CN104274419A - Trimetazidine hydrochloride sustained release tablet taking glyceryl behenate as framework material and preparation method of trimetazidine hydrochloride sustained release tablet - Google Patents
Trimetazidine hydrochloride sustained release tablet taking glyceryl behenate as framework material and preparation method of trimetazidine hydrochloride sustained release tablet Download PDFInfo
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Abstract
The invention belongs to the field of sustained-release drug preparations, and particularly relates to a trimetazidine hydrochloride sustained release tablet taking glyceryl behenate as a framework material and a preparation method of the trimetazidine hydrochloride sustained release tablet. According to the main technical scheme disclosed by the invention, a sustained-release preparation is prepared from trimetazidine hydrochloride as an effective component, only glyceryl behenate as a sustained-release framework material and auxiliary materials such as a small amount of release speed regulator. According to the trimetazidine hydrochloride sustained release tablet provided by the invention, an in vitro release rate experiment shows that the drug release is not affected by the pH environment, compared with commercially available 'vasorel' (trimetazidine dihydrochloride tablet), the trimetazidine hydrochloride sustained release tablet has good similarity (f2 is greater than 65); and the Beagle pharmacokinetic experiment in dogs shows that the trimetazidine hydrochloride sustained release tablet has bioequivalence in comparison with 'vasorel'. One trimetazidine hydrochloride sustained release tablet provided by the invention is taken twice a day, and the trimetazidine hydrochloride sustained release tablet is convenient to take, has good medicine compliance in patients, and is capable of keeping steady state plasma concentration for a long period of time. The preparation method disclosed by the invention is simple and stable in process, and is easily put into volume production.
Description
Technical field:
The invention belongs to sustained release pharmaceutical formulation field, relate to a kind of novel form of Trimetazidine Hydrochloride, for the prophylactic treatment of angina pectoris attacks, and complementary symptomatic treatment that is dizzy, tinnitus, specifically a kind of take Glyceryl Behenate as trimetazidine hydrochloride sustained-release tablets of framework material and preparation method thereof.
Background technology:
Trimetazidine Hydrochloride (Trimetazidine dihydrochloride); chemical name: 1-(2; 3; 4 one trimethoxy benzyls) piperazine hydrochloride; being first medicine acting on metabolism of myocardium, is also first 3-ketone Acyl-CoA thiolase (3-KAT) inhibitor.Trimetazidine Hydrochloride can suppress fatty acid beta oxidation; impel pyruvic dehydrogenase (PDH) to activate to accelerate; myocardium glucose, lactic acid are oxidized increase; optimize energy metabolism of myocardial; protection adenosine triphosphate generative process; alleviate intracellular acidosis and stop the gathering of sodium and calcium in myocardial cell, keep the stable state of intracellular environment.In clinical practice, Trimetazidine Hydrochloride is mainly used in that anginal prophylactic treatment chord is swooned, the auxiliary treatment of tinnitus.
Trimetazidine Hydrochloride is different from traditional angina pectoris treatment medicine in chemical constitution and pharmacological action, as nitrate esters, beta-blocker and calcium ion antagonist etc., it does not rely on speed or the blood pressure drops of heart, there is the effect to antiadrenergic drug, norepinephrine and vassopressin, the resistance of blood vessel can be reduced, increase arteria coronaria and blood flow, promote the generation of myocardial metabolism and cardiac energy.Heart working load can be reduced simultaneously, reduce the consumption of myocardial oxygen consumption and cardiac energy, thus improve the equilibrium of supply and demand of myocardium oxygen.In addition, the toleration to cardiac glycoside can also be increased.The control experiment display of patient with angina pectoris, trimetazidine can increase Coronary Blood Flow Reserve, rising for the 15th day of starting to treat, can bring out the generation of ischemia by lag motion; Limit the rapid fluctuations of blood pressure and heart rate does not significantly change; The frequency of obvious reduction angina pectoris attacks, thus the use reducing glyceryl trinitrate.
Trimetazidine Hydrochloride as the new class metabolic drug of angina pectoris prevention and therapy, Europe and multiple national extensive use.Enter China in 2000, and list National essential drugs list in; National healthcare insurance catalogue is listed again in 2004.
At present, conventional tablet, the capsule of domestic main use Trimetazidine Hydrochloride, specification: 20mg/ sheet, takes 3 times/day, 1 piece/times.Trimetazidine Hydrochloride ordinary preparation water solublity is strong, and within 10 minutes, stripping quantity reaches more than 90%, and absorbed following oral administration is rapid, about 1.5 hours peak plasma concentrations time, needs repeatedly repetitively administered just can reach steady plasma-drug concentration, clinically needs to take medicine every day 3 times.Cause can not taking medicine on time, missing because patient is busy, old people forgets etc., occur that patient is to the phenomenon of drug compliance difference.Trimetazidine Hydrochloride oral absorption fast and half-life short (about 6 hours), the peak value of blood drug level can be reached at short notice after taking medicine, and upper once take medicine before will there is the minimum of blood drug level, there is the peak value of blood drug level, the recurrent fluctuations of valley, bring bad side reaction to patient.Therefore, Trimetazidine Hydrochloride ordinary preparation multiple dosage regimen, patient dependence is poor, is difficult to maintain stable blood drug level, affects the performance of drug effect.
Shi Weiya (Tianjin) pharmaceutical Co. Ltd in 2010, take the lead in going on the market at home trimetazidine hydrochloride sustained-release tablets, English name: Trimetazidine Dihydrochloride Modified Release Tablets, trade name: vasorel, specification: 35mg/ sheet, take 2 times/day, 1 piece/times.After slow releasing tablet is oral, discharge medicine lentamente, compare with corresponding ordinary preparation, administration frequency is few, can increase the compliance of patient; Blood drug level is steady, and can significantly improve the curative effect of medicine, be the focus of new drug development.
Trimetazidine Hydrochloride very easily dissolves in water, and its dissolubility is greater than 0.5g/mL, and therefore, controlling that high solubility agents prominent release is the key of trimetazidine hydrochloride sustained-release film-making.So-called dashing forward is released, and refers to a large amount of release phenomenon of medicine that sustained-release preparation occurred at the release initial stage.In addition, whole dispose procedure drug release should be non-constant velocity slow releasing.
Patent CN1124140A describes the oral trimetazidine pharmaceutical composition delaying to discharge; by the release of depots system control drug; described system is selected from ethyl cellulose (Ethyl cellulose, EC), the insoluble polymer of polymethacrylic acid polymer and the mixture of plasticizer citroflex A-4 and forms film.
