CN109646417A - A kind of Trimetazidine sustained release tablets and preparation method thereof - Google Patents
A kind of Trimetazidine sustained release tablets and preparation method thereof Download PDFInfo
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- CN109646417A CN109646417A CN201810614996.3A CN201810614996A CN109646417A CN 109646417 A CN109646417 A CN 109646417A CN 201810614996 A CN201810614996 A CN 201810614996A CN 109646417 A CN109646417 A CN 109646417A
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- 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
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- 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
- A61K9/20—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
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of 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
- A61K9/48—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
- A61K9/5078—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 with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention belongs to technical field of medicine, it is related to a kind of Trimetazidine sustained release tablets and preparation method thereof.The sustained release tablets include tablet thin film coating coating material and the label by its coating; label includes pellet and auxiliary material; pellet successively includes carrying medicine coatings, sustained-release coating layer and protection coatings from the inside to the outside; carrying medicine coatings includes Trimetazidine and load medicine coating of pellets adhesive; sustained-release coating layer includes sustained release pellet coating coating material, pore-foaming agent, plasticizer and antiplastering aid; protecting coatings includes protection coating of pellets coating material and protection coating of pellets plasticizer, and auxiliary material includes filler, disintegrating agent and lubricant.The sustained release tablets except slow release layer due to having wrapped up protective layer again; slow-release capability decline and because the problems such as uniformity of dosage units is unqualified caused by excess liquidity caused by solve that pellet easily occurs in tableting processes destroyed because of slow release layer, while solving the problems, such as soluble drug Trimetazidine existing burst release in water.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, are related to the preparation process of Trimetazidine sustained release tablets.
Background technique
Angina pectoris is a kind of common cardiovascular disease, is to lead to coronary artery due to coronary atherosclerosis, narrow
Caused by blood supply insufficiency, myocardium ischemia and anoxic, using precordialgia as one group of syndrome of main clinical manifestation,
It is one kind of the highest coronary heart disease of incidence, seriously threatens the Health and Living of the mankind.It is broadly divided into stable angina cordis
And unstable angina pectoris.Angina pectoris can break out any time at 24 hours, but in the majority with early morning to the morning, and the variability heart twists
Mostly at night, timing breaks out pain.It is therefore desirable to which therapeutic agent can maintain always effective treatment concentration interior for 24 hours, to guarantee to control
The validity for the treatment of, safety and stability.Trimetazidine Hydrochloride belongs to other class antianginal cardiovascular drugs, is first
Act on metabolism of myocardium, by being widely used in cardiac energy metabolism and rationalizing and play direct cytoprotection
The drug of antianginal.
Trimetazidine absorbed following oral administration is rapid, half-life period relatively short [t1/2=(6.0 ± 1.4) h], Trimetazidine concentration
It can stablize interior for 24 hours, and (15d) concentration can remain relatively constant during administration.Single oral Trimetazidine 20mg, 1.8h
Reach peak plasma concentration, peak plasma concentration is 53.6 μ g/L, and area is up to 508.9 μ g/ (h under Cot curve
L).Oral Trimetazidine 20mg every time, 2 times a day, after even served 15d, peak plasma concentration can reach 84.8 μ g/L, when concentration
Area is up to 831.4 μ g/ (hL) under half interval contour.Trimetazidine bioavilability is high, and up to 88.7%, protein binding rate is about
It is 16%, blood plasma distribution volume is 318.6L, and removing half-life period is 6h, and from kidney excretion, (wherein 62% is original to 80% drug
Shape), total body clearance 37.45L/h.Trimetazidine does not influence the haemodynamics of heart, dog animal experiments show that vein is infused
0.25-1.0mg Trimetazidine is penetrated to all have no significant effect heart rate, blood pressure, cardiac output and left ventricular pressure.
The common daily single taking dose of trimetazidine tablets is 20mg, at least needs to take 3 times daily, therefore intracorporal blood medicine is dense
Degree is easy to appear " peak valley " phenomenon, and effective blood drug concentration is held time short, and toxic side effect is big, and patient compliance is poor.
Official listing sells trimetazidine hydrochloride sustained-release tablets, English to Shi Weiya (Tianjin) pharmaceutical Co. Ltd in 2010 at home
Literary fame claims Trimetazidine Dihydrochloride Modified Release Tablets, and active constituent is hydrochloric acid
Trimetazidine, specification 35mg/ piece, trade name Vasorel, daily medication 2 times.Reach maximum concentration after 5 hours oral, blood medicine is dense
Time of the degree not less than 75% is more than 24 hours, reaches stable state within 60 hours.Number is taken in reduction, improves patient's compliance.
Patent CN00138060.5 can discharge the substrate tablet of Trimetazidine, feature after providing oral administration for a long time
Be in substrate tablet to discharge without containing hydrophobic combination and for a long time be by with the hydroxypropyl first that accounts for tablet total weight 25-50%
Cellulose (HypromelloseCellulose, HPMC) mixing is controlled.Trimetazidine dihydrochloride accounts for tablet in tablet
Gross weight 15-30%, adhesive PVP account for tablet total weight 3-12%, diluent CaHPO4·2H2O accounts for tablet total weight 25-75%,
Remaining is magnesium stearate lubricant and flowable colloidal anhydrous SiO2, using wet granulation.
