201010181402A CN102247366B CN 102247366 B CN102247366 B CN 102247366B CN 201010181402 A CN201010181402 A CN 201010181402A CN 102247366 B CN102247366 B CN 102247366B
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Abstract
The invention relates to a medicinal composition containing Enalapril or Enalapril-acid addition salt and Felodipine, prepared by putting slow-release pellets containing Felodipine and quick-release pellets containing Enalapril or Enalapril-acid addition salt in capsules. Each dosage unit of the medicinal composition contains 2.5-25mg of Enalapril maleate and 2.5-25mg of Felodipine. The medicinal composition can stabilize blood pressure quickly, and keep effective blood concentration for 24 hours, with increasing patient compliance. The medicinal composition is administered only once a day.
Description
Technical field
The present invention relates to one and be used for the treatment of hypertensive drug combination preparation, be specifically related to a kind of drug combination preparation containing the fast release micropill part of enalapril or enalapril-acid-addition salts and the slow-release micro-pill part containing felodipine, belong to medical art.
Background technology
Enalapril is Angiotensin-Converting (ACE) inhibitor, is hydrolyzed into dicarboxylic acids enalaprilat after oral in liver, strong inhibition Angiotensin-Converting, reduces angiotensinⅡ content, causes systemic vasodilatation, blood pressure drops.Its usual amounts 5 ~ 10mg, for accelerating onset time, must intravenous injection.This medicine treatment moderate or severe hypertension, dosage must increase to 80mg/ days, and only having an appointment, 60% hyperpietic is alone to prove effective.Enalapril is developed by merck company of the U.S. at first, within 1984, go on the market in Germany, one of best-selling prescription drug of Zeng Zuowei European & American Market, but after calendar year 2001, sales volume starts to decline, and main cause has: enalapril Patent expiry in 2000, and various countries copy one after another, similar new product constantly occurs, self there are some problems: (1) efficacy of antihypertensive treatment has certain limit, lot of documents report total effective rate is only about 60%, and 40% is invalid or curative effect is not remarkable; (2) target organ protection function is without clear superiority.And develop enalapril compound drug and can overcome above-mentioned deficiency, improve enalapril curative effect, reduce using dosage, reduce untoward reaction.
Felodipine is calcium antagonist class (CCB) antihypertensive drug, belongs to dihydropyridines.All dilating effect is had to arteria coronaria and peripheral blood vessel, have concurrently during high concentration and suppress calmodulin thus the utilization of calcium in interference cell, its feature is to small artery tool selectivity dilating effect, when therapeutic dose to cardiac muscle without negative inotropic action, prolonged application is conducive to the reverse of left ventricular hypertrophy; Slight inhibitory action is heavily absorbed with to the water of renal tubules and collecting tubule, sodium, to angina pectoris and the expansible coronary artery of patients with heart failure, increases myocardial oxygen delivery and reduce oxygen consumption; Felodipine is applicable to the treatment of each phase hypertension, especially the patients with hypertension of accompanying renal hypofunction, raynaud's sign, asthma, gout and diabetes is suitable for, also effective to pulmonary hypertension or renal hypertension, untoward reaction is light, not easily produces water, sodium retention phenomenon.The dosage form of current use is ordinary tablet and slow releasing tablet, and the felodipine sustained-release tablets carried out in the patient suffering from essential hypertension research finds, is used alone said preparation treatment mild hypertension.
Since nearly half a century, through clinical research for many years, it is found that most blood pressure can not be down to optimum level as given initial blood pressure higher patient's single drug.A large amount of clinical research shows, single medication only can make the patients' blood of 40 ~ 50% control to arrive target blood pressure.And apply two kinds of antihypertensive drugs curative effects and be greater than single medication, the blood pressure of the hyperpietic of 70 ~ 80% can be made to obtain control (Yin Hongqian. Shandong medical industry, 2000,19 (6): 58 ~ 59).Therefore, when using a kind of medicine of enough dose can not reach blood pressure target, the medicine by other classifications a kind of should be added.Most hyperpietic needs two or more antihypertensive drug to reach blood pressure target.International clinical trial proves that drug combination has it to need and is worth, the dosage of often kind of medicine is little, the effect that the therapeutical effect of medicine is worked in coordination with or is at least added, its untoward reaction can be cancelled out each other or at least not overlapping or addition (Chinese hypertension prevention and control guide Drafting Committee.China's hypertension prevention and control guide.Hypertension magazine, 2000:8 (1) 94 ~ 102,103 ~ 112).Angiotensin converting enzyme inhibitor (ACEI)+calcium antagonist (CCB) is two kinds of drug regimens metabolism being had to protective effect without any untoward reaction to the heart, kidney, used more and more by people: in expansion blood vessel, calcium antagonist (CCB) has direct expansion artery effect, and angiotensin converting enzyme inhibitor (ACEI) reduces sympathetic activity by blocking renin-angiotensin system (RAS), can artery and vein be expanded, therefore have Synergistic Hypotensive Effects; Expand vein effect because angiotensin converting enzyme inhibitor (ACEI) has, still can offset the ankle edema side effect that bihydropyridine type calcium antagonist (CCB) is common; Two medicines share the infringement also contributing to reversing target organ.In addition, in blood vessel wall localised protection and the heart, renal protection, confirmed two kinds of medicines at antiproliferative, reduce in urinaryalbumin etc. and have synergism.(Sha Chunming. combination of Chinese and Western medicine cardiovascular and cerebrovascular disease magazine, 2003,1 (7) 418-419).
