CN100571703C - Sustained-release micro-pellet of trimetazidine and preparation method thereof - Google Patents
Sustained-release micro-pellet of trimetazidine and preparation method thereof Download PDFInfo
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- CN100571703C CN100571703C CNB2006101662052A CN200610166205A CN100571703C CN 100571703 C CN100571703 C CN 100571703C CN B2006101662052 A CNB2006101662052 A CN B2006101662052A CN 200610166205 A CN200610166205 A CN 200610166205A CN 100571703 C CN100571703 C CN 100571703C
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Abstract
A kind of slow-release micro-pill that contains active pharmaceutical ingredient trimetazidine or its officinal salt, it is characterized in that forming by the film-coat layer that contains pill core and control drug release, the weight ratio that contains the film-coat layer of pill core and control drug release is 20: 1～5: 1, the content of Trimetazidine Hydrochloride is 10%～60% in the ball core, main employing is extruded spheronization and is prepared the ball core, and fluid bed carries out coating.
Description
Technical field
The invention belongs to the technical field of medicament slow release preparation, exactly relate to a kind of slow-release micro-pill that contains active component trimetazidine or its officinal salt and preparation method thereof.
Background technology
The trimetazidine chemical name is 1-(2,3, a 4-trimethoxy benzyl) piperazine, and structural formula is as follows:
Trimetazidine can with sour salify, its dihydrochloride is widely used in clinically at home and abroad at present, is mainly used in the prophylactic treatment of angina pectoris attacks, and dizzy and complementary symptomatic treatment tinnitus.Along with going deep into gradually of clinical research, trimetazidine promises to be a line medicine that resists myocardial ischemia.
Trimetazidine belongs to other class antianginal cardiovascular drugses.Trimetazidine stops the decline of ATP level in the cell by the energy metabolism of protection cell under anoxia or ischemia, thereby has guaranteed the normal operation of the normal function and the permeable membrane sodium-potassium stream of ionic pump, keeps the stable of intracellular environment.
Therefore the control experiment of patient with angina pectoris shows: (1) trimetazidine can increase the coronary blood flow deposit, rises the 15th day of begin treatment, and lag motion brings out the generation of ischemia; (2) trimetazidine can limit the rapid fluctuations of blood pressure and the rhythm of the heart does not significantly change; (3) trimetazidine can significantly reduce the frequency of angina pectoris attacks; (4) trimetazidine can obviously reduce the use of trinitroglycerin.
The oral post-absorption of trimetazidine is rapid.Single oral trimetazidine 20mg, 1.8h reach peak plasma concentration 53.6 μ gL
-1, area can reach 508.9 μ ghL under the Cot curve
-1Each oral trimetazidine 20mg, every day 3 times, behind the 15d, peak plasma concentration can reach 84.8 μ gL
-1, continuing to take for a long time, area can reach 831.4 μ ghL under the Cot curve
-1The trimetazidine bioavailability can reach 88.7%, and protein binding rate is about 16%, and the blood plasma distribution volume is 318.6L, T
1/2Be 6h, 80% medicine is from renal excretion (wherein 62% is original shape), and total body clearance is 37.45Lh
-1Trimetazidine does not influence liver enzyme activity, and the pharmacokinetics of medicines such as digoxin, theophylline class is not had obvious influence.
According to the slow releasing preparation requirement, its delivery time should prolong to some extent than ordinary preparation.The original purpose of slow releasing preparation mainly is to improve the safety of medication and effectiveness and patient's compliance, and this mainly realizes by control drug plasma level and reduction administration frequency.With regard to ordinary preparation, most drug all exists the treatment window, and blood level is lower than the treatment window, does not then reach due therapeutic effect, is higher than the treatment window and then poisoning symptom can occurs.Therefore safe and effective for medication proposed the notion of therapeutic index (TI).So-called therapeutic index can be with the highest blood drug level (C that can tolerate
Max) and can produce the minimum blood drug level (C of appropriate therapeutic effect
Min) between ratio represent.
For medicine with linearity, single compartment model characteristic, the relation between its spacing of doses (τ) and the therapeutic index (TI) as shown in the formula:
τ＜t
1/2(lnTI/ln2) (1)
T in the following formula
1/2Be the half-life of medicine because the therapeutic index of most drug is about about 2, so the spacing of doses of most drug less than its half-life, this dosage regimen will reduce patient's compliance greatly.