The substrate tablet of trimetazidine can be discharged for a long time after patent CN1302663A describes oral administration, medicine is released through for a long time and controls with the hydroxypropyl emthylcellulose (Hypromellose Cellulose, HPMC) accounting for the heavy 25-50% of sheet.
Patent CN1931143A describes a kind of trimetazidine osmotic pump controlled-release medicinal composition, medicine discharged permeation-promoter for a long time and filmogen controls, described permeation-promoter is selected from one or more in polyoxyethylene, HPMC, hydroxyethyl-cellulose, methylcellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, friendship sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, carbomer, acrylic resin, sodium alginate, chitin, and filmogen is selected from cellulose acetate, EC.
Patent CN1994280A describes sustained-release micro-pellet of trimetazidine and preparation method thereof, by controlling the release of medicine containing pill core and slow controlled release coating layer, described coatings is selected from polyvinyl acetate Kollicoat SR3D or ethyl acrylate-methyl methacrylate Eudragit NE30D is Sustained release coating materials.
Patent CN102133195A slow controlled release micro pill describing Trimetazidine Hydrochloride and preparation method thereof, by controlling the release of medicine containing pill core and slow controlled release coating layer, described coating blocker is selected from EC or acrylic resin a kind of, and plasticizer is selected from the one in SA dibutyl ester, triglyceride or triethyl citrate.
Patent CN102764261A describes the composition and method of making the same of oral control Trimetazidine Hydrochloride release, it is characterized in that: it is controlled by chitosan, anionic polymer that slow releasing tablet Chinese medicine discharges for a long time, described anionic polymer is selected from a kind of in sodium alginate, carrageenan, carboxymethyl cellulose, acrylic resin element or compositions.
Patent CN101455668A describes preparation method and the application thereof of trimetazidine hydrochloride sustained-release tablets, and it is controlled by 25% ethyl cellulose liquid and calcium hydrogen phosphate that medicine discharges for a long time.
Patent CN10255217A describes trimetazidine slow releasing capsule and preparation method thereof, by controlling the release of medicine containing pill core and slow controlled release coating layer, it is Sustained release coating materials that described sustained-release coating layer is selected from cellulose acetate, celluloseacetate butyrate, HPMC, hypromellose titanate esters and acrylic resin.
Patent CN102670537A describes a kind of trimetazidine hydrochloride sustained-release tablets and preparation method thereof, and by the release of sustained-release matrix control of material medicine, described sustained-release matrix material is selected from vinylacetate and povidone mixture Kollidon SR, EC mixture.
Patent CN102319225A describes a kind of trimetazidine hydrochloride sustained-release tablets and preparation method thereof, and medicine is released through for a long time to mix with polyoxyethylene (Polyethylene oxide, PEO) and controls.
Patent CN102885795A describes trimetazidine hydrochloride sustained-release tablets and preparation method thereof, by the release of sustained-release matrix control of material medicine, described system is selected from one or more in ethyl cellulose, hydroxyethylmethyl-cellulose, hyprolose, hydroxypropyl methylcellulose, hydroxy methocel, hydroxy methocel, pectin, agar, Glyceryl Behenate, glyceryl monostearate, polyvidone, carbomer.In sheet, Trimetazidine Hydrochloride accounts for that sheet weighs 5 ~ 60%, sustained-release matrix material 10 ~ 24%, filler 20 ~ 80%, binding agent 1 ~ 8%, fluidizer 0.1 ~ 5% and lubricant 0.2 ~ 3%.
Formula or the preparation technology of the trimetazidine hydrochloride sustained-release preparation (slow releasing tablet, slow releasing capsule, slow-release micro-pill) described in above patent are summarized as follows:
1. from technology type, three major types can be divided into: 1. matrix type, namely medicine mix with adjuvants such as sustained-release matrix materials, pelletizing press sheet, or direct powder compression, as patent CN1302663A, CN102764261A, CN101455668A, CN102670537A, CN102319225A and CN102885795A; 2. film controlling type, namely medicine and adjuvant make granule, micropill, tablet, bag sustained-release coating layer, then tabletted or filled capsules, as CN1124140A, CN1994280A, CN102133195A and CN10255217A; 3. osmotic pump type, namely medicine and permeation-promoter etc. make label, and outer coating also punches, as CN1931143A.
Skeleton type sustained release preparation, production technology is simple, and cost is low, is the main production technology of current slow releasing preparation, existing kind of going on the market in a large number.
Film controlling type slow releasing preparation, production technology is comparatively complicated, and production equipment is expensive, and coating amount is comparatively large, and the coating cycle is longer, and production cost is high.
Osmotic pump type slow releasing preparation, production craft step is loaded down with trivial details, and quality is unstable, is unfavorable for suitability for industrialized production.
2. in skeleton type sustained release preparation, framework material used is mainly cellulose family in hydrophilic gel material, crylic acid resin, non-cellulosic polysaccharide, natural product class and insoluble framework material, wherein more with application such as HPMC, EC, acrylic resins.Hydrophilic gel material HPMC is the most frequently used sustained-release matrix material, with the slow releasing tablet that it is prepared for framework material, there is burst effect at the release initial stage, have a strong impact on slow release effect, particularly to some need accurate administration or the less drug influence of dosage more obvious; Drug release process also changes because of gastrointestinal pH change, and therefore, in HPMC slow releasing preparation, application is subject to a definite limitation, normal and other framework material conbined usage.
Glyceryl Behenate is a kind of novel pharmaceutic adjuvant, is mainly used as tablet, the lubricant of capsule, controlled release agent and mask agent.Glyceryl Behenate is insoluble type framework material, with the slow releasing preparation that it is prepared, having drug release does not affect by pH value, avoids burst effect with flooding mechanism release, without features such as digestion, high physiological tolerances, be substitute the desirable adjuvant of HPMC as sustained-release matrix material at present.
Summary of the invention:
The object of the present invention is to provide a kind of trimetazidine hydrochloride sustained-release tablets and preparation method thereof, this slow releasing tablet take Glyceryl Behenate as framework material, consumption accounts for sheet and weighs 25% ~ 80%, be aided with a small amount of stearic acid, lactose, mannitol, Polyethylene Glycol etc. are release regulator, effectively can control prominent the releasing in Trimetazidine Hydrochloride early stage, slow releasing tablet release in vitro does not affect by medium pH, the number of times of taking of medicine is down to 2 times by 3 times simultaneously, the compliance of patient consumes can be improved, sustained release maintains steady plasma-drug concentration and longer release time, there is toxic and side effects little, advantage easy to use.