Patent CN95103558.4 discloses the oral Trimetazidine pharmaceutical composition for delaying release, by depots system come
Ensure the control release of Trimetazidine, the system be selected from EC and polymethacrylic acid polymer insoluble polymer and
The mixture of plasticizer citroflex A-4 forms film, which is wrapped in tablet or pill little particle.
Patent ZL200610166205.2 discloses sustained-release micro-pellet of trimetazidine and preparation method thereof, provides pellet core control
The weight ratio of the film coating of drug release processed is 20:1-5:1, and the content of Trimetazidine is 10-60% in capsule core, is mainly adopted
Capsule core is prepared with extrusion spheronization method, fluidized bed carries out sustained release coating.
Patent 20111005676.5 discloses a kind of trimetazidine hydrochloride sustained-release tablets and preparation method thereof, using poly-vinegar acid
The mixture of vinyl acetate and povidone mixture and ethyl cellulose is as sustained-release matrix material, it is characterised in that: with weight hundred
Divide than meter, it is as follows that each component accounts for total weight of tablet: 15-25% Trimetazidine Hydrochloride, 45-55%KollidonSR and ethyl are fine
Plain mixture, 25-35% filler, 0-2% lubricant and 0-1% other auxiliary materials are tieed up, using wet granulation.
Above-mentioned sustained release tablets, the formula of sustained release pellet and release membranes package piece or preparation process have the following problems:
(1) patent CN00138060.5 is slow-release material, CaHPO using the HPMC of higher proportion4·2H2O is filler,
The patent uses a large amount of dicalcium phosphate dihydrate for diluent, the calcium monohydrogen phosphate of excessively high dosage, at lower pH, medicine
After object rate of release can be dramatically speeded up, therefore drug enters stomach, it may be influenced by gastric acid and accelerate drug release.
(2) patent CN95103558.4 provides a kind of oral Trimetazidine pharmaceutical composition for delaying release, to be surrounded by
The purpose of piece or particle of release-controlled film, inventor is that daily single dose is taken.So the composition cumulative release 16h only has 80%,
Release is incomplete, the not up to requirement (>=85%) of States Pharmacopoeia specifications.In addition, drug only has 9- in the effective soak time of gastrointestinal tract
12h, design sustained release 16h or more is unnecessarily.
(3) patent ZL200610166205.2 provides a kind of preparation side of sustained-release micro-pellet of trimetazidine containing active pharmaceutical ingredient
Method mainly prepares capsule core using extrusion spheronization it is characterized in that being made of the film coating of pellet core and Drug controlled release,
Fluidized bed is coated, and in that patent, the preferred diameter of pellet is 0.6mm-1.5mm, which is relatively large in diameter and auxiliary material grain
Diameter difference is larger, can only fill and use for capsule, and Yuan Yanwei sustained release tablets are such as used for compaction of pellet, then it is uneven to be likely to occur mixing
Even phenomenon, while the patent carries pill core using extrusion spheronization preparation, obtained capsule core particle size distribution range is wider, puts
Mass production reproducibility need to take tightened up measure.
(4) patent 20111005676.5, using the mixing of polyvinyl acetate and povidone mixture and ethyl cellulose
For object as sustained-release matrix material, the composition release time is long, but drug discharged about 75% at 16 hours, and release is incomplete, not
Reach the requirement (>=85%) of States Pharmacopoeia specifications.
(5) existing Trimetazidine sustained release tablets are less weakens the rule that releases the drug using multiple-unit particle or pellet system
Reproducibility (different batches) and consistency (same batch), Trimetazidine Hydrochloride easily dissolves in water, there are problems that burst release.
Trimetazidine Hydrochloride easily dissolves in water, and solubility is greater than 1000mg/ml, therefore controls high solubility agents
Burst release be the key that of the invention.So-called burst release just refers to that slow, controlled release preparation is released in the drug bolus that release initial stage occurs
Put phenomenon.
Foreign countries have the trimetazidine hydrochloride sustained-release tablets listing for taking daily 2 times, both at home and abroad also in development, Trimetazidine at present
Water-soluble very good, simple skeleton type sustained release preparation is difficult to control the rate of release of drug, needs to add a large amount of framework material
And retarding agent, the substrate tablet Drug controlled release of the release Trimetazidine of long-time described in patent CN00138060.5 reach 3-4h.
Summary of the invention
Existing Trimetazidine sustained release tablets weaken the weight of drug release rule because not using multiple-unit particle or pellet system
Existing property (different batches) and consistency (same batch), Trimetazidine Hydrochloride easily dissolves in water, there are problems that burst release.
The present invention provides a kind of Trimetazidine sustained release tablets, by blank capsule core, Trimetazidine and carry medicine coating of pellets use
Adhesive, which is formed, carries medicine pellet, by load medicine pellet, sustained release pellet coating coating material, pore-foaming agent, plasticizer and anti-stick dosage form
At sustained release pellet, it is micro- that protection is formed by sustained release pellet, protection coating of pellets coating material and protection coating of pellets plasticizer
Ball forms label by pellet, filler, disintegrating agent and lubricant, is formed most by label and tablet thin film coating coating material
Whole Trimetazidine sustained release tablets.The piece finite element is quality controllable, and drug effect release behavior can reach expected in various media
Effect is all larger than 70 or more with reference preparation similar factors.