Concerning the medicine with many compartments characteristic, its spacing of doses can be described with following formula.
τ＜0.693MRT(lnTI/In2) (2)
MRT is a mean residence time in the body, will be by the spacing of doses of gained in (2) formula more less than (1) formula, and administration is more frequent.
Generally, prolonging dosing interval can solve by following two approach.The first is by the molecular structure of revising medicine, the elimination speed (k that reduces medicine
E1); It two is by reducing the rate of release of medicine from preparation to reduce the infiltration rate constant K of medicine
aThese two kinds of approach all can significantly reduce the fluctuation of blood drug level in the multiple dose administration.But utilize to reduce infiltration rate and postpone to discharge the restriction that will be subjected to some physiologic factor, as in the holdup time of absorption site, medicine is about 9～12h at the effective soak time of gastrointestinal.If infiltration rate is too slow, then some medicines can not be absorbed fully.If certain drug half-life is 6h or shorter, and its therapeutic index is less than 3, and then designing spacing of doses can not be greater than 12h.The preparation that short medication preparation 24h of this half-life is administered once will be very difficult.
Patent CN95103558.4 provides a kind of oral trimetazidine pharmaceutical composition that delays to discharge, and is sheet or the granule that is surrounded by release-controlled film.May be because trimetazidine T
1/2Only be 6h, inventor's purpose be again every day single dose take, so said composition cumulative release 16h has also only disengaged the medicine less than 80%, but medicine has only 9～12h at the effective soak time of gastrointestinal, is insignificant so the design medicine continues to discharge more than the 16h.In addition, the storage storehouse system of said composition control drug release is selected from the insoluble polymer of ethyl cellulose and polymethacrylic acid polymer and the mixture formation film of plasticizer.This release-controlled film has two shortcomings in forming process: the one, and film material film-forming temperature height must add a large amount of plasticizers promoting film forming, and plasticizer has a significant impact the release behavior of medicine, this is unfavorable for keeping stable drug release curve very much; The 2nd, if, also must heat-treat more than the 24h after finishing, so not only make complex process at 40 ℃～60 ℃ with the aqueous dispersion coating of above-mentioned film material, production cost increases greatly, and also very unfavorable to stability of drug.
Along with the development of pharmaceutic adjuvant new technique, the coating material of control drug release is also brought in constant renewal in.Below two kinds of sustained release coating material filming performances better.
(1) polyvinyl acetate, its chemical structural formula is as follows:
For example Kollicoat SR 30D is polyvinyl acetate 30% aqueous dispersion, wherein contains 2.5% polyvidone and 0.3% sodium lauryl sulphate as stabilizing agent; Film-forming temperature is low, does not need or only needs small amount of plasticizer, stable in properties; Become film-coat can effectively stop ingredient diffusion, swelling hardly in water; Do not need after coating is finished to do any heat treatment, have the good slow release effect, can add porogen yet to regulate drug releasing rate; Prepared sustained release coating preparation is not influenced by ion and pH value when discharging medicine; Because pliability is good, the micropill of institute's coating can be pressed into tablet.
(2) ethyl acrylate-methyl methacrylate (2: 1) copolymer is a kind of neutral polymer, and Mr is about 800,000, and its basic structure is as follows:
For example Eudragit NE 30D is a kind of white size whey dispersion liquid that contains 30% decentralized photo made from emulsion polymerization method, the tool low viscosity; This dispersion plasticity is good, easy film forming, and the time spent need not added any plasticizer, and coating is finished the after-baking time and can be shortened to several hours; Become the water insoluble and Digestive system of coating membrane, but swelling therein has lower permeability; Can share with other hydrophilic film materials such as HPMC, PVP, PEG, PVA, PVA-PVP etc., obtain the coated preparation of the good slow releasing function of tool, and this coated preparation release not influenced by ion and pH value; Because pliability is good, the micropill of institute's coating can be pressed into tablet equally.