Trimetazidine hydrochloride sustained-release tablets provided by the invention, adopts direct compression, dry granulation tabletting or wet granule compression tablet, and technique is simple, is easy to suitability for industrialized production.Vitro release experiment shows, trimetazidine hydrochloride sustained-release tablets provided by the invention is respectively 25% ~ 45% of labelled amount 1 hour, 2 hours and 8 hours burst sizes, more than 43% ~ 63% and 80%, compared with commercially available " vasorel " (Trimetazidine Hydrochloride Tablets in healthy) release in vitro result, similarity f
2> 65, two kinds of preparations have high similarity.
The present invention implements by following technical solution:
Trimetazidine hydrochloride sustained-release tablets of the present invention, only uses
888ATO is as sustained-release matrix material.
888ATO and Glyceryl Behenate, originate from good method lion (GATTEFOSSE, original name Jia Fasai) company of France.
Described Trimetazidine Hydrochloride preferably accounts for sheet and weighs 7% ~ 35% in slow releasing tablet.When tablet fill weights is certain, the ratio shared by prescription Chinese medicine increases, and the ratio of sustained-release matrix material just reduces relatively, cannot by the release of sustained-release matrix control of material medicine; Otherwise medicine proportion hour, sustained-release matrix material proportion increases, and drug release may be caused incomplete, do not reach effective blood drug level.In slow releasing tablet, account for sheet through experiment sieving determination Trimetazidine Hydrochloride and weigh 7% ~ 35%.
Described
preferably account for sheet in 888ATO and weigh 30% ~ 75%.Determine the determination of Glyceryl Behenate amount ranges, be because sustained-release matrix material usage cross conference cause medicine not discharge completely or pharmaceutical release time long, do not reach the effect for the treatment of after patient takes; And sustained-release matrix material usage is crossed young pathbreaker and caused medicine not reach slow releasing function or occur at the release initial stage phenomenon that drug bolus discharges, it is excessive to discharge, and dosage may be caused after patient takes excessive, there will be serious untoward reaction or intoxicating phenomenon.
Described rate of release regulator is selected from one or more in stearic acid, lactose, mannitol, Polyethylene Glycol, but is not limited to that these are several, preferably accounts for sheet and weighs 5% ~ 15%.When tablet fill weights, Glyceryl Behenate consumption are certain, if when drug releasing rate is too fast, just relatively increases stearic consumption, make the release of each time point be reduced in preset range; Otherwise, when drug releasing rate is too small, just relatively increases the consumption of lactose, the release of each time point brought up in preset range.One or more in experiment sieving determination stearic acid, lactose account for sheet and weigh 5% ~ 15%.
Described filler is selected from one or more in microcrystalline Cellulose, silicon dioxide, calcium hydrogen phosphate, but is not limited to this several filler, and the consumption according to prescription screening result and sustained-release matrix material is determined, preferably accounts for sheet and weighs 10% ~ 35%.Microcrystalline cellulose have good mobility, can slow down drug release several times compared with water-soluble filler, simultaneously not by pH environmental effect.Particularly preferably not there is the model microcrystalline Cellulose of disintegration, as PH101.
Described wetting agent is selected from purified water.
Described binding agent is selected from one or more in 0.5% ~ 2% sodium carboxymethyl cellulose solution, 8% ~ 15% starch slurry, 1% ~ 10% polyvidone alcoholic solution, but is not limited to this several binding agent, preferably accounts for sheet and weighs 0% ~ 3%.
Described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, but is not limited to this several lubricant, preferred magnesium stearate.Compare according to list of references and preliminary result, determine that lubricant preferably accounts for sheet and weighs 0.5% ~ 2% in slow releasing tablet.The stripping of lubricant quantity excessive then tablet is slow, consumption too small then pressing process solution generation sticking.
Trimetazidine hydrochloride sustained-release tablets preparation method of the present invention, comprises direct compression process, dry granulation tabletting or wet granule compression tablet method.
Particularly, direct compression process comprises the steps:
A. mix: by Trimetazidine Hydrochloride and release regulator, filler,
888ATO mix homogeneously;
B. always mix: lubricant is added to mix homogeneously in mixed-powder;
C. tabletting: always will mix pressed powder, and to obtain final product.
Or compressing dry granulation comprises the steps:
I mix: by Trimetazidine Hydrochloride with
888ATO, release regulator, filler mix homogeneously;
Ii granule: mixed-powder is compressed into sheet or plate object, crosses pharmacopeia sieve granulate;
Iii always mixes: lubricant is added to mix homogeneously in granule;
Iv tabletting: always will mix thing tabletting, and to obtain final product.
Again or, wet granule compression tablet method comprises the steps:
(1) mix: by Trimetazidine Hydrochloride and release regulator, filler,
888ATO mix homogeneously;
(2) soft material processed: mixed-powder is mixed homogeneously with wetting agent or binding agent;
(3) granule processed: soft material mixture is crossed pharmacopeia sieve series wet granular, 50 DEG C ~ 80 DEG C dryings, dry granule crosses pharmacopeia sieve granulate;
(4) always mix: lubricant is added to mix homogeneously in dry granule;
(5) tabletting: by mixture tabletting obtained above, to obtain final product.
After tabletting, as required, non-functional film coating can be carried out in a conventional manner.
Wherein in an enforcement, 16 ~ 40 mesh sieve granule and granulate are crossed in affiliated step I i, (3).
Wherein in an enforcement, affiliated step c, iv or (5) also have coating steps afterwards, and the film-coating material needed for described coating steps is selected from one or more in cellulosic polymer.By tablet coating, being to improve outward appearance, being convenient to storage, easy to use, cover abnormal smells from the patient, improve the object such as drug quality and stability.
The present invention adopts vitro release algoscopy (two, " Chinese Pharmacopoeia " (2010) annex XD first method), adopt dissolution method second subtraction unit (two, " Chinese Pharmacopoeia " (2010) annex XC second method), measure the drug release characteristics of trimetazidine hydrochloride sustained-release tablets of the present invention.
The present invention for gastrointestinal tract environment in release medium analogue body, evaluates the impact whether slow releasing tablet Chinese medicine release characteristic of the present invention is subject to gastrointestinal tract pH with the phosphate buffer of the Acetic acid-sodium acetate buffer of purified water, 0.1mol/L hydrochloric acid solution, pH4.5, pH6.8.By " Chinese Pharmacopoeia " (2010) version regulation, with release medium 900mL, rotating speed 50r/min, temperature 37 DEG C, in 0.5,1,2,4,6, within 8 hours, draw 5mL solution and filter, and supplement 5mL release medium in time, get subsequent filtrate as need testing solution.Separately get Trimetazidine Hydrochloride reference substance, also dilute into about 701 μ g/mL product solution in contrast with release medium solubilize.Adopt ultraviolet spectrophotometry to measure absorbance at 230nm place, calculate the burst size of every sheet at different time.Meanwhile, separately getting commercially available Shi Weiya (Tianjin) pharmaceutical Co. Ltd " vasorel " is that release medium is tested with method with purified water.Release the results are shown in Table 1.