In the inventive solutions, it will include to carry medicine coating of pellets adhesive that the load medicine pellet, which is with fluidized bed,
It is made in blank capsule core with the aqueous solution liquid phase lamination of Trimetazidine.
In the inventive solutions, the sustained release pellet is that will be coated comprising pore-foaming agent, sustained release pellet with fluidized bed
It is made on carrying medicine pellet with the solution of coating material, plasticizer and antiplastering aid by liquid phase lamination.
In the inventive solutions, the protection pellet is that will be coated material comprising protection coating of pellets with fluidized bed
Material and protection coating of pellets are made on sustained release pellet with plasticizer solution by liquid phase lamination.
In the inventive solutions, the label is that will protect pellet, filler, disintegrating agent and mix lubricant,
Then tabletting is made.
In the inventive solutions, the Trimetazidine sustained release tablets are by liquid phase lamination method by tablet thin film coating
It is made with the solution liquid deposition of coating material in piece wicking surface.
In the inventive solutions, the ratio of each component is 10~20 parts of Trimetazidine, blank according to the mass fraction
10~15 parts of capsule core carries 3~5 parts of adhesive of medicine coating of pellets, 8~14 parts of sustained release pellet coating coating material, pore-foaming agent
1~5 part, 0.5~5 part of plasticizer, 0.5~2 part of antiplastering aid, protection 10~17 parts of coating material of coating of pellets, protection pellet
1~5 part of plasticizer of coating, 25~35 parts of filler, 3~4 parts of disintegrating agent, 0.1~1 part of lubricant, tablet thin film coating are used
2~5 parts of coating material.
In the inventive solutions, the sustained release tablets by following weight percent meter following component:
| Component | Mass fraction |
| Trimetazidine | 10~20 |
| Blank capsule core | 10~15 |
| Carry medicine coating of pellets adhesive | 3~5 |
| Coating material is used in sustained release pellet coating | 8~14 |
| Pore-foaming agent | 1~5 |
| Plasticizer | 0.5~5 |
| Antiplastering aid | 0.5~2 |
| Protect coating of pellets coating material | 10~17 |
| Protect coating of pellets plasticizer | 1~5 |
| Filler | 25~35 |
| Disintegrating agent | 3~4 |
| Lubricant | 0.1~1 |
| Tablet thin film coating coating material | 2~5 |
Another aspect of the invention provides a kind of preparation method of sustained-release micro-pellet of trimetazidine tabletting comprising following step
It is rapid:
1) it is sequentially added into purified water and carries medicine coating of pellets adhesive, Trimetazidine, obtain carrying medicine coating of pellets liquid；
Blank capsule core will be carried into the coating of medicine coating of pellets liquid in blank pellet surface by liquid phase lamination, obtain carrying medicine pellet；
2) pore-foaming agent, sustained release pellet coating coating material, alcoholic solvent, plasticizer and anti-stick are sequentially added into purified water
Agent obtains sustained release pellet coating solution after mixing evenly；Medicine pellet will be carried and pass through liquid phase lamination for the sustained release pellet coating solution packet
Clothing is carrying medicine pellet surface, obtains sustained release pellet；
3) protection coating of pellets coating material and protection coating of pellets plasticizer, stirring are sequentially added into purified water
Protection coating of pellets liquid is obtained after uniformly；The protection coating of pellets liquid is coated slow by sustained release pellet by liquid phase lamination
Pellet surface is released, protection pellet is obtained；
4) pellet, filler, disintegrating agent and mix lubricant, tabletting will be protected to obtain label；
5) tablet thin film coating coating material is added into purified water, obtains tablet thin film coating liquid after mixing evenly；
Tablet thin film coating liquid is coated in piece wicking surface by label by liquid phase lamination method, obtains Trimetazidine sustained release tablets.
Blank capsule core used in the present invention, be starch capsule core or microcrystalline cellulose pellet, preferably microcrystalline cellulose capsule core,
Because microcrystalline cellulose pellet does not dissolve in most of organic solvents and water, it is suitable for solution lamination medicine-feeding method, and microcrystalline cellulose
The surface of vegetable pill core is smooth, hardness is higher, is being preferably selected for coating of pellets and tabletting, and preferable particle size is 50~1000 μm, more
The microcrystalline cellulose pellet that preferable particle size is 50~500 μm, because lesser partial size and relatively narrow particle diameter distribution are conducive to pellet
Coating and tabletting.
Load medicine coating of pellets adhesive used in the present invention, is hydroxyethyl cellulose (HEC) or hydroxypropyl methyl is fine
Plain (HPMC), preferably hydroxypropyl methyl cellulose are tieed up, because hydroxypropyl methyl cellulose has preferable dispersibility, more
It is suitable for spray coating.
Sustained release pellet used herein coating coating material, is cellulose acetate (CA) or ethyl cellulose (EC),
Preferred, ethyl, because ethyl cellulose is the higher slow-release material of compactness, the clothing that cooperation organic solvent is coated
Film resistance to pressure is preferable, more suitable for compaction of pellet, the ethyl cellulose of more preferable low viscosity, because of the ethyl cellulose of low viscosity
Element generally requires more release polymer coatings, so as to obtain with certain thickness sustained release clothing film, is more advantageous to pressure
Piece.