Slow-release micro-pill belongs to multiple agent type, medicine is divided and is interposed between in multiple compartment, compared with single dose, there is good curative effect repeatability and less adverse reaction rate, its superiority is also: (1), micropill are evenly distributed in gastrointestinal tract, and local excitation is little; (2), oral rear and gastrointestinal tract mucous contact area increases, thus improves the bioavailability of medicine; (3) junior unit of several different release rule can be combined into multiple unit system to obtain desirable rate of releasing drug, obtain the blood drug level of expection, reach desirable curative effect; (4) its drug release behavior is the summation of multiple junior unit drug release behaviors of a composition dosage, defect in indivedual junior unit preparation technology can not produce serious influence to the drug release behavior of whole preparation, and therefore drug release kinetics can obtain predicting more accurately and favorable reproducibility; (5) junior unit can be made respectively by different pharmaceutical, then be combined into compound preparation, the stability of medicine can be increased, improve curative effect, reduce untoward reaction, and be convenient to quality control and assay when producing.(Chen Shengjun. foreign medical science pharmacy fascicle, 2004,31 (3) 177-181).In recent years, due to the development and production of new adjuvant, make slow-release micro-pill show unique superiority in slow controlled release field, be acknowledged as one of comparatively ideal slow release formulation so far.
In addition, although some micropill in the past also all contains multi-medicament component, whole drug component all mixes by work in-process, and what the preparation of existing slow release formulation medicine adopted is also same method.The present invention then have employed felodipine sustained-release according to two kinds of medicines different rate of release in vivo, the difference design that enalapril is often released, namely the way of a kind of " side's two-system " has been implemented, so more really can realize medicine to keep in vivo maintaining blood drug level effectively in 24 hours, the release of medicine is also more even.Not only increase the compliance of patient, be applicable to the needs of clinical application development, but also there is many advantages such as safety, efficient, low toxicity and taking convenience.
By retrieval, have no the pertinent literature about enalapril felodipine sustained-release micropill and patent report.
Summary of the invention
The object of this invention is to provide a kind of pharmaceutical composition slow releasing preparation containing enalapril and felodipine.This slow releasing preparation can maintain blood drug level effectively in 24 hours, and release evenly; The Drug combination of two kinds of different action pathway, has played the effect of cooperative compensating greatly, is applicable to the patient that single medicine is difficult to control blood pressure, significantly reduces again the burden of patient simultaneously; Said preparation medicine have employed rapid release and adds slow release design, both can fast and stable blood pressure, and can maintain again blood pressure lastingly steady, untoward reaction is few, and patient dependence is strong.
Technical scheme of the present invention is summarized as follows:
A pharmaceutical composition slow releasing preparation containing enalapril or enalapril-acid-addition salts and felodipine, said composition dosage form is micropill, is mixed by felodipine sustained-release micropill and enalapril or enalapril-acid-addition salts fast release micropill.
The acid of enalapril-acid-addition salts is selected from pharmaceutically useful acid, be preferably selected from maleic acid, lactic acid, sulphuric acid, acetic acid, hydrochloric acid or phosphoric acid one or both or two or more.
Aforementioned pharmaceutical compositions slow releasing preparation, in each dosage unit, the content of enalapril or enalapril-acid-addition salts is 2.5 ~ 25mg, and the content of felodipine is 2.5 ~ 25mg.
Aforementioned pharmaceutical compositions slow releasing preparation, in each dosage unit, the content of enalapril or enalapril-acid-addition salts is 5 ~ 10mg, and the content of felodipine is 5 ~ 10mg.
Aforementioned pharmaceutical compositions slow releasing preparation, in each dosage unit, the content of enalapril or enalapril-acid-addition salts is 5mg, and the content of felodipine is 5mg.
Aforementioned pharmaceutical compositions slow releasing preparation, wherein enalapril or enalapril-acid-addition salts fast release micropill are made up of enalapril or enalapril-acid-addition salts, other pharmaceutically acceptable auxiliaries and/or celphere.