The release result of trimetazidine hydrochloride sustained-release tablets and vasorel made by oneself by table 1
Adopt matching factorization method can evaluate with " vasorel " release in vitro result self-control trimetazidine hydrochloride sustained-release tablets, the basic assumption that similar factors calculates is that the quadratic sum of the Accumulation dissolution difference of experimental preparation and control formulation is minimum.Computing formula is:
In formula, R
tand T
tbe respectively reference preparation with self-control preparation at each sampling time point Average dissolution, n is sampling time point number.F
2similar both > 50 represents, f
2larger expression is more similar.
Inventor is groped by a large amount of experiments, and invented a kind of new trimetazidine hydrochloride sustained-release tablets preparation technology, can be used for the Controlled release of Trimetazidine Hydrochloride, formula and preparation technology have following characteristics:
1. only adopt Glyceryl Behenate to be framework material, consumption accounts for sheet and weighs 25% ~ 80%, can control prominent the releasing in Trimetazidine Hydrochloride early stage, reduce complexity and the production cost of technique.
2. by adding the ratio of a small amount of release regulator and control and framework material, the rate of release of energy regulating drug.
3. the present invention adopts framework material Glyceryl Behenate, diluents microcrystalline cellulose have toleration to acid-base value, the total consumption of this two classes material accounts for sheet and weighs more than 60%, can ensure that the release of slow releasing tablet of the present invention is not by pH environmental effect, change not by gastrointestinal pH when making slow releasing tablet absorb in vivo, produce the blood drug level of stable state and lasting drug effect, thus reduce untoward reaction and drug resistance.
4. trimetazidine hydrochloride sustained-release tablets provided by the invention, adopt direct compression process, compressing dry granulation or wet granule compression tablet, can select pressed disc method according to adjuvant, preparation technology is easy, and low-carbon energy-saving is cost-saving, is easy to batch production.
Trimetazidine hydrochloride sustained-release tablets provided by the invention, it is only framework material with Glyceryl Behenate, consumption accounts for sheet and weighs 25% ~ 80%, and being aided with a small amount of stearic acid, lactose, mannitol, Polyethylene Glycol etc. is release regulator, effectively can control the rate of release of Trimetazidine Hydrochloride.Trimetazidine hydrochloride sustained-release tablets vitro release experiment of the present invention, the medicine release of the 1st hour release of the 25% ~ 45%, 2nd hour release of the 43% ~ 63%, 8th hour is more than 80%, drug release behavior, compared with commercially available " vasorel ", has the similarity (f of height
2> 65), preparation method technique is simple, stable, is easy to suitability for industrialized production.
Accompanying drawing explanation
The releasing curve diagram of trimetazidine hydrochloride sustained-release tablets in four kinds of media of Fig. 1 test example 1
Blood plasma drug concentration comparison diagram after the trimetazidine hydrochloride sustained-release tablets of Fig. 2 test example 1 and vasorel administration
The releasing curve diagram of trimetazidine hydrochloride sustained-release tablets in purified water of the embodiment 1 of Fig. 3 and vasorel same size, embodiment 5, embodiment 7
Detailed description of the invention
Set forth the present invention further below in conjunction with specific embodiment, those skilled in the art can be made more fully to understand the present invention, but do not limit the present invention in any way.
The main supplementary material used in enforcement and instrument and equipment: Trimetazidine Hydrochloride (Wuhan Wuyao Pharmaceutical Co., Ltd); Glyceryl Behenate (French Jia Fa lion company); SY-2D tablet four-function analyzer (Shanghai Huanghai Sea medicine inspection instrument company); ZRS-8G intelligence dissolution tester (Radio Factory of Tianjin Univ.); DP30A single punch tablet machine (Beijing Gylongli Sci.&Tech. Co., Ltd.); BY-400S tests coating pan (Taizhou City Jin Tai pharmaceutical machine company limited of Jiangsu Province).
Embodiment 1:
A kind of trimetazidine hydrochloride sustained-release tablets, comprises following component (by 1000):
Preparation method comprises the following steps:
(1) grind and sieve: Trimetazidine Hydrochloride is ground to form fine powder, get Trimetazidine Hydrochloride,
60 mesh sieves crossed by 888ATO, stearic acid, lactose, microcrystalline Cellulose, calcium hydrogen phosphate, micropowder silica gel crossed 100 mesh sieves;
(2) weigh: precise Trimetazidine Hydrochloride 35.00g,
888ATO120.00g, stearic acid 8.50g, lactose 1.50g, microcrystalline Cellulose 25.00g, calcium hydrogen phosphate 9.00g, magnesium stearate 1.00g, for subsequent use;
(3) mix: by load weighted Trimetazidine Hydrochloride,
888ATO, stearic acid, lactose, microcrystalline Cellulose, calcium hydrogen phosphate mix 30 minutes in mixer;
(4) always mix: micropowder silica gel is joined in mixed-powder, continue mixing 5 minutes;
(5) tabletting: the heavy 200mg of adjustment sheet, hardness 6 ~ 10 kilograms, friability less than 0.6%, carries out tabletting by always mixing thing.In tableting processes, to tracking measurements such as sheet weight, hardness, friabilities, ensure that the corresponding index of tablet requirement is in controlled range.
Embodiment 2:
A kind of trimetazidine hydrochloride sustained-release tablets, comprises following component (by 1000):
Preparation method comprises the following steps:
(1) grind and sieve: Trimetazidine Hydrochloride is ground to form fine powder, get Trimetazidine Hydrochloride,
60 mesh sieves crossed by 888ATO, mannitol, lactose, microcrystalline Cellulose, calcium hydrogen phosphate, Pulvis Talci crossed 100 mesh sieves;
(2) weigh: precise Trimetazidine Hydrochloride 35.00g,
888ATO140.00g, mannitol 7.00g, lactose 12.00, microcrystalline Cellulose 93.00g, calcium hydrogen phosphate 11.00g, Pulvis Talci 2.00g, for subsequent use;
(3) mix: by load weighted Trimetazidine Hydrochloride,
888ATO, mannitol, lactose, microcrystalline Cellulose, calcium hydrogen phosphate mix 30 minutes in mixer;
(4) always mix: Pulvis Talci is joined in mixed-powder, continue mixing 5 minutes;
(5) tabletting: the heavy 300mg of adjustment sheet, hardness 5 ~ 10 kilograms, friability less than 0.6%, carries out tabletting by always mixing thing.In tableting processes, to tracking measurements such as sheet weight, hardness, friabilities, ensure that the corresponding index of tablet requirement is in controlled range.