Pore-foaming agent used in the present invention is polyethylene glycol (PEG), povidone (PVP), sucrose or hydroxypropyl methyl fiber
Plain (HPMC), preferably hydroxypropyl methyl cellulose, because hydroxypropyl methyl cellulose has suitable water solubility, as
Pore-foaming agent cooperates the ethyl cellulose of high compactness and water-insoluble, can guarantee the reasonable release of drug.
Plasticizer used in the present invention, it is excellent for repefral, dibutyl sebacate or triethyl citrate
Triethyl citrate is selected, because being applied alone clothing film physical property obtained by ethyl cellulose poor, spreading factor and anti-pressure ability
It is limited, it is often accompanied by the rupture of clothing film in tableting processes and changes the release behavior of drug, the lemon triethylenetetraminehexaacetic acid as plasticizer
Ester is introduced into, and can effectively solve the problems, such as that clothing film ruptures in tableting processes.
Antiplastering aid used in the present invention is silica, titanium dioxide or talcum powder, preferably talc powder, because selecting second
When base cellulose is coated as slow-release material, pellet is easy adhesion, and after antiplastering aid talcum powder is added, adhesion phenomenon can
It is overcome, preferred size is 500~2000 mesh, and more preferable granularity is 500~1500 mesh talcum powder, because if talcum powder
Partial size it is excessive, sedimentation is easy to happen in coating process, spray gun is caused to block；In addition, the lesser talcum powder of partial size can
Keep clothing film more closely knit complete.
Protection coating of pellets coating material used in the present invention is hydroxyethyl cellulose (HEC) or hydroxypropyl methyl
Cellulose (HPMC), preferably hydroxypropyl methyl cellulose, it is same because hydroxypropyl methyl cellulose has preferable dispersion energy
Power is more suitable for spray coating.
Protection coating of pellets plasticizer used in the present invention is polyethylene glycol (PEG), povidone (PVP) or hydroxypropyl
Ylmethyl cellulose (HPMC), preferably polyethylene glycol, because polyethylene glycol has very strong elastic deformation ability, tabletting
There is preferable protective effect to sustained release clothing film in journey, more preferable elastic deformation ability is excellent and the common polyethylene glycol being easy to get.
Filler used in the present invention is starch, dextrin, lactose or microcrystalline cellulose (MCC), preferably microcrystalline cellulose
Element works as a buffer because microcrystalline cellulose is the ideal filler of compaction of pellet in compression, can be to avoid between pellet
It directly contacts, can be obtained greater hardness under lesser pressure, to avoid destruction of the pressure to clothing film.
Disintegrating agent used in the present invention is sodium carboxymethyl starch (CMS-Na), low-substituted hydroxypropyl cellulose (L-HPC)
Or croscarmellose sodium (CCMC-Na), preferred croscarmellose sodium, because of croscarmellose sodium
Fiber properties can generate strong capillarity, thus have good water absorbing capacity；Meanwhile cross-linked carboxymethyl is fine
The cross-linking chemistry structure for tieing up plain sodium is capable of forming one kind hydrophily not soluble in water, high-hydroscopicity substance, has good quick
Expansion characteristics.Compared with other disintegrating agents, this dual function makes croscarmellose sodium when in use and has super
It is disintegrated function.
Lubricant used in the present invention is talcum powder, superfine silica gel powder or magnesium stearate, preferably magnesium stearate, because firmly
Fatty acid magnesium is easy to mix with to compressed tablet pharmaceutical particle, can reduce the frictional force between particle and punch die, plate surface after tabletting is bright and clean
It is beautiful.
Tablet thin film coating coating material used in the present invention is stomach dissolution type Opadry film coating pre-mix dose, because
For in compaction of pellet, polymer wrapped particle can deformation occurs in tableting processes, cause unilateral appearance undesirable, need
Film coating is carried out, and the covering power of Opadry is stronger, and finally obtained tablet appearance can be made uniform, beautiful, in addition,
Stomach dissolution type Opadry film coating pre-mix dose can make main ingredient begin to release and stablize in gastrointestinal tract whole process inhale in stomach
It receives.
Preparation process
The present invention also provides a kind of preparation methods of Trimetazidine sustained release tablets comprising the following steps:
1) load medicine coating of pellets adhesive, the recipe quantity of recipe quantity under agitation, are sequentially added into purified water
Trimetazidine, obtain after mixing evenly carry medicine coating of pellets liquid；The blank capsule core of recipe quantity is placed in bottom spraying type fluidized bed packet
In clothing machine, the load medicine coating of pellets liquid is coated in the blank pellet surface by liquid phase lamination method, it is micro- to obtain load medicine
Ball.
2) the sustained release pellet coating of the pore-foaming agent, recipe quantity of recipe quantity under agitation, is sequentially added into purified water
With coating material, alcohol solvent, the plasticizer of recipe quantity and recipe quantity antiplastering aid, obtain sustained release pellet packet after mixing evenly
Clothing liquid；The load medicine pellet of recipe quantity is placed in bottom spraying type fluidized-bed coating machine, by liquid phase lamination method by the sustained release pellet
Coating solution is coated on load medicine pellet surface, obtains sustained release pellet.