Present commercially available product Trimetazidine Hydrochloride Tablets in healthy (trade name: vasorel) after the oral administration, trimetazidine absorbs rapidly, promptly reach plasma peaks less than 2h, eliminating the half-life approximately is 6h, need take 3 every day at least, so intravital blood drug level is easy to occur " peak valley " phenomenon, and the effective blood drug concentration weak point of holding time so not only, and toxic and side effects is big, and patient's compliance is poor.Especially take medicine evening, to morning interval long, blood drug level is very low during early morning, thereby drug effect can not steadily be brought into play.The trimetazidine hydrochloride sustained-release tablets listing that at present external existing day clothes are 2 times is domesticly also developed.The Trimetazidine Hydrochloride water solublity is very good, so as if the slow releasing preparation of matrix type be difficult to the control release rate of drugs, need to add a large amount of framework materials and blocker just can, the substrate tablet control drug release of the described long-time release trimetazidine of patent CN00138060.5 reaches 3～4h.
The sustained-release micro-pellet of trimetazidine of the present invention's preparation is compared with slow releasing tablet with ordinary tablet has following advantage: 1. micropill belongs to multiple agent type, and the defective of indivedual micropills in preparation is unlikely to the drug release behavior generation of whole preparation is had a strong impact on; 2. big at the gastrointestinal tract distribution area, the bioavailability height, zest is little; 3. be not subjected to the gastric emptying factor affecting substantially, the interior infiltration rate of the body of medicine is even and bioavailability among individuals difference is less; 4. the good fluidity of micropill is evenly big or small, is easy to handle (as coating, divided dose), can be mixed with the pastille micropill of different rates of release, to reach required release; 5. micropill pastille percentage rate scope is big, can be from 5% to more than 95%, and the maximal dose of the micropill of packing in the single capsule can reach 600～700mg; 6. the micropill that is surrounded by some slow release film-coat can be pressed into tablet, and the release behavior of medicine is unaffected substantially.
Summary of the invention
An object of the present invention is to overcome the shortcoming and defect of above-mentioned prior art, provide a kind of prescription and preparation technology more reasonable easier, patient's compliance is good, safer and more effective clinically sustained-release micro-pellet of trimetazidine preparation.
Another object of the present invention provides a kind of preparation method of sustained-release micro-pellet of trimetazidine, mainly is to use Kollicoat SR 30D or Eudragit NE 30D will contain pill core and carry out coating, makes the sustained-release micro-pellet of trimetazidine with the film-coat control drug release.Because the pliability of above-mentioned two kinds of film-coats that coating material becomes is all quite good, therefore the slow-release micro-pill that makes also can add an amount of diluent and disintegrating agent except the hard capsule of can packing into, is pressed into tablet then.
Sustained-release micro-pellet of trimetazidine of the present invention is made up of the film-coat that contains pill core and control drug release, and the weight ratio that contains the film-coat layer of pill core and control drug release is 30: 1～3: 1, preferred 20: 1～5: 1.The content of Trimetazidine Hydrochloride is 7%～80% in the ball core, preferred 10%～60%.
Sustained-release micro-pellet of trimetazidine prescription of the present invention is composed as follows:
Contain pill core and contain (pill core that contains in 100g is a Unit Weight) at least:
Trimetazidine Hydrochloride 7～80g
Diluent 20～93g
The film-coat layer contains (the film-coat layer in 100g is a Unit Weight) at least:
Film-coat material 30～98g
Porogen 0.1～20g
Containing pill core and can also adding following binding agent of 15g or an amount of wetting agent in forming of above-mentioned prescription can also add the following plasticizer of 20g during the film-coat layer is formed, respectively in 100g contain pill core and the film-coat layer is a Unit Weight.
The present invention adopts two-step method to prepare micropill, and ball core preparation method is preferably extruded spheronization, and trimetazidine and mixing diluents is even, add binding agent or only with wetting agent system soft material, regulate and suitable extrude rotating speed, round as a ball rotating speed and round as a ball time, make fine pellet core, dry then; The preferred fluidized bed coating of coating method.Film-coat material Kollicoat SR 30D or Eudragit NE 30D are diluted with an amount of water, add plasticizer, porogen and antiplastering aid, ball core coating can be made sustained-release micro-pellet of trimetazidine after the homogenize.Extruding spheronization has at present become a kind of pill method of attaching great importance in the world and using always the most, and also is the inexorable trend of domestic development, and it has following characteristics: 1. production capacity is big, and cost of equipment is lower, is easy to satisfy suitability for industrialized production; 2. the micropill diameter is determined by the hole diameter of sieve (perforated) plate, control easily, and making the ball scope is 0.5～5mm; 3. because the aperture of extruding is certain, the particle diameter size is identical, and particle size distribution range is more concentrated; 4. micropill density is big, and medicament contg is even.