Embodiment 3:
A kind of trimetazidine hydrochloride sustained-release tablets, comprises following component (by 1000):
Preparation method comprises the following steps:
(1) grind and sieve: Trimetazidine Hydrochloride is ground to form fine powder, get Trimetazidine Hydrochloride,
888ATOg, stearic acid, mannitol, microcrystalline Cellulose, silicon dioxide cross 60 mesh sieves, Pulvis Talci are crossed 100 mesh sieves;
(2) weigh: precise Trimetazidine Hydrochloride 35.00g,
888ATO161.00g, stearic acid 45.00g, mannitol 15.00g, microcrystalline Cellulose 132.00g, silicon dioxide 8.00g, Pulvis Talci 4.00g, for subsequent use;
(3) mix: by load weighted Trimetazidine Hydrochloride,
888ATO, stearic acid, mannitol, microcrystalline Cellulose, silicon dioxide mix 30 minutes in mixer;
(4) always mix: Pulvis Talci is joined in mixed-powder, continue mixing 5 minutes;
(5) tabletting: the heavy 400mg of adjustment sheet, hardness 6 ~ 10 kilograms, friability less than 0.6%, carries out tabletting by always mixing thing.In tableting processes, to tracking measurements such as sheet weight, hardness, friabilities, ensure that the corresponding index of tablet requirement is in controlled range.
(6) coating: obtained trimetazidine hydrochloride sustained-release tablets is carried out film coating.
Embodiment 4:
A kind of trimetazidine hydrochloride sustained-release tablets, comprises following component (by 1000):
Preparation method comprises the following steps:
(1) grind and sieve: Trimetazidine Hydrochloride is ground to form fine powder, get Trimetazidine Hydrochloride,
60 mesh sieves crossed by 888ATO, stearic acid, lactose, microcrystalline Cellulose, calcium hydrogen phosphate, magnesium stearate crossed 100 mesh sieves;
(2) weigh: precise Trimetazidine Hydrochloride 35.00g,
888ATO49.00g, stearic acid 2.50g, lactose 0.50g, microcrystalline Cellulose 12.00g, magnesium stearate 1.00g, for subsequent use;
(3) mix: by load weighted Trimetazidine Hydrochloride, Trimetazidine Hydrochloride,
888ATO, stearic acid, lactose, microcrystalline Cellulose, calcium hydrogen phosphate mix 30 minutes in mixer;
(4) granule processed: mixed-powder is compressed into sheet or plate object, crosses 20 mesh sieve granulate, screened out 60 object fine powders;
(5) always mix: magnesium stearate is joined in granule, mix 5 minutes;
(6) tabletting: the heavy 100mg of adjustment sheet, hardness 6 ~ 10 kilograms, friability less than 0.6%, carries out tabletting by always mixing thing.In tableting processes, to tracking measurements such as sheet weight, hardness, friabilities, ensure that the corresponding index of tablet requirement is in controlled range.
Embodiment 5:
A kind of trimetazidine hydrochloride sustained-release tablets, comprises following component (by 1000):
Preparation method comprises the following steps:
(1) grind and sieve: Trimetazidine Hydrochloride is ground to form fine powder, get Trimetazidine Hydrochloride,
888ATO, stearic acid, Polyethylene Glycol PEG4000, microcrystalline Cellulose, silicon dioxide cross 60 mesh sieves, magnesium stearate are crossed 100 mesh sieves;
(2) weigh: precise Trimetazidine Hydrochloride 35.00g,
888ATO125.00g, stearic acid 12.00g, Polyethylene Glycol PEG40009.50g, microcrystalline Cellulose 15.00g, silicon dioxide 2.00g, magnesium stearate 1.50g, for subsequent use;
(3) mix: by load weighted Trimetazidine Hydrochloride,
888ATO, stearic acid, Polyethylene Glycol PEG4000, microcrystalline Cellulose, silicon dioxide mix 30 minutes in mixer;
(4) granule processed: mixed-powder is compressed into sheet or plate object, crosses 16 mesh sieve granulate, screened out 60 object fine powders;
(5) always mix: magnesium stearate is joined in granule, mix 5 minutes;
(6) tabletting: the heavy 200mg of adjustment sheet, hardness 6 ~ 10 kilograms, friability less than 0.6%, carries out tabletting by always mixing thing.In tableting processes, to tracking measurements such as sheet weight, hardness, friabilities, ensure that the corresponding index of tablet requirement is in controlled range.
Embodiment 6:
A kind of trimetazidine hydrochloride sustained-release tablets, comprises following component (by 1000):
Preparation method comprises the following steps:
(1) grind and sieve: Trimetazidine Hydrochloride is ground to form fine powder, get Trimetazidine Hydrochloride,
60 mesh sieves crossed by 888ATO, Polyethylene Glycol PEG4000, lactose, microcrystalline Cellulose, calcium hydrogen phosphate, magnesium stearate crossed 100 mesh sieves;
(2) weigh: precise Trimetazidine Hydrochloride 35.00g,
888ATO185.50, Polyethylene Glycol PEG400042.50g, lactose 10.00g, microcrystalline Cellulose 55.00g, calcium hydrogen phosphate 15.00g, magnesium stearate 7.00g, for subsequent use;
(3) mix: by load weighted sour trimetazidine,
888ATO, Polyethylene Glycol PEG4000, lactose, microcrystalline Cellulose, calcium hydrogen phosphate mix 30 minutes in mixer:
(4) granule processed: mixed-powder is compressed into sheet or plate object, crosses 16 mesh sieve granulate, screened out 60 object fine powders;
(5) always mix: magnesium stearate is joined in granule, mix 5 minutes;
(6) tabletting: the heavy 350mg of adjustment sheet, hardness 6 ~ 10 kilograms, friability less than 0.6%, carries out tabletting by always mixing thing.In tableting processes, to tracking measurements such as sheet weight, hardness, friabilities, ensure that the corresponding index of tablet requirement is in controlled range.
(7) coating: obtained trimetazidine hydrochloride sustained-release tablets is carried out film coating.
