CN103550183B - A kind of Trimetazidine Hydrochloride osmotic pump controlled release tablet and preparation method thereof - Google Patents
A kind of Trimetazidine Hydrochloride osmotic pump controlled release tablet and preparation method thereof Download PDFInfo
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- CN103550183B CN103550183B CN201310397342.7A CN201310397342A CN103550183B CN 103550183 B CN103550183 B CN 103550183B CN 201310397342 A CN201310397342 A CN 201310397342A CN 103550183 B CN103550183 B CN 103550183B
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Abstract
The invention discloses a kind of Trimetazidine Hydrochloride osmotic pump controlled release tablet and preparation method thereof, it is monocompartment osmotic pump controlled release formulation, comprises monolayer label, insoluble semipermeable membrane clothing and small delivery aperture.The present invention is combined by screening and optimizing filler, effectively can improve medicine sluggishness and release end residual phenomena, regulating drug rate of release and controlled release period, and in the short period, reach certain blood drug level, formed and stablize constant release, realize the medicine controlled releasing purpose of design of quick acting, steadily release, reduction side effect.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of Trimetazidine Hydrochloride osmotic pump controlled release tablet and preparation method thereof.
Background technology
Oros controlled-release technology has had the applicating history more than 30 years so far since the eighties in last century first launch, it utilizes the osmotic pressure being derived from medicament system to provide release power, relative to matrix type and reservoir devices slow release method, medicine be released in the impact not relying on pH value and physiological parameter to a great extent, and the release characteristic that can adjust medicine makes the drug action optimization of system, be one of the most promising controlled-release technology, be particularly useful for the treatment of cardiovascular and cerebrovascular vessel chronic disease.
In all kinds of osmotic pumps technology, elementary osmotic pump is (also known as primary osmotic pump or basic model osmotic pumps, elementary osmotic pump, EOP) version and preparation technology the simplest: adopt conventional tablet producing technology to suppress pastille label, wrap insoluble semipermeable membrane, on semipermeable membrane, beat small delivery aperture with laser-beam drilling machine.The osmotic pumps technology of this structure is considered suitable for the good medicine of water solublity usually.
The drug release process of primary osmotic pump configuration controlled release preparation is the indoor constant drug level (being generally saturated concentration) of holding pump, and under permeable pressure head effect constant inside and outside semipermeable membrane, appropriate ambient moisture enters semipermeable membrane, and takes appropriate medicine to gastroenteric environment by drug release hole and absorbed.In release interval (period) pump chamber, drug level and osmotic pressure remain constant, thus ensure that at rate of releasing drug be during this period constant, i.e. so-called " Zero order release ".
Although elementary osmotic pump version is simple, but because under this version, be relevant to formula composition and affect a lot of because have of rate of release, such as, inside and outside the load capacity of the physicochemical property of medicine, the rate of dissolution of medicine, medicine, the dissolubility of medicine, semipermeable membrane, the permeable pressure head of both sides and the osmotically active of generation osmotic pressure form the rate of dissolution etc. with them, and the screening therefore for prescription needs to pay a large amount of creative works.
Trimetazidine Hydrochloride to be developed in nineteen sixties by French Les Laboratoires servier and is produced, and is first medicine acting on metabolism of myocardium, under myocardial ischemia, makes cardiac energy metabolism be in optimum state.Trimetazidine Hydrochloride is first 3-keto acyl coenzyme A thiolase (3-KAT) inhibitor class metabolic drug.This medicine has played the effect of ischemia resisting under not affecting blood supply of cardiac muscle and not relying on the hemodynamic situation of change.Clinical research shows, medicine precise mechanism optionally suppresses fatty acid beta oxidation cyclophorase-long-chain 3-KAT, after suppressing fatty acid beta oxidation, myocardial metabolism is transferred to glycoxidative, thus improves myocardial cell energy, improve cardiac function.Trimetazidine Hydrochloride, in clinical popularization and application, not only to the Nutrition improving myocardial metabolism, and is the clinical antianginal metabolic drug of old people, diabetes and patients with heart failure, in the treatment of ischemic heart desease, has played positive role.
After 2000, Shi Weiya company develops trimetazidine hydrochloride sustained-release tablets, adopts matrix type slow release method, is improved as each a slice sooner or later, reduces the drug administration frequency, improve patient compliance by three administrations in a day of ordinary preparation.Slow releasing preparation exploitation has another prior object, after taking slow releasing preparation before sleeping, higher relative to blood drug level in the body of ordinary preparation when morning rises, this is very crucial for the cardiopathic medicine for the treatment of, because this period is also cardiopathic most high incidence period.
The granted patent EP1108424/CN1166408C executing NIVEA Corp describes the preparation of trimetazidine slow releasing tablet, release in vitro situation, and the plasma kinetics result of study of this medicine in healthy volunteer.Described by patent specification, adopt hydroxypropyl