Material (belonging to the adjuvant described in the application) in this application for the preparation of celphere (namely not drug containing) is not particularly limited.Such as, celphere can be formed by the microcrystalline Cellulose of 100%, or mainly to comprise percentage by weight be 50% ~ 70% filler, 10% ~ 30% binding agent and 5% ~ 20% lubricant.Generally, celphere only plays a part to load or carrying medicament.Centrifugal granulation is adopted to prepare celphere (certainly can also adopt other method to prepare) in this application: to get microcrystalline Cellulose or get 50% ~ 70% filler, 10% ~ 30% binding agent and 5% ~ 20% lubricant are placed in centrifugal granulator, take purified water as binding agent, prepare parent nucleus, drying, the ball core of screening 50 ~ 60 order particle diameters;
Adjuvant is or comprises coating material (more preferably slow release filmogen and/or framework material), filler, binding agent or lubricant etc. in this application.These adjuvants are selected according to purposes.
Preferably, aforementioned pharmaceutical compositions slow releasing preparation, the slow-release micro-pill wherein containing felodipine is the felodipine micropill of the felodipine micropill of film-controlled slow-release or the felodipine micropill of skeleton slow release or film-controlled slow-release and the combination of skeleton slow release.
Aforementioned pharmaceutical compositions slow releasing preparation, the micropill containing felodipine of film-controlled slow-release forms by containing the plain ball of felodipine, sustained release coating membrane material and other optional pharmaceutically acceptable auxiliaries, and the plain ball wherein containing felodipine adopts to be obtained by extrusion spheronization method or Blank Pellets Loading Method.
In one of the application selective embodiment, celphere may be used for preparing felodipine sustained-release micropill and enalapril (or enalapril-acid-addition salts) fast release micropill:
Felodipine sustained-release micropill is prepared by following two steps: (1) celphere Loading Method prepares felodipine element ball: by felodipine and adjuvant mix homogeneously, what be placed in centrifugal granulator supplies powder room, get celphere in pelletize pot, add binding agent, regulate whitewashing rotating speed, for powder speed, preparation, containing the plain ball of felodipine, is dried; (2) prepare felodipine sustained-release micropill: ethyl cellulose or the Aquacoat of getting recipe quantity, add purified water and make it to be uniformly dispersed, obtained sustained release coating liquid is for subsequent use; Get the plain ball of the felodipine containing step (1), be placed in coating fluid bed, spray into the sustained release coating liquid prepared and carry out coating, dry after coating; With
Enalapril (or enalapril-acid-addition salts) fast release micropill containing coatings is prepared by following two steps: (1) celphere Loading Method prepares enalapril (or enalapril-acid-addition salts) fast release micropill: celphere is placed in centrifugal coating granulator, powder is supplied with the mixture of enalapril (or enalapril-acid-addition salts) and adjuvant, additive binding agent, regulate whitewashing rotating speed, for powder speed, dry, obtained enalapril (or enalapril-acid-addition salts) micropill; (2) this micropill is placed in coating fluid bed, sprays into the ordinary coating liquid prepared and carry out coating, dry after coating.
In the present invention, also can according to extrusion spheronization legal system for enalapril (or enalapril-acid-addition salts) fast release micropill: get enalapril (or enalapril-acid-addition salts) and adjuvant and to sieve mix homogeneously, add purified water water or mass concentration is the ethanol water of 10 ~ 95%, soft material processed, 14 ~ 20 order apertures are extruded into the bar being about 3 ~ 5cm, bottom rotary speed is adjusted to 800 ~ 1000rpm, round as a ball about 3 ~ 5 minutes, dry obtained micropill; Be placed in coating fluid bed with by above-mentioned micropill, spray into and carry out coating with the coating solution of coating material preparation, dry after coating.
In an alternate embodiment of the present invention, the preparation of felodipine sustained-release micropill comprises:
(1) containing the preparation of the plain ball of felodipine: the plain ball containing felodipine can adopt a or b two kinds of method preparations:
A, extrusion spheronization method: mix after felodipine and adjuvant being sieved are the ethanol water soft material of 10 ~ 95% by water or mass concentration, through extrusion spheronization machine-processed micropill, dry, for subsequent use;
B, Blank Pellets Loading Method: first preparation contains the solution of felodipine and adjuvant, then gets celphere and is placed on the surface in fluid bed, this solution being loaded into celphere; With
(2) sustained-release coating layer: first coating membrane material with water or mass concentration are the ethanol water preparation sustained release coating liquid of 10 ~ 95%, then get plain ball and are placed in fluid bed, coating solution is sprayed to plain ball surface and carries out coating, drier.