Embodiment 7:
A kind of trimetazidine hydrochloride sustained-release tablets, comprises following component (by 1000):
Preparation method comprises the following steps:
(1) grind and sieve: Trimetazidine Hydrochloride is ground to form fine powder, get Trimetazidine Hydrochloride,
60 mesh sieves crossed by 888ATO, stearic acid, Polyethylene Glycol PEG4000, microcrystalline Cellulose, calcium hydrogen phosphate, magnesium stearate crossed 100 mesh sieves;
(2) weigh: precise Trimetazidine Hydrochloride 35.00g,
888ATO60.00g, stearic acid 11.00g, Polyethylene Glycol PEG400010.00g, microcrystalline Cellulose 62.00g, calcium hydrogen phosphate 9.00g, magnesium stearate 2.00g, 10% starch slurry 11g, for subsequent use;
(3) mix: by load weighted Trimetazidine Hydrochloride,
888ATO, stearic acid, microcrystalline Cellulose, calcium hydrogen phosphate mix 30 minutes in mixer;
(4) soft material processed: in mixed-powder, gradation adds 10% starch slurry, and mix homogeneously makes soft material;
(5) granule processed: soft material is crossed 20 mesh sieve wet granulars, put baking oven 50 DEG C of dryings 4 hours, dry granule crosses 16 mesh sieve granulate, screens out 60 object fine powders;
(6) always mix: magnesium stearate is joined in dry granule, mix 5 minutes;
(7) tabletting: the heavy 200mg of adjustment sheet, hardness 6 ~ 10 kilograms, friability less than 0.6%, carries out tabletting by always mixing thing.In tableting processes, to tracking measurements such as sheet weight, hardness, friabilities, ensure that the corresponding index of tablet requirement is in controlled range.
Embodiment 8:
A kind of trimetazidine hydrochloride sustained-release tablets, comprises following component (by 1000):
Preparation method comprises the following steps:
(1) grind and sieve: Trimetazidine Hydrochloride is ground to form fine powder, get Trimetazidine Hydrochloride,
60 mesh sieves crossed by 888ATO, stearic acid, lactose, microcrystalline Cellulose, calcium hydrogen phosphate, magnesium stearate crossed 100 mesh sieves;
(2) weigh: precise Trimetazidine Hydrochloride 35g,
888ATO120g, stearic acid 13g, lactose 2g, microcrystalline Cellulose 46g, calcium hydrogen phosphate 19g, magnesium stearate 2g, 5% polyvidone alcoholic solution 16g, for subsequent use;
(3) mix: by load weighted Trimetazidine Hydrochloride,
888ATO, stearic acid, lactose, microcrystalline Cellulose, calcium hydrogen phosphate mix 30 minutes in mixer;
(4) soft material processed: in mixed-powder, gradation adds 5% polyvidone alcoholic solution, and mix homogeneously makes soft material;
(5) granule processed: soft material is crossed 20 mesh sieve wet granulars, put baking oven 50 DEG C of dryings 4 hours, dry granule crosses 16 mesh sieve granulate, screens out 60 object fine powders;
(6) always mix: magnesium stearate is joined in dry granule, mix 5 minutes;
(7) tabletting: the heavy 250mg of adjustment sheet, hardness 6 ~ 10 kilograms, friability less than 0.6%, carries out tabletting by always mixing thing.In tableting processes, to tracking measurements such as sheet weight, hardness, friabilities, ensure that the corresponding index of tablet requirement is in controlled range;
(8) coating: obtained trimetazidine hydrochloride sustained-release tablets is carried out film coating.
Embodiment 9:
A kind of trimetazidine hydrochloride sustained-release tablets, comprises following component (by 1000):
Preparation method comprises the following steps:
(1) grind and sieve: Trimetazidine Hydrochloride is ground to form fine powder, get Trimetazidine Hydrochloride,
888ATO, Polyethylene Glycol PEG4000, lactose, microcrystalline Cellulose, silicon dioxide cross 60 mesh sieves, magnesium stearate are crossed 100 mesh sieves;
(2) weigh: precise Trimetazidine Hydrochloride 35.00g,
888ATO165.00g, Polyethylene Glycol PEG400061.00g, lactose 10.00g, microcrystalline Cellulose 145.00g, silicon dioxide 35.00g, magnesium stearate 9.00g, 1% sodium carboxymethyl cellulose 40.00g, for subsequent use;
(3) mix: by load weighted Trimetazidine Hydrochloride,
888ATO, Polyethylene Glycol PEG4000, lactose, microcrystalline Cellulose, silicon dioxide mix 30 minutes in mixer;
(4) soft material processed: in mixed-powder, gradation adds 1% carboxymethylcellulose sodium solution, and mix homogeneously makes soft material;
(5) granule processed: soft material is crossed 16 mesh sieve wet granulars, put baking oven 50 DEG C of dryings 4 hours, dry granule crosses 16 mesh sieve granulate, screens out 60 object fine powders;
(6) always mix: magnesium stearate is joined in dry granule, mix 5 minutes;
(7) tabletting: the heavy 500mg of adjustment sheet, hardness 6 ~ 10 kilograms, friability less than 0.6%, carries out tabletting by always mixing thing.In tableting processes, to tracking measurements such as sheet weight, hardness, friabilities, ensure that the corresponding index of tablet requirement is in controlled range;
(8) coating: obtained trimetazidine hydrochloride sustained-release tablets is carried out film coating.
Test example 1:
A kind of trimetazidine hydrochloride sustained-release tablets, comprises following component (by 1000):
Preparation method comprises the following steps:
(1) grind and sieve: Trimetazidine Hydrochloride is ground to form fine powder, get Trimetazidine Hydrochloride,
60 mesh sieves crossed by 888ATO, stearic acid, lactose, microcrystalline Cellulose, calcium hydrogen phosphate, magnesium stearate crossed 100 mesh sieves;
(2) weigh: precise Trimetazidine Hydrochloride 35.00g,
888ATO95.00g, stearic acid 13.00g, lactose 3.00g, microcrystalline Cellulose 36.00g, calcium hydrogen phosphate 8.00g, magnesium stearate 1.50g, 8% polyvidone alcoholic solution 8.5g, for subsequent use;
(3) mix: by load weighted Trimetazidine Hydrochloride,
888ATO, stearic acid, lactose, microcrystalline Cellulose, calcium hydrogen phosphate mix 30 minutes in mixer;
(4) soft material processed: in mixed-powder, gradation adds 8% polyvidone alcoholic solution, and mix homogeneously makes soft material;
(5) granule processed: soft material is crossed 20 mesh sieve wet granulars, put baking oven 50 DEG C of dryings 4 hours, dry granule crosses 16 mesh sieve granulate, screens out 60 object fine powders;
(6) always mix: magnesium stearate is joined in dry granule, mix 5 minutes;
(7) tabletting: the heavy 200mg of adjustment sheet, hardness 6 ~ 10 kilograms, friability less than 0.6%, carries out tabletting by always mixing thing.In tableting processes, to tracking measurements such as sheet weight, hardness, friabilities, ensure that the corresponding index of tablet requirement is in controlled range.