3) the protection coating of pellets coating material and prescription of recipe quantity under agitation, are sequentially added into purified water
The protection coating of pellets adhesive of amount obtains protection coating of pellets liquid after mixing evenly；The sustained release pellet of recipe quantity is placed in
In bottom spraying type fluidized-bed coating machine, the protection coating of pellets liquid is coated in the sustained release pellet table by liquid phase lamination method
Face obtains protection pellet.
4) lubricant of the protection pellet of recipe quantity, the filler of recipe quantity, the disintegrating agent of recipe quantity and recipe quantity is set
It is mixed in mixed machine eventually, is subsequently placed in tabletting in tablet press machine, obtains label.
5) the tablet thin film coating coating material of recipe quantity under agitation, is added into purified water, stirs evenly
After obtain tablet thin film coating liquid；The label of recipe quantity is placed in high-efficiency coating machine, by liquid phase lamination method by the tablet
Film coating liquid is coated in described wicking surface, obtains Trimetazidine sustained release tablets.
In the inventive solutions, the group of each component becomes
Or
Or
Or
Or
Beneficial effect
(1) of the invention that tablet is prepared by multiple agent type pellet, even if defect of individual pellets in preparation is not
It is seriously affected as the drug release behavior generation to whole preparation, ensure that the reproducibility (difference batch of drug release rule on the whole
It is secondary) and consistency (same batch), a possibility that reducing burst release.
Detailed description of the invention
Fig. 1 is In-vitro release curves of the trimetazidine hydrochloride sustained-release tablets in pH6.8 dissolution medium of embodiment 1,2,3,4,5
Figure.
Fig. 2 is In-vitro release curves of the trimetazidine hydrochloride sustained-release tablets in pH1.2 dissolution medium of embodiment 1,2,3,4,5
Figure.
Fig. 3 is In-vitro release curves of the trimetazidine hydrochloride sustained-release tablets in pH4.0 dissolution medium of embodiment 1,2,3,4,5
Figure.
Fig. 4 is In-vitro release curves figure of the trimetazidine hydrochloride sustained-release tablets in dissolution medium water of embodiment 1,2,3,4,5.
Specific embodiment
Instrument used in the present invention can be obtained by regular commercial means, and concrete condition is as follows:
| Device name | Model | Producer |
| It is multifunctional fluidized bed | FLZB-15 | Powerise is electromechanical |
| Ternary spin vibration sieve | S49-600-S | Henan Xinxiang screening plant |
| Efficient wet mixer-granulator | HLSG-200 | Wenzhou pharmaceutical machine |
| Boiling drier | FG-120C | Chongqing spacious mansion |
| Oscillating granulator | YK-160 | Wenzhou pharmaceutical machine |
| It is centrifuged shaking screen | ZG-550 | Wenzhou pharmaceutical machine |
| Crushing and pelletizing machine | FZB-300 | Wenzhou pharmaceutical machine |
| Mixers with Multi-direction Movement | HD-600A | Jiangnan pharmaceutical machine |
| High speed tablet press | GZPL-620 | Traditional Chinese medicines dragon is vertical |
| High-efficiency coating machine | BGB-75C | Small human relations pharmaceutical machine |
Embodiment 1:
Preparation method:
(1) medicine coating of pellets adhesive and Trimetazidine will be carried, will be dissolved in aqueous solution；Blank microcrystalline cellulose pellet
(50~500 μm) are placed in Ge Late fluidized bed, carry out the medicine-feeding of solution lamination, and intake is 300~500m3/ h, inlet air temperature
It is 40~70 DEG C, atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled 25~45
DEG C, it is prepared and carries medicine pellet；
(2) it by pore-foaming agent, sustained release pellet coating coating material, plasticizer and antiplastering aid, dissolves and is scattered in ethanol water
In solution；It carries medicine pellet to be placed in Ge Late fluidized bed, carries out sustained release coating, intake is 300~500m3/ h, inlet air temperature
It is 40~70 DEG C, atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled 25~45
DEG C, sustained release pellet is prepared；
(3) coating of pellets coating material and protection coating of pellets plasticizer will be protected, will be dissolved in aqueous solution；Sustained release
Pellet is placed in Ge Late fluidized bed, carries out protection coating, and intake is 300~500m3/ h, inlet air temperature are 40~70 DEG C,
Atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled at 25~45 DEG C, is prepared
Protect pellet.
(4) pellet and filler, disintegrating agent and mix lubricant is uniform, tablet press machine prepares label rotate at high speed, punching
Mould is No. 9 scrobiculas, and hardness is 4.0~6.0kg.
(5) label being placed in high-efficiency coating pot, film coating is carried out to it with Opadry, Opadry solid content is 10~
15%, coating weight gain is 3~5%.
Embodiment 2:
Preparation method:
(1) medicine coating of pellets adhesive and Trimetazidine will be carried, will be dissolved in aqueous solution；Blank microcrystalline cellulose pellet
(50~500 μm) are placed in Ge Late fluidized bed, carry out the medicine-feeding of solution lamination, and intake is 300~500m3/ h, inlet air temperature
It is 40~70 DEG C, atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled 25~45
DEG C, it is prepared and carries medicine pellet；
(2) it by pore-foaming agent, sustained release pellet coating coating material, plasticizer and antiplastering aid, dissolves and is scattered in ethanol water
In solution；It carries medicine pellet to be placed in Ge Late fluidized bed, carries out sustained release coating, intake is 300~500m3/ h, inlet air temperature
It is 40~70 DEG C, atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled 25~45
DEG C, sustained release pellet is prepared；
(3) coating of pellets coating material and protection coating of pellets plasticizer will be protected, will be dissolved in aqueous solution；Sustained release
Pellet is placed in Ge Late fluidized bed, carries out protection coating, and intake is 300~500m3/ h, inlet air temperature are 40~70 DEG C,
Atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled at 25~45 DEG C, is prepared
Protect pellet.