In another alternate embodiment of the present invention, the preparation of the felodipine sustained-release micropill of skeleton slow release comprises:
(1) adopt extrusion spheronization legal system for the felodipine micropill of skeleton slow release: mix after felodipine and framework material being sieved, is the ethanol water soft material of 10 ~ 95% by water or mass concentration, through extrusion spheronization is machine-processed must micropill, drying, for subsequent use;
(2) ordinary coating liquid layer: the slow-release micro-pill prepared is placed in fluid bed, is sprayed to micropill surface and carries out coating by coating solution, dry.
Aforementioned pharmaceutical compositions, wherein slow-release micro-pill mainly comprises percentage by weight is 5% ~ 20% felodipine, 25% ~ 40% filler, 10% ~ 25% binding agent and 20% ~ 50% framework material.Skeleton slow-release material is one or more in Cera Flava, Brazil wax, stearic acid, octadecanol, hypromellose, ethyl cellulose, methylcellulose, Lac.
In another alternate embodiment of the present invention, it is the Pharmaceutical ingredients mainly comprising following percentage by weight that felodipine film-controlled slow-release releases micropill:
(1) containing the plain ball of felodipine:
Plain ball containing felodipine can adopt a or b two kinds of method preparations:
A, extrusion spheronization method (by weight): felodipine 5% ~ 40%, filler 35% ~ 70%, binding agent 5% ~ 25%;
B, Blank Pellets Loading Method (by weight): felodipine 5% ~ 20%, filler 5% ~ 20%, binding agent 5% ~ 25%, celphere 30% ~ 70%;
(2) sustained-release coating layer (by llowing group of materials pure water prepare coating solution and then carry out coating and drying and obtain)
Slow release filmogen 60% ~ 90%, lubricant 10% ~ 40%;
Be 1: 0.5 to 1: 1 (weight) containing the plain ball of felodipine and the allocation ratio of sustained-release coating layer; Above-mentioned slow release filmogen can be selected from ethyl cellulose and aqueous dispersion, cellulose acetate, crylic acid resin wherein one or more; Above-mentioned filler is selected from one or more in starch, saccharide, microcrystalline Cellulose; Above-mentioned binding agent is selected from one or more in sucrose, methylcellulose, hypromellose, polyvinylpyrrolidone; Lubricant is selected from one or more in magnesium stearate, stearic acid, silicon dioxide, Pulvis Talci.
Aforementioned pharmaceutical compositions slow releasing preparation can be capsule.
Aforementioned pharmaceutical compositions slow releasing preparation comprises the preparation of enalapril or enalapril-acid-addition salts fast release micropill and the preparation of felodipine sustained-release micropill, then the enalapril obtained or enalapril-acid-addition salts micropill and felodipine micropill is filled in by a certain percentage in capsule shells according to assay result.
Aforementioned pharmaceutical compositions, wherein the preparation of enalapril or enalapril-acid-addition salts fast release micropill comprises: from enalapril or enalapril-acid-addition salts, microcrystalline Cellulose and/or hypromellose, then micropill is prepared in presence of water with optional sucrose and lactose, dry, with optionally carry out coating at outer surface ordinary coating liquid further, drier.
Preferably, the coating material (or ordinary coating material) of coatings comprises or is selected from hypromellose (HPMC), ethyl cellulose and aqueous dispersion thereof, stearic acid, cellulose acetate, crylic acid resin wherein one or more.One or more in these materials prepare coating solution with water, and the part by weight of coating material and water is preparing in proportion conventional in the field of medicaments containing the various pharmaceutical dosage forms of coatings and is that those skilled in the art are known.
Other adjuvant is selected from one or both or the two or more combinations in lactose, microcrystalline Cellulose, Pulvis Talci, magnesium stearate, castor oil hydrogenated and polyvidone class (such as PVP K30) in this application.
Beneficial effect of the present invention is: the slow releasing preparation pharmaceutical composition that the invention provides a kind of enalapril and felodipine, the antihypertensive drugs that two kinds of mechanism of action are different, and not only have complementary hypotensive effect, also can cancel each other its side effect.Present invention employs felodipine sustained-release, the difference design that enalapril is often released, both can fast and stable blood pressure, medicine can be made again within 24 hours, to maintain effective blood drug level in vivo, the release of medicine evenly.Improve the compliance of patient, safety, efficient, low toxicity and taking convenience, be applicable to the needs of clinical application development.
Detailed description of the invention
By following instance enalapril felodipine pharmaceutical combination preparation of the present invention done and illustrate further, but be not limited in following instance.