That prepares for proof the present invention has identical absorption process with commercially available trimetazidine hydrochloride sustained-release tablets, with " vasorel " of Shi Weiya (Tianjin) pharmaceutical Co. Ltd for standard reference preparation, trimetazidine hydrochloride sustained-release tablets is obtained to test example 1 and carries out inside and outside investigation, evaluate release and the bioequivalence of medicine.
Experimental group: trimetazidine hydrochloride sustained-release tablets (Trimetazidine Hydrochloride content 35mg/ sheet, the heavy 200mg/ sheet of sheet, lot number: 20121101) prepared by test example 1
" vasorel " (Trimetazidine Hydrochloride content 35mg/ sheet, the heavy 200mg/ sheet of sheet, lot number: 20130601) of matched group: Shi Weiya (Tianjin) pharmaceutical Co. Ltd
1. vitro release is investigated
Experimental technique: respectively with the phosphate buffer of the Acetic acid-sodium acetate buffer of purified water, 0.1mol/L hydrochloric acid solution, pH4.5, pH6.8 for release medium, measure release medium 900mL, rotating speed 50r/min, temperature 37 DEG C, 0.5,1,2,4,6, within 8 hours, draw 5mL solution to filter, and supplement 5mL release medium in time, get subsequent filtrate as need testing solution.Separately get Trimetazidine Hydrochloride reference substance, also dilute into about 70 μ g/mL product solution in contrast with release medium solubilize.Adopt ultraviolet spectrophotometry to measure absorbance at 230nm place, calculate the burst size of every sheet at different time.Meanwhile, getting commercially available " vasorel " is that release medium is tested with method with purified water.Stripping release the results are shown in Table 1, and release profiles is shown in Fig. 1.
Experimental result: can be found out by the release result of trimetazidine hydrochloride sustained-release tablets in four kinds of media of table 1 test example 1, trimetazidine hydrochloride sustained-release tablets of the present invention is equal energy slow releasing medicine in different pH medium (the Acetic acid-sodium acetate buffer of purified water, 0.1mol/L hydrochloric acid solution, pH4.5, the phosphate buffer of pH6.8), medicine is 25% ~ 45% the release of the 1st hour, the release of the 2nd hour is 43% ~ 63%, the release of the 8th hour is more than 80%, drug release behavior, compared with commercially available " vasorel ", has the similarity (f of height
2> 65).
Experiment conclusion: the trimetazidine hydrochloride sustained-release tablets release characteristic of test example 1 is less by the impact of medium pH, less by patient's gastrointestinal tract acid-base value variable effect in the release of clinical practice Chinese medicine, ensure that patient can absorb the drug slowly.
2. in body, bioequivalence is investigated
Experimental technique: get Beagle dog 12, be divided into 2 groups at random, be respectively experimental group and matched group, often organizes 6.Respectively oral administration, dosage is 70mg, respectively at after administration 1,2,3,4,5,6,8,10,12,16 and 24 hours, gather whole blood 3mL in forelimb cephalic vein place, centrifugal separation plasma, puts-70 DEG C of Refrigerator stores, adopt the concentration of Trimetazidine Hydrochloride in high effective liquid chromatography for measuring different time blood plasma, draw blood concentration-time curve, see Fig. 2.
Experimental result: the trimetazidine hydrochloride sustained-release tablets of test example 1 of the present invention shows in Beagle dog experiment in vivo result, the variance analysis of each main pharmacokinetic parameters after Logarithm conversion, by there was no significant difference between test preparation and reference preparation, also there was no significant difference between the test period; C
maxask that the result of inspection is all within the scope of regulation with AUC Doubled haploid population and (1-2 α) confidence district, T
maxthere was no significant difference is asked by test preparation and reference preparation through non parametric tests.
Experiment conclusion: judged by experimental result, " vasorel " (reference preparation) that the trimetazidine hydrochloride sustained-release tablets (by test preparation) that self-control provides and Shi Weiya (Tianjin) pharmaceutical Co. Ltd produce has bioequivalence, illustrates that the trimetazidine hydrochloride sustained-release tablets of test example 1 is consistent with the drug effect of " vasorel ".
3. Different Preparation amplifies investigation
For proving the quality influence of preparation technology of the present invention to trimetazidine hydrochloride sustained-release tablets, trimetazidine hydrochloride sustained-release tablets is prepared by embodiment 1, embodiment 5 and embodiment 7 respectively with direct power compressing method, compressing dry granulation and wet granule compression tablet method, specification is: the heavy 200mg/ sheet of sheet, hydrochloric trimetazidine 35mg/ sheet is identical with commercially available " vasorel " specification.Feed intake by 10000/batches and amplify production three batches of products, lot number is respectively: 20130501,20130505,20130507, then (lot number: 20121101) carry out vitro release experiment, the results are shown in Table 2 and Fig. 3 to get three batches of slow releasing tablet and commercially available " vasorel ".
The trimetazidine hydrochloride sustained-release tablets of the embodiment 1 of table 2 and vasorel same size, embodiment 5, embodiment 7 discharges result
| Time/hour | Vasorel | Embodiment 1 | Embodiment 5 | Embodiment 7 |
| 0.5 | 18.85 | 17.57 | 22.08 | 20.04 |
| 1 | 38.98 | 35.81 | 43.13 | 38.35 |
| 2 | 53.93 | 51.13 | 60.96 | 55.10 |
| 4 | 75.96 | 73.32 | 81.62 | 78.83 |
| 6 | 86.87 | 83.58 | 90.27 | 87.82 |
| 8 | 92.16 | 96.39 | 96.78 | 93.74 |
| f 2 | 100.00 | 81.13 | 65.19 | 86.39 |
Discharge result by the trimetazidine hydrochloride sustained-release tablets of the embodiment 1 of table 2 and vasorel same size, embodiment 5, embodiment 7 can find out, trimetazidine hydrochloride sustained-release tablets release in vitro result is obtained by the present invention's three kinds of preparation methoies, medicine is 25% ~ 45% the release of the 1st hour, the release of the 2nd hour is 43% ~ 63%, the release of the 8th hour is more than 80%, drug release behavior, compared with commercially available " vasorel ", has the similarity (f of height
2> 65).
Comprehensive above-mentioned result of the test, the present invention take Glyceryl Behenate as sustained-release matrix material, adopt direct compression process, compressing dry granulation or wet granule compression tablet method, the trimetazidine hydrochloride sustained-release tablets of preparation, drug release is not by pH environmental effect, and drug absorption has high similarity compared with " vasorel "; Body absorption can produce steady plasma-drug concentration, has bioequivalence compared with " vasorel ".Preparation technology is easy, steady quality, is easy to batch production, can meet the requirement that reality is produced.