(4) pellet and filler, disintegrating agent and mix lubricant is uniform, tablet press machine prepares label rotate at high speed, punching
Mould is No. 9 scrobiculas, and hardness is 4.0~6.0kg.
(5) label being placed in high-efficiency coating pot, film coating is carried out to it with Opadry, Opadry solid content is 10~
15%, coating weight gain is 3~5%.
Embodiment 3:
Preparation method:
(1) medicine coating of pellets adhesive and Trimetazidine will be carried, will be dissolved in aqueous solution；Blank microcrystalline cellulose pellet
(50~500 μm) are placed in Ge Late fluidized bed, carry out the medicine-feeding of solution lamination, and intake is 300~500m3/ h, inlet air temperature
It is 40~70 DEG C, atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled 25~45
DEG C, it is prepared and carries medicine pellet；
(2) it by pore-foaming agent, sustained release pellet coating coating material, plasticizer and antiplastering aid, dissolves and is scattered in ethanol water
In solution；It carries medicine pellet to be placed in Ge Late fluidized bed, carries out sustained release coating, intake is 300~500m3/ h, inlet air temperature
It is 40~70 DEG C, atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled 25~45
DEG C, sustained release pellet is prepared；
(3) coating of pellets coating material and protection coating of pellets plasticizer will be protected, will be dissolved in aqueous solution；Sustained release
Pellet is placed in Ge Late fluidized bed, carries out protection coating, and intake is 300~500m3/ h, inlet air temperature are 40~70 DEG C,
Atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled at 25~45 DEG C, is prepared
Protect pellet.
(4) pellet and filler, disintegrating agent and mix lubricant is uniform, tablet press machine prepares label rotate at high speed, punching
Mould is No. 9 scrobiculas, and hardness is 4.0~6.0kg.
(5) label being placed in high-efficiency coating pot, film coating is carried out to it with Opadry, Opadry solid content is 10~
15%, coating weight gain is 3~5%.
Embodiment 4:
Preparation method:
(1) medicine coating of pellets adhesive and Trimetazidine will be carried, will be dissolved in aqueous solution；Blank microcrystalline cellulose pellet
(50~500 μm) are placed in Ge Late fluidized bed, carry out the medicine-feeding of solution lamination, and intake is 300~500m3/ h, inlet air temperature
It is 40~70 DEG C, atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled 25~45
DEG C, it is prepared and carries medicine pellet；
(2) it by pore-foaming agent, sustained release pellet coating coating material, plasticizer and antiplastering aid, dissolves and is scattered in ethanol water
In solution；It carries medicine pellet to be placed in Ge Late fluidized bed, carries out sustained release coating, intake is 300~500m3/ h, inlet air temperature
It is 40~70 DEG C, atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled 25~45
DEG C, sustained release pellet is prepared；
(3) coating of pellets coating material and protection coating of pellets plasticizer will be protected, will be dissolved in aqueous solution；Sustained release
Pellet is placed in Ge Late fluidized bed, carries out protection coating, and intake is 300~500m3/ h, inlet air temperature are 40~70 DEG C,
Atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled at 25~45 DEG C, is prepared
Protect pellet.
(4) pellet and filler, disintegrating agent and mix lubricant is uniform, tablet press machine prepares label rotate at high speed, punching
Mould is No. 9 scrobiculas, and hardness is 4.0~6.0kg.
(5) label being placed in high-efficiency coating pot, film coating is carried out to it with Opadry, Opadry solid content is 10~
15%, coating weight gain is 3~5%.
Embodiment 5:
Preparation method:
(1) medicine coating of pellets adhesive and Trimetazidine will be carried, will be dissolved in aqueous solution；Blank microcrystalline cellulose pellet
(50~500 μm) are placed in Ge Late fluidized bed, carry out the medicine-feeding of solution lamination, and intake is 300~500m3/ h, inlet air temperature
It is 40~70 DEG C, atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled 25~45
DEG C, it is prepared and carries medicine pellet；
(2) it by pore-foaming agent, sustained release pellet coating coating material, plasticizer and antiplastering aid, dissolves and is scattered in ethanol water
In solution；It carries medicine pellet to be placed in Ge Late fluidized bed, carries out sustained release coating, intake is 300~500m3/ h, inlet air temperature
It is 40~70 DEG C, atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled 25~45
DEG C, sustained release pellet is prepared；
(3) coating of pellets coating material and protection coating of pellets plasticizer will be protected, will be dissolved in aqueous solution；Sustained release
Pellet is placed in Ge Late fluidized bed, carries out protection coating, and intake is 300~500m3/ h, inlet air temperature are 40~70 DEG C,
Atomizing pressure is 3.0~5.0bar, and wriggling revolution speed is 40~80rpm, and temperature of charge is controlled at 25~45 DEG C, is prepared
Protect pellet.