Embodiment 1 enalapril maleate felodipine sustained-release pellet capsule (1000 formula)
Ball core:
Felodipine 5g
Enalapril maleate 5g
Microcrystalline Cellulose 160g
HPMC 30g
Purified water 200g
Sustained release coating composition (coating solution):
Aquacoat 250g
Purified water adds to 1000ml
Common outer coatings composition (ordinary coating liquid):
Opadry 15g
Purified water adds to 1000ml
(1) felodipine element ball is prepared: felodipine, microcrystalline Cellulose, HPMC are crossed 80 mesh sieves respectively, felodipine is mixed homogeneously with 100g microcrystalline Cellulose, 35gHPMC, add purified water soft material, 14 ~ 20 order apertures are extruded into the bar being about 3 ~ 5cm, bottom rotary speed is adjusted to 800 ~ 1000rpm, round as a ball about 3 ~ 5 minutes, dry, for subsequent use;
(2) prepare felodipine sustained-release micropill: get recipe quantity Aquacoat, add purified water and make it to be uniformly dispersed, obtained sustained release coating liquid, for subsequent use; Get the plain ball containing felodipine, be placed in coating fluid bed, spray into the sustained release coating liquid prepared and carry out coating, dry after coating;
(3) enalapril maleate fast release micropill is prepared: separately get enalapril maleate and sieve mix homogeneously with surplus (i.e. 80g) microcrystalline Cellulose, 15gHPMC, add purified water, soft material processed, 14 ~ 20 order apertures are extruded into the bar being about 3 ~ 5cm, bottom rotary speed is adjusted to 800 ~ 1000rpm, round as a ball about 3 ~ 5 minutes, dry; Enalapril maleate micropill is placed in coating fluid bed, sprays into the ordinary coating liquid prepared and carry out coating, dry after coating;
(4) slow releasing capsule of enalapril maleate and felodipine is prepared: according to the felodipine content recorded and enalapril maleate content, get during the felodipine sustained-release micropill of above drying and enalapril maleate fast release micropill incapsulate by a certain percentage according to assay result, to obtain final product.
Embodiment 2 enalapril maleate felodipine sustained-release pellet capsule (1000 formula)
Ball core:
Felodipine 2.5g
Enalapril maleate 25g
Sucrose 50g
Microcrystalline Cellulose 400g
HPMC 10g
Purified water 300g
Sustained release coating composition (coating solution):
Aquacoat 250g
Purified water adds to 1000ml
Common outer coatings composition (ordinary coating liquid):
Opadry 15g
Purified water adds to 1000ml
Preparation method:
(1) prepare celphere: adopt centrifugal granulation to prepare the blank pill heart: to get 300g microcrystalline Cellulose and be placed in centrifugal granulator, be binding agent, prepare parent nucleus with purified water, dry, the ball core of screening 50 ~ 60 order particle diameters is for subsequent use;
(2) celphere Loading Method prepares felodipine element ball: felodipine, 40g microcrystalline Cellulose cross 80 mesh sieves, and 60 mesh sieves crossed by sucrose.Felodipine, sucrose, microcrystalline Cellulose mix homogeneously; what be placed in centrifugal granulator supplies powder room; get the blank pill heart prepared by step (1) in pelletize pot; with 3%HPMC aqueous solution for binding agent; regulate whitewashing rotating speed, for powder speed; preparation, containing the plain ball of felodipine, is dried, for subsequent use.
(3) prepare felodipine sustained-release micropill: get recipe quantity Aquacoat, add purified water and make it to be uniformly dispersed, obtained sustained release coating liquid is for subsequent use; Get the plain ball containing felodipine, be placed in coating fluid bed, spray into the sustained release coating liquid prepared and carry out coating, dry after coating;
(4) celphere Loading Method prepares enalapril maleate fast release micropill: the celphere that step (1) is obtained is placed in centrifugal coating granulator, with enalapril maleate, 60g microcrystalline Cellulose and sucrose mixture for powder, with 5%HPMC aqueous solution for binding agent, regulate whitewashing rotating speed, for powder speed, dry, for subsequent use; Enalapril maleate micropill is placed in coating fluid bed, sprays into the ordinary coating liquid prepared and carry out coating, dry after coating;
(5) enalapril maleate felodipine sustained-release capsule is prepared: according to the felodipine content recorded and enalapril maleate content, get during the felodipine sustained-release micropill of above drying and enalapril maleate fast release micropill incapsulate by a certain percentage according to assay result, to obtain final product.