The method that optimal preparation of the present invention contains pill core is as follows: 1. get the raw materials ready and batch mixing: get the trimetazidine crude drug, pulverize and cross 100 mesh sieves, add microcrystalline Cellulose, fully mixing; 2. make soft material: the material of mixing is added a certain amount of wetting agent (as 50% ethanol) make soft material; 3. soft material is extruded: soft material is dropped into be squeezed into the strip extrudate in the extruder; 4. round as a ball: as the rapid gradation of extrudate to be added in the spheronizator round as a ball, to take out behind the certain hour and promptly make micropill; 5. oven dry: the micropill that makes is promptly obtained dry micropill in 50 ℃ of baking 3～6h; 6. granulate and evaluation: screening 18～24 purpose micropills carry out quality evaluation and release is investigated.
The optimum coating method of the present invention is as follows: the trimetazidine micropill is added in the fluidising chamber, regulate air quantity most of micropill is blown afloat in fluidising chamber, regulate atomization gas pressure and constant flow pump flow velocity, make the coating solution atomizing effect good.A kind of film-coat is to form with Kollicoat SR 30D, plasticizer, Pulvis Talci and water to mix coating solution and carry out coating and get; Another kind of film-coat is to form uniform mixed liquor coating with Eudragit NE 30D, Pulvis Talci (or glyceryl monostearate), porogen and water to make.
Sustained-release micro-pellet of trimetazidine diameter of the present invention is 0.5～2.5mm, and preferred diameter is 0.6～1.5mm, can directly load hard capsule or be pressed into tablet.
It is as follows that sustained-release micro-pellet of trimetazidine of the present invention contains the adjuvant of pill core:
Diluent is one or more mixing wherein such as microcrystalline Cellulose, lactose, sucrose, starch, hypromellose, preferably microcrystalline cellulose;
Binding agent is hypromellose, polyvidone, carboxymethyl cellulose etc.;
Wetting agent is that water or concentration are the ethanol of≤95% (V/V) etc.
The used coating material of sustained-release micro-pellet of trimetazidine of the present invention is as follows:
The thin film coating material of control drug release comprises polyvinyl acetate, for example its aqueous dispersion KollicoatSR 30D; Or ethyl acrylate-methyl methacrylate (2: 1) copolymer, for example its aqueous dispersion EudragitNE 30D.
The adjunct ingredient of sustained-release micro-pellet of trimetazidine film-coat layer of the present invention is as follows:
Plasticizer comprises one or more mixing in propylene glycol, triacetin, acetyl list monoglyceride, phthalic acid ester, triethyl citrate, the Semen Ricini wet goods plasticizer;
Porogen comprises one or more mixing of water-soluble substanceses such as HPMC, PVP, PEG, PVA, PVA-PVP, mannitol, lactose, sucrose, carbamide, sodium lauryl sulphate;
Antiplastering aid comprises one or more mixing of materials such as Pulvis Talci, glyceryl monostearate and micropowder silica gel.
Sustained-release micro-pellet of trimetazidine of the present invention can be made up of the micropill of different drug release rates.The fast release micropill that can contain 10-30% in the capsule of unit dose, this fast release micropill are meant the dry micropill of no coating or are surrounded by the micropill of water-soluble film clothing.Its slow-release micro-pill part can be regulated the rate of release of medicine by adjusting coating thickness and porogen consumption.
Sustained-release micro-pellet of trimetazidine single dose 20～40mg of the present invention, day clothes secondary, its drug release rate characteristic is as follows:
The specific embodiment
Following examples just describe, and do not limit the scope of the invention.
(1) prescription:
Trimetazidine Hydrochloride 250g
Microcrystalline Cellulose 750g
50% ethanol is an amount of
(2) preparation technology:
Get the trimetazidine crude drug, pulverize and cross 100 mesh sieves, add microcrystalline Cellulose, fully mixing; An amount of wetting agent (as 50% ethanol) of material adding of mixing is made soft material; Soft material dropped into be squeezed into the strip extrudate in the extruder; The rapid gradation of extrudate is added in the spheronizator round as a ball, takes out behind the certain hour and promptly make micropill; The micropill that makes is promptly obtained dry micropill in 50 ℃ of baking 3～6h.Micropill outward appearance slyness is all spherical in shape as a result, and this moment is filling capsule or wrap film-coat with the water solublity coating material directly, makes fast release micropill.
The prepared pill core (promptly not the fast release micropill of coating) that contains of embodiment 1 is carried out coating with Kollicoat SR 30D, promptly make sustained-release micro-pellet of trimetazidine.
(1) coating fluid prescription:
Kollicoat SR 30D 100g
Propylene glycol 3g
Pulvis Talci 12g
Water 250g
(2) preparation technology:
With Kollicoat SR 30D and water mixing, add propylene glycol and Pulvis Talci, the high-speed stirred homogenize promptly gets coating solution.Adopt the low type fluid unit that declines that sprays, with 18～24 purposes not the trimetazidine fast release micropill 120g of coating add in the fluidising chamber, use the spray gun of nozzle diameter 1mm, regulate fan frequency converter and make air blast flux be about 125Lmin-1, make most of micropill be blown afloat 7～12cm in fluidising chamber, atomization gas pressure transfers to 0.2Mpa, constant flow pump flow velocity 0.9～1.2mLmin-1, make the coating solution atomizing effect good, be unlikely to again to lose too many coating solution, also do not have adhesion phenomenon between micropill substantially.The coating temperature is 35～40 ℃, coating weightening finish 9%～10%.
Release experiment: with two appendix XC first subtraction units of Chinese Pharmacopoeia version in 2005, according to the release of two appendix XD first method working samples of Chinese Pharmacopoeia version in 2005.Every capsules dress coated micropill 155mg (being equivalent to Trimetazidine Hydrochloride 35mg) is a dissolution medium with water 500ml, and rotating speed is that per minute 75 changes, operation in accordance with the law, through 1h, 2h, when 4h and 8h, it is an amount of to get solution, filters, precision is measured subsequent filtrate 5ml, puts in the 10ml measuring bottle, is diluted to scale with the sulfuric acid solution of 0.1mol/L, shake up, according to ultraviolet visible spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2005 A), measure absorbance at the wavelength place of 232nm, press C
14H
22N
2O
3Absorptance (the E of 2HCl
1cm 1%) be the release of every of 286 calculating, result such as Fig. 1.
The pill core (promptly not the fast release micropill of coating) that contains that embodiment 1 is made carries out coating according to following coating fluid prescription, makes sustained-release micro-pellet of trimetazidine.
(1) coating fluid prescription:
Eudragit NE 30D 100g
5%HPMC solution 8mL
Pulvis Talci 40g
Water 110g
(2) preparation technology:
Get Eudragit NE 30D, HPMC and Pulvis Talci by above-mentioned prescription, the high speed homogenize gets final product coating, and art for coating is substantially with embodiment 2,25～28 ℃ of coating temperature, and coating weightening finish 11%～12%, coating finishes baking 6h in rearmounted 40 ℃ of calorstats.Every capsules dress 150mg coated micropill (being equivalent to Trimetazidine Hydrochloride 35mg) is measured release, result such as Fig. 2 with the method described in the embodiment 2.
Every capsules slow-release micro-pill 123mg (being equivalent to Trimetazidine Hydrochloride 28mg) that fast release micropill 28mg (being equivalent to Trimetazidine Hydrochloride 7mg) that embodiment 1 makes and embodiment 2 make that packs into, measure release, result such as Fig. 3 according to the method described in the embodiment 2.
Every capsules slow-release micro-pill 117mg (being equivalent to Trimetazidine Hydrochloride 26mg) that fast release micropill 36mg (being equivalent to Trimetazidine Hydrochloride 9mg) that embodiment 1 makes and embodiment 3 make that packs into, measure release, result such as Fig. 4 according to the method described in the embodiment 2.
Description of drawings
Fig. 1 embodiment 2 sustained-release micro-pellet of trimetazidine cumulative release curves
Fig. 2 embodiment 3 sustained-release micro-pellet of trimetazidine cumulative release curves
Fig. 3 embodiment 4 sustained-release micro-pellet of trimetazidine cumulative release curves
Fig. 4 embodiment 5 sustained-release micro-pellet of trimetazidine cumulative release curves
Claims (6)
1, a kind of preparation method of sustained-release micro-pellet of trimetazidine is characterized in that this preparation method comprises following prescription and step:
The I composition of writing out a prescription:
(1) contains pill core composition consumption (g/g)
Trimetazidine Hydrochloride 7%～80%
Diluent 20%～93%
Binding agent 0～15%
Wetting agent is an amount of
(2) film-coat layer composition consumption (g/g)
Film-coat material 30%～98%
Plasticizer 0～20%
Porogen 0～20%
Antiplastering aid 2%～70%
II preparation method and step:
(1) microsphere and its preparation is selected from centrifugal granulation or extrudes spheronization.Extruding spheronization is that trimetazidine and mixing diluents is even, adds binding agent or only with wetting agent system soft material, regulates suitable to extrude rotating speed, round as a ball rotating speed and round as a ball time, makes fine pellet core, then drying;
(2) coating method is selected from coating pan method or fluidized bed process.Fluidized bed coating is that coating material Kollicoat SR 30D is diluted with an amount of water, adds plasticizer, porogen and antiplastering aid, ball core coating can be made sustained-release micro-pellet of trimetazidine after the homogenize.
Wherein:
A. the thin film coating material of control drug release is selected from the aqueous dispersion product K ollicoat SR 30D of polyvinyl acetate;
B. the plasticizer that cooperates coating material to use is selected from one or more mixing in propylene glycol, triethyl citrate, triacetin, acetyl list monoglyceride, phthalic acid ester or the Oleum Ricini;
C. porogen is selected from one or more mixing in hydroxypropyl methylcellulose, polyvinylpyrrolidone, Polyethylene Glycol, polyvinyl alcohol, polyvinyl alcohol-polyvinylpyrrolidone mixture, mannitol, lactose, sucrose or the sodium lauryl sulphate;
D. antiplastering aid is selected from one or more mixing in Pulvis Talci, glyceryl monostearate or the micropowder silica gel.
2, the preparation method of sustained-release micro-pellet of trimetazidine according to claim 1 is characterized in that:
(1) diluent that contains pill core is selected from one or more the mixing in microcrystalline Cellulose, lactose, sucrose, starch or the hydroxypropyl methylcellulose;
(2) binding agent that contains pill core is selected from hydroxypropyl methylcellulose, polyvidone or carboxymethyl cellulose;
(3) contain pill core wetting agent be selected from water or concentration ethanol for≤95% (v/v).
3, a kind of trimetazidine pellet composition is characterized in that comprising fast release micropill and slow-release micro-pill as claimed in claim 1.Wherein fast release micropill is the dry micropill of no coating or the micropill that is surrounded by the water-soluble film clothing.
4, sustained-release micro-pellet of trimetazidine according to claim 1 is characterized in that single dose is 30～40mg, and its drug release rate characteristic is as follows:
5, trimetazidine pellet composition according to claim 3 is characterized in that single dose is 30～40mg, contains fast release micropill 10%～30% in the compositions, and its drug release rate characteristic is as follows:
6,, it is characterized in that the micropill diameter is 0.5～2.5mm according to claim 1 or 3 described sustained-release micro-pellet of trimetazidine.
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| CN102429872B (en) * | 2011-11-25 | 2013-07-10 | 舒泰神（北京）生物制药股份有限公司 | Zileuton-containing membrane-controlled slow release pellets and preparation method thereof |
| FR2986431B1 (en) * | 2012-02-03 | 2017-03-17 | Servier Lab | PROLONGED RELEASE OF TRIMETAZIDINE PHARMACEUTICAL COMPOSITION, PROCESS FOR THE PRODUCTION THEREOF AND USE IN THERAPEUTIC TREATMENTS |
| CN103565751A (en) * | 2013-10-17 | 2014-02-12 | 广州帝奇医药技术有限公司 | Long-acting sustained-release pellet and preparation method thereof |
| 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 |
| CN109925290B (en) * | 2017-12-18 | 2021-03-16 | 广州白云山明兴制药有限公司 | Theophylline sustained release tablet and preparation process thereof |
| CN110237053A (en) * | 2019-07-26 | 2019-09-17 | 湖北欣泽霏药业有限公司 | A kind of trimetazidine hydrochloride sustained-release pellet and preparation method thereof |
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