(4) pellet and filler, disintegrating agent and mix lubricant is uniform, tablet press machine prepares label rotate at high speed, punching
Mould is No. 9 scrobiculas, and hardness is 4.0~6.0kg.
(5) label being placed in high-efficiency coating pot, film coating is carried out to it with Opadry, Opadry solid content is 10~
15%, coating weight gain is 3~5%.
The detection of 6 Trimetazidine sustained release tablets dissolution in vitro of embodiment
Using vitro release measuring method (2010 editions two the first methods of annex XD of Chinese Pharmacopoeia) and using dissolution measuring method
Hydrochloric acid Sibutramine Hydrochloride obtained by the device measurement embodiment of the present invention 1~10 of (2010 editions two the first methods of annex XC of Chinese Pharmacopoeia)
The drug release characteristics of his piperazine sustained release tablets and the commercially available trimetazidine hydrochloride sustained-release tablets of reference substance (name Vasorel, 35mg/ piece).
Detection to embodiment 1-5 can be seen that Sibutramine Hydrochloride in embodiment 1,2,3,4,5 by result (Fig. 1-4, table 1-4)
His piperazine sustained release tablets batch between release behavior reproducibility and batch in release behavior homogeneity it is good, show formulation and technology of the invention
Stablize, is controllable.
Table 1
Table 2
Table 3
Table 4
Claims (10)
1. a kind of Trimetazidine sustained release tablets are formed by blank capsule core, Trimetazidine and load medicine coating of pellets adhesive and are carried medicine
Pellet forms sustained release pellet by load medicine pellet, sustained release pellet coating coating material, pore-foaming agent, plasticizer and antiplastering aid, by delaying
It releases pellet, protection coating of pellets coating material and protection coating of pellets plasticizer and forms protection pellet, by pellet, filling
Agent, disintegrating agent and lubricant form label, form final Trimetazidine with coating material by label and tablet thin film coating and delay
Release piece.
2. Trimetazidine sustained release tablets according to claim 1, the load medicine pellet is will be comprising carrying medicine pellet with fluidized bed
The aqueous solution of coating adhesive and Trimetazidine is made in blank capsule core by liquid phase lamination method；The sustained release pellet be with
Fluidized bed will be existed comprising the solution of pore-foaming agent, sustained release pellet coating coating material, plasticizer and antiplastering aid by liquid phase lamination
It carries and is made on medicine pellet；The protection pellet is will be comprising protection coating of pellets coating material and protection pellet packet with fluidized bed
The solution liquid phase lamination of clothing adhesive is made on sustained release pellet；The label be will protect pellet, filler, disintegrating agent and
Mix lubricant, then tabletting is made；The Trimetazidine sustained release tablets are to be wrapped tablet thin film coating by liquid phase lamination method
The solution liquid deposition of clothing material is made in piece wicking surface.
3. a kind of preparation method of sustained-release micro-pellet of trimetazidine tabletting comprising following steps:
1) it is sequentially added into purified water and carries medicine coating of pellets adhesive, Trimetazidine, obtain carrying medicine coating of pellets liquid；It will be empty
White capsule core will carry the coating of medicine coating of pellets liquid in blank pellet surface by liquid phase lamination, obtain carrying medicine pellet；
2) pore-foaming agent, sustained release pellet coating coating material, alcoholic solvent, plasticizer and antiplastering aid are sequentially added into purified water,
Sustained release pellet coating solution is obtained after mixing evenly；Medicine pellet will be carried and be coated the sustained release pellet coating solution by liquid phase lamination
Medicine pellet surface is carried, sustained release pellet is obtained；
3) protection coating of pellets coating material and protection coating of pellets plasticizer are sequentially added into purified water, are stirred evenly
After obtain protection coating of pellets liquid；The protection coating of pellets liquid is coated in sustained release pellet by sustained release pellet by liquid phase lamination
Surface obtains protection pellet；
4) pellet, filler, disintegrating agent and mix lubricant, tabletting will be protected to obtain label；
5) tablet thin film coating coating material is added into purified water, obtains tablet thin film coating liquid after mixing evenly；By piece
Tablet thin film coating liquid is coated in piece wicking surface by core by liquid phase lamination method, obtains Trimetazidine sustained release tablets.
4. -2 described in any item Trimetazidine sustained release tablets or preparation method as claimed in claim 3 according to claim 1,
In, the ratio of each component is 10~20 parts of Trimetazidine, 10~15 parts of blank capsule core, carries medicine coating of pellets use according to the mass fraction
3~5 parts of adhesive, sustained release pellet coating 8~14 parts of coating material, 1~5 part of pore-foaming agent, 0.5~5 part of plasticizer, antiplastering aid
0.5~2 part, protection 10~17 parts of coating material of coating of pellets, protection 1~5 part of coating of pellets plasticizer, filler 25~
35 parts, 3~4 parts of disintegrating agent, 0.1~1 part of lubricant, tablet thin film coating is with 2~5 parts of coating material.
5. -2 described in any item Trimetazidine sustained release tablets or preparation method as claimed in claim 3 according to claim 1,
In, medicine coating of pellets adhesive is carried, is hydroxyethyl cellulose (HEC) or hydroxypropyl methyl cellulose (HPMC), preferably hydroxypropyl
Ylmethyl cellulose.