Embodiment 3 enalapril maleate felodipine sustained-release pellet capsule (1000 formula)
Ball core:
Felodipine 25g
Enalapril maleate 2.5g
Octadecanol 60g
PVP 12g
Microcrystalline Cellulose 150g
0.5%HPMC aqueous solution 200g
Common outer coatings composition (ordinary coating liquid):
Opadry 10g
Purified water 450g
(1) felodipine sustained-release micropill is prepared: felodipine crosses 80 mesh sieves, join after stirring in the octadecanol of melting, add PVP mix homogeneously, let cool and solidify rear porphyrize, mix homogeneously with 60g microcrystalline Cellulose, with 0.5%HPMC aqueous solution soft material, 14 ~ 20 order apertures are extruded into the bar being about 3 ~ 5cm, and bottom rotary speed is adjusted to 800 ~ 1000rpm, round as a ball about 3 ~ 5 minutes, drying, for subsequent use; Get containing felodipine micropill, be placed in coating fluid bed, spray into the ordinary coating liquid prepared and carry out coating, dry after coating;
(2) spheronization prepares enalapril maleate fast release micropill: separately get enalapril maleate and surplus (90g) microcrystalline Cellulose and progressively increase after principle mixs homogeneously according to equivalent, add purified water soft material, 14 ~ 20 order apertures are extruded into the bar being about 3 ~ 5cm, bottom rotary speed is adjusted to 800 ~ 1000rpm, round as a ball about 3 ~ 5 minutes, drying, for subsequent use;
(3) enalapril maleate felodipine sustained-release capsule is prepared: according to the felodipine content recorded and enalapril maleate content, get during the felodipine sustained-release micropill of above drying and enalapril maleate fast release micropill incapsulate by a certain percentage according to assay result, to obtain final product.
Embodiment 4 enalapril maleate felodipine sustained-release pellet capsule (1000 formula)
Ball core:
Felodipine 15g
Enalapril maleate 10g
Glyceryl monostearate 50g
Palmic acid wax 20g
Lactose 80g
Microcrystalline Cellulose 300g
3%HPMC aqueous solution 200g
Common outer coatings composition (ordinary coating liquid):
Opadry 25g
Purified water 800g
(1) spheronization prepares felodipine sustained-release micropill: felodipine crosses 100 mesh sieves, join after stirring in the glyceryl monostearate of melting, Palmic acid wax, cooling, scrapes porphyrize, mixs homogeneously with lactose (60g), with 3%HPMC aqueous solution soft material, 14 ~ 20 order apertures are extruded into the bar being about 3 ~ 5cm, and bottom rotary speed is adjusted to 800 ~ 1000rpm, round as a ball about 3 ~ 5 minutes, drying, for subsequent use; Get containing felodipine micropill, be placed in coating fluid bed, spray into the ordinary coating liquid prepared and carry out coating, dry after coating;
(2) prepare celphere: adopt centrifugal granulation to prepare the blank pill heart: to get 200g microcrystalline Cellulose and be placed in centrifugal granulator, be binding agent, prepare parent nucleus with purified water, dry, the ball core of screening 50 ~ 60 order particle diameters is for subsequent use;
(3) celphere Loading Method prepares enalapril maleate fast release micropill: the blank pill heart of step (2) is placed in centrifugal coating granulator, with enalapril maleate, 100g microcrystalline Cellulose and lactose (20g) mixture for powder, with 3%HPMC aqueous solution for binding agent, regulate whitewashing rotating speed, for powder speed, dry, for subsequent use; Enalapril maleate micropill is placed in coating fluid bed, sprays into the ordinary coating liquid prepared and carry out coating, dry after coating;
(4) enalapril maleate felodipine sustained-release capsule is prepared: according to the felodipine content recorded and enalapril maleate content, get during the felodipine sustained-release micropill of above drying and enalapril maleate fast release micropill incapsulate by a certain percentage according to assay result, to obtain final product.
Embodiment 5 enalapril maleate felodipine sustained-release pellet capsule (1000 formula)
Ball core:
Felodipine 5g
Enalapril maleate 5g
Stearic acid 50g
Microcrystalline Cellulose 200g
2%PVP-K30 alcoholic solution 200g
Purified water 200g
Sustained release coating composition (coating solution)
Eudragit RS 50g
Eudragit S 3g
Triethyl citrate 2.5g
Purified water adds to 1000ml
Preparation method:
(1) spheronization prepares felodipine element ball: felodipine, 100g microcrystalline Cellulose cross 80 mesh sieves, 60 mesh sieves crossed by ethyl cellulose, stearic acid, former/adjuvant mix homogeneously, add 2%PVP-K30 alcoholic solution soft material, 14 ~ 20 order apertures are extruded into the bar being about 3 ~ 5cm, and bottom rotary speed is adjusted to 800 ~ 1000rpm, round as a ball about 3 ~ 5 minutes, drying, for subsequent use;
(2) prepare felodipine sustained-release micropill: get recipe quantity Eudragit RS, Eudragit S, triethyl citrate, add purified water and make it to be uniformly dispersed and make coating solution, for subsequent use; Get the plain ball containing felodipine, be placed in coating fluid bed, spray into the sustained release coating liquid prepared and carry out coating, dry after coating;
(3) spheronization prepares enalapril maleate fast release micropill: separately get enalapril maleate and surplus 100g microcrystalline Cellulose and progressively increase after principle mixs homogeneously according to equivalent, add purified water soft material, 14 ~ 20 order apertures are extruded into the bar being about 3 ~ 5cm, bottom rotary speed is adjusted to 800 ~ 1000rpm, round as a ball about 3 ~ 5 minutes, drying, obtained enalapril maleate fast release micropill, for subsequent use;
(4) enalapril maleate felodipine sustained-release capsule is prepared: according to the felodipine content recorded and enalapril maleate content, get during the felodipine sustained-release micropill of above drying and enalapril maleate fast release micropill incapsulate by a certain percentage according to assay result, to obtain final product.
Pharmaceutical composition embodiment 1 prepared measures according to the method for the relevant requirements of the Pharmacopoeia of the People's Republic of China 2010 editions.
(1) dissolution determination
Get this product, put in sedimentation basket, according to dissolution method (Chinese Pharmacopoeia 2010 editions two annex XC second methods), with water 500ml for solvent, rotating speed is 50 turns per minute, through 30 minutes time, get solution appropriate, filter, get subsequent filtrate high-efficient liquid phase method and measure, result is as shown in table 1.
Table 1 enalapril maleate dissolution determination result
(2) drug release determination
Get this product, according to drug release determination method (Chinese Pharmacopoeia version in 2010 two annex X D first methods), adopt dissolution method second subtraction unit, [sodium dihydrogen phosphate liquid (1mol/L) 206ml is got with 0.4% CTAB phosphate buffer (pH6.5), sodium hydrogen phosphate liquid (0.5mol/L) 196ml, cetyl trimethyl ammonium bromide 20.0g, adding water to 5000ml] 500ml is solvent, rotating speed is 200 turns per minute, start and rotate about 30 seconds, get test sample 6, drop into respectively in 6 process containers, start timing immediately.Get solution 2ml respectively to filter at 1,4 and 7 hour, and immediately in process container, supplement same solvent 2ml.Get subsequent filtrate high-efficient liquid phase method to measure, result is as shown in table 2.
Table 2 felodipine drug release determination result
Above test data shows: the pharmaceutical composition in the embodiment of the present invention, is carrying out in vitro release test, and drug release feature meets Chinese Pharmacopoeia version annex in 2010 about the regulation of slow releasing preparation, has obvious slow releasing function.
Claims (6)
1. the preparation method of the pharmaceutical composition of Capsule form, it comprises preparation contains the slow-release micro-pill of felodipine step containing the step of the fast release micropill of enalapril maleate and preparation, then by the micropill containing enalapril maleate obtained and the step be filled in by a certain percentage according to assay result containing the micropill of felodipine in capsule shells, this ratio makes the content of enalapril maleate in each dosage unit be 5 ~ 10mg, and the content of felodipine is 5 ~ 10mg;
Wherein preparation comprises containing the step of the slow-release micro-pill of felodipine:
(1) adopt the preparation of a method containing the plain ball of felodipine:
A, extrusion spheronization method: mix after felodipine and adjuvant being sieved respectively are the ethanol water soft material of 10-95% by water or mass concentration, through extrusion spheronization machine-processed micropill, dry; Wherein: felodipine 5% ~ 40%, filler 35% ~ 70%, binding agent 5% ~ 25%; With
(2) sustained-release coating layer is formed: first use coating membrane material formulation sustained release coating liquid, then get plain ball and be placed in fluid bed, coating solution is sprayed to plain ball surface and carries out coating, drier; Wherein: slow release filmogen 60% ~ 90%, lubricant 10% ~ 40%;
Be wherein 1: 0.5 to 1: 1 (weight) containing the plain ball of felodipine and the allocation ratio of sustained-release coating layer; Above-mentioned slow release filmogen is selected from ethyl cellulose and aqueous dispersion, cellulose acetate, crylic acid resin wherein one or more; Above-mentioned filler is selected from one or more in starch, saccharide, microcrystalline Cellulose; Above-mentioned binding agent is selected from one or more in sucrose, methylcellulose, hypromellose, polyvinylpyrrolidone; Lubricant is selected from one or more in magnesium stearate, stearic acid, silicon dioxide, Pulvis Talci; And
Wherein preparation comprises containing the step of the fast release micropill of enalapril maleate:
(1) with enalapril maleate, microcrystalline Cellulose and/or hypromellose, and optional sucrose and lactose prepare micropill in presence of water, dry, and
(2) with the coating solution from coating material and Opadry and purified water preparation, coating is carried out to the micropill prepared by above step, dry.
2. method according to claim 1, wherein in each dosage unit, the content of enalapril or enalapril-acid-addition salts is 5mg, and the content of felodipine is 5mg.
3. according to the method for claim 1 or 2, wherein celphere consist of 100% microcrystalline Cellulose, or mainly to comprise percentage by weight be 50% ~ 70% filler, 10% ~ 30% binding agent and 5% ~ 20% lubricant.
4. method according to claim 1, wherein slow release filmogen is ethyl cellulose and aqueous dispersion thereof.
5. method according to claim 4, wherein binding agent is hypromellose or polyvinylpyrrolidone.
6. enalapril maleate felodipine sustained-release pellet capsule, wherein the formula of 1000 capsules is:
Ball core:
Sustained release coating composition, i.e. coating solution:
Aquacoat 250g
Purified water adds to 1000ml
Common outer coatings composition, i.e. ordinary coating liquid:
Opadry 15g
Purified water adds to 1000ml
Making each process is:
(1) felodipine element ball is prepared: felodipine, microcrystalline Cellulose, HPMC are crossed 80 mesh sieves respectively, felodipine is mixed homogeneously with 100g microcrystalline Cellulose, 35g HPMC, add purified water soft material, 14 ~ 20 order apertures are extruded into the bar of long 3 ~ 5cm, bottom rotary speed is adjusted to 800 ~ 1000rpm, round as a ball 3 ~ 5 minutes, dry, for subsequent use;
(2) prepare felodipine sustained-release micropill: get recipe quantity Aquacoat, add purified water and make it to be uniformly dispersed, obtained sustained release coating liquid, for subsequent use; Get the plain ball containing felodipine, be placed in coating fluid bed, spray into the sustained release coating liquid prepared and carry out coating, dry after coating;
(3) enalapril maleate fast release micropill is prepared: separately get enalapril maleate and surplus and 80g microcrystalline Cellulose, 15g HPMC sieves and mix homogeneously, add purified water, soft material processed, 14 ~ 20 order apertures are extruded into the bar of long 3 ~ 5cm, bottom rotary speed is adjusted to 800 ~ 1000rpm, round as a ball 3 ~ 5 minutes, dry; Enalapril maleate micropill is placed in coating fluid bed, sprays into the ordinary coating liquid prepared and carry out coating, dry after coating;
(4) slow releasing capsule of enalapril maleate and felodipine is prepared: according to the felodipine content recorded and enalapril maleate content, get during the felodipine sustained-release micropill of above drying and enalapril maleate fast release micropill incapsulate by a certain percentage according to assay result, to obtain final product.
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| CN103211793B (en) * | 2012-01-18 | 2017-06-06 | 北京天衡医院管理有限公司 | Felodipine film-controlled slow-release micro pill capsule |
| CN103222960B (en) * | 2013-05-15 | 2016-06-15 | 中国药科大学 | Oral time controlled released micropill of a kind of enalapril maleate and preparation method thereof |
| CN105287435A (en) * | 2015-12-07 | 2016-02-03 | 黑龙江省智诚医药科技有限公司 | Nicardipine hydrochloride sustained release pellets and preparation method thereof |
| CN105748422B (en) * | 2016-04-05 | 2019-02-22 | 广州白云山医药集团股份有限公司白云山制药总厂 | Pharmaceutical composition comprising enalapril and felodipine |
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| CN101548973A (en) * | 2008-03-31 | 2009-10-07 | 扬州制药有限公司 | Composition containing dihydropyridine calcium channel blocker and preparation method thereof |
| CN101674811A (en) * | 2007-02-09 | 2010-03-17 | 阿尔法制药有限公司 | A dosage form containing two or more active pharmaceutical ingredients in different physical forms |
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| KR100636546B1 (en) * | 2005-02-15 | 2006-10-19 | 한국유나이티드제약 주식회사 | Extended-release Felodipine and Enalarpril maleate Containing Oral Complexed Drug Preparations and it?s Manufacturing Process |
| CN101697970A (en) * | 2009-11-16 | 2010-04-28 | 广西方略集团崇左制药有限公司 | Medicine composite for treating and relieving high blood pressure |
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| CN101674811A (en) * | 2007-02-09 | 2010-03-17 | 阿尔法制药有限公司 | A dosage form containing two or more active pharmaceutical ingredients in different physical forms |
| CN101548973A (en) * | 2008-03-31 | 2009-10-07 | 扬州制药有限公司 | Composition containing dihydropyridine calcium channel blocker and preparation method thereof |
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Address after: Baiyun District of Guangzhou City, Guangdong province 510515 street and with the Cloud Road No. 88 Patentee after: GUANGZHOU BAIYUNSHAN PHARMACEUTICAL HOLDINGS CO., LTD., BAIYUNSHAN PHARMACEUTICAL GENERAL FACTORY Address before: Baiyun District of Guangzhou City, Guangdong province 510515 street and with the Cloud Road No. 88 Patentee before: Baiyunshan Pharmaceutical General Factory, Baiyunshan Pharmaceutical Co., Ltd, G |
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