The above embodiment only expresses several embodiment of the present invention, but can not be interpreted as the restriction to the scope of the claims of the present invention thus.Without departing from the inventive concept of the premise, can also produce some distortion and improvement, these all belong to protection scope of the present invention, should be as the criterion with the scope of claims of the present invention protection.
Claims (10)
1. one kind take Glyceryl Behenate as trimetazidine hydrochloride sustained-release tablets of framework material and preparation method thereof, it is characterized in that: described slow releasing tablet only uses
888ATO is as sustained-release matrix material, and also containing release regulator, filler, wetting agent or binding agent and lubricant, by percentage to the quality, each component is composed as follows:
Described
888ATO and Glyceryl Behenate, be insoluble framework material, have non-pH-dependent drug release, can avoid burst effect by flooding mechanism release, without features such as digestion, high physiological tolerances.
2. trimetazidine hydrochloride sustained-release tablets according to claim 1, is characterized in that: described Trimetazidine Hydrochloride is the principal agent of slow releasing tablet, accounts for sheet and weighs 5% ~ 40%.
3. trimetazidine hydrochloride sustained-release tablets according to claim 1, is characterized in that: described
888ATO is the framework material of slow releasing tablet, accounts for sheet and weighs 25% ~ 80%.
4. trimetazidine hydrochloride sustained-release tablets according to claim 1, is characterized in that: described rate of release regulator is selected from one or more in stearic acid, lactose, mannitol, Polyethylene Glycol, but is not limited to that these are several, accounts for sheet and weighs 0% ~ 20%.
5. trimetazidine hydrochloride sustained-release tablets according to claim 1, is characterized in that: described filler is selected from one or more in microcrystalline Cellulose, silicon dioxide, calcium hydrogen phosphate, but is not limited to this several filler, accounts for sheet and weighs 5% ~ 40%.
6. trimetazidine hydrochloride sustained-release tablets according to claim 1, it is characterized in that: described wetting agent is selected from purified water: described binding agent is selected from one or more in 0.5% ~ 2% sodium carboxymethyl cellulose solution, 8% ~ 15% starch slurry, 1% ~ 10% polyvidone alcoholic solution, but be not limited to this several binding agent, account for sheet and weigh 0% ~ 10%.
7. trimetazidine hydrochloride sustained-release tablets according to claim 1, is characterized in that: described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, but is not limited to this several lubricant, accounts for sheet and weighs 0% ~ 3%.
8. prepare the method for the trimetazidine hydrochloride sustained-release tablets described in any one of claim 1-7, comprise direct compression process, dry granulation tabletting or wet granule compression tablet method, it is characterized in that: direct compression process concrete steps are:
(1) mix: by Trimetazidine Hydrochloride with
888ATO, release regulator, filler mix homogeneously;
(2) always mix: lubricant is added to mix homogeneously in mixed-powder;
(3) tabletting: carry out tabletting by always mixing thing;
(4) coating: can select as required obtained tablet coating.
9. the preparation method of trimetazidine hydrochloride sustained-release tablets according to claim 8, is characterized in that: compressing dry granulation concrete steps are:
(1) mix: by Trimetazidine Hydrochloride with
888ATO, release regulator, filler mix homogeneously;
(2) granule processed: mixed-powder is compressed into sheet or plate object, crosses pharmacopeia sieve granulate;
(3) always mix: lubricant is added to mix homogeneously in granule;
(4) tabletting: carry out tabletting by always mixing thing;
(5) coating: can select as required obtained tablet coating.
10. the method preparing trimetazidine hydrochloride sustained-release tablets according to claim 8, is characterized in that: wet granule compression tablet method concrete steps are:
(1) mix: by Trimetazidine Hydrochloride with
888ATO, release regulator, filler mix homogeneously;
(2) soft material processed: mixed-powder is mixed homogeneously with wetting agent or binding agent;
(3) granule processed: soft material mixture is crossed pharmacopeia sieve series granule, 50 DEG C ~ 80 DEG C dryings, dry granule crosses pharmacopeia sieve granulate;
(4) always mix: lubricant is added to mix homogeneously in dry granule;
(5) tabletting: carry out tabletting by always mixing thing;
(6) coating: can select as required obtained tablet coating.
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| CN110354093A (en) * | 2019-07-31 | 2019-10-22 | 常州恒邦药业有限公司 | A kind of mosapride citrate pharmaceutical composition |
| CN111888476A (en) * | 2020-08-17 | 2020-11-06 | 深圳市道科思医药有限公司 | Modified release pharmaceutical composition of trimetazidine dihydrochloride |
| CN112106889A (en) * | 2020-08-07 | 2020-12-22 | 珠海天凯生物科技有限公司 | Preparation method and application of coated granules |
| CN112516099A (en) * | 2020-12-11 | 2021-03-19 | 广东华南药业集团有限公司 | Gliclazide sustained release tablet and preparation method thereof |
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| CN102319225A (en) * | 2011-09-23 | 2012-01-18 | 广州白云山光华制药股份有限公司 | Trimetazidine hydrochloride sustained release tablet and preparation method thereof |
| CN102885795A (en) * | 2012-10-31 | 2013-01-23 | 广州帝奇医药技术有限公司 | Trimetazidine dihydrochloride sustained-release tablet and preparation method thereof |
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| CN101455668A (en) * | 2007-12-14 | 2009-06-17 | 北京琥珀光华医药科技开发有限公司 | Preparation of trimetazidine hydrochloride sustained-release tablets and use thereof |
| CN102319225A (en) * | 2011-09-23 | 2012-01-18 | 广州白云山光华制药股份有限公司 | Trimetazidine hydrochloride sustained release tablet and preparation method thereof |
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| CN110354093A (en) * | 2019-07-31 | 2019-10-22 | 常州恒邦药业有限公司 | A kind of mosapride citrate pharmaceutical composition |
| CN110354093B (en) * | 2019-07-31 | 2021-09-17 | 常州恒邦药业有限公司 | Mosapride citrate pharmaceutical composition |
| CN112106889A (en) * | 2020-08-07 | 2020-12-22 | 珠海天凯生物科技有限公司 | Preparation method and application of coated granules |
| CN111888476A (en) * | 2020-08-17 | 2020-11-06 | 深圳市道科思医药有限公司 | Modified release pharmaceutical composition of trimetazidine dihydrochloride |
| CN112516099A (en) * | 2020-12-11 | 2021-03-19 | 广东华南药业集团有限公司 | Gliclazide sustained release tablet and preparation method thereof |
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