6. -2 described in any item Trimetazidine sustained release tablets or preparation method as claimed in claim 3 according to claim 1,
In, sustained release pellet coating is cellulose acetate (CA) or ethyl cellulose (EC), preferred, ethyl with coating material；
Pore-foaming agent is polyethylene glycol (PEG), povidone (PVP), sucrose or hydroxypropyl methyl cellulose (HPMC), preferably hydroxypropyl
Methylcellulose；
Plasticizer is repefral, dibutyl sebacate or triethyl citrate, optimization citric acid triethyl；
Antiplastering aid is silica, titanium dioxide or talcum powder, preferably talc powder.
7. -2 described in any item Trimetazidine sustained release tablets or preparation method as claimed in claim 3 according to claim 1,
In, coating of pellets plasticizer is protected, is polyethylene glycol (PEG), povidone (PVP) or hydroxypropyl methyl cellulose (HPMC),
It is preferred that polyethylene glycol；
Coating of pellets coating material is protected, is hydroxyethyl cellulose (HEC) or hydroxypropyl methyl cellulose (HPMC), preferably hydroxyl
Propyl methocel.
8. -2 described in any item Trimetazidine sustained release tablets or preparation method as claimed in claim 3 according to claim 1,
In, filler is starch, dextrin, lactose or microcrystalline cellulose (MCC), preferably microcrystalline cellulose；
Disintegrating agent is sodium carboxymethyl starch (CMS-Na), low-substituted hydroxypropyl cellulose (L-HPC) or cross-linked carboxymethyl cellulose
Sodium (CCMC-Na), preferably croscarmellose sodium；
Lubricant is talcum powder, superfine silica gel powder or magnesium stearate, preferably magnesium stearate.
9. -2 described in any item Trimetazidine sustained release tablets or preparation method as claimed in claim 3 according to claim 1,
In, film coating coating material is stomach dissolution type Opadry film coating pre-mix dose.
10. -2 described in any item Trimetazidine sustained release tablets or preparation method as claimed in claim 3 according to claim 1,
Wherein, blank capsule core is starch capsule core or microcrystalline cellulose pellet, preferably microcrystalline cellulose capsule core.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810614996.3A CN109646417B (en) | 2018-06-14 | 2018-06-14 | Trimetazidine sustained release tablet and preparation method thereof |
| PCT/CN2018/095425 WO2019237446A1 (en) | 2018-06-14 | 2018-07-12 | Trimetazidine sustained-release tablet and preparation method therefor |
Applications Claiming Priority (1)
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| CN201810614996.3A CN109646417B (en) | 2018-06-14 | 2018-06-14 | Trimetazidine sustained release tablet and preparation method thereof |
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Cited By (2)
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| CN114010615A (en) * | 2021-12-28 | 2022-02-08 | 郑州大学第一附属医院 | Donepezil hydrochloride sustained-release tablet and preparation method thereof |
| CN116270514A (en) * | 2023-03-22 | 2023-06-23 | 北京恒创星远医药科技有限公司 | Micropill tablet and preparation method thereof |
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| WO2010084397A2 (en) * | 2009-01-20 | 2010-07-29 | Micro Labs Limited | Modified release solid pharmaceutical compositions of trimetazidine and process thereof |
| WO2012113894A1 (en) * | 2011-02-25 | 2012-08-30 | Deva Holding Anonim Sirketi | Pharmaceutical combination of betahistine and trimetazidine |
| CN104473905A (en) * | 2014-11-20 | 2015-04-01 | 美吉斯制药（厦门）有限公司 | Trimetazidine hydrochloride sustained-release capsule and preparation method thereof |
| CN107595795A (en) * | 2017-08-30 | 2018-01-19 | 北京华素制药股份有限公司 | A kind of Metoprolol succinate sustained-release tablets and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102133195A (en) * | 2011-03-17 | 2011-07-27 | 王国栋 | Trimetazidine dihydrochloride sustained control release pellet and preparation method thereof |
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2018
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- 2018-07-12 WO PCT/CN2018/095425 patent/WO2019237446A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010084397A2 (en) * | 2009-01-20 | 2010-07-29 | Micro Labs Limited | Modified release solid pharmaceutical compositions of trimetazidine and process thereof |
| WO2012113894A1 (en) * | 2011-02-25 | 2012-08-30 | Deva Holding Anonim Sirketi | Pharmaceutical combination of betahistine and trimetazidine |
| CN104473905A (en) * | 2014-11-20 | 2015-04-01 | 美吉斯制药（厦门）有限公司 | Trimetazidine hydrochloride sustained-release capsule and preparation method thereof |
| CN107595795A (en) * | 2017-08-30 | 2018-01-19 | 北京华素制药股份有限公司 | A kind of Metoprolol succinate sustained-release tablets and preparation method thereof |
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| CN114010615A (en) * | 2021-12-28 | 2022-02-08 | 郑州大学第一附属医院 | Donepezil hydrochloride sustained-release tablet and preparation method thereof |
| CN114010615B (en) * | 2021-12-28 | 2023-03-24 | 郑州大学第一附属医院 | Donepezil hydrochloride sustained-release tablet and preparation method thereof |
| CN116270514A (en) * | 2023-03-22 | 2023-06-23 | 北京恒创星远医药科技有限公司 | Micropill tablet and preparation method thereof |
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| WO2019237446A1 (en) | 2019-12-19 |
| CN109646417B (en) | 2020-10-16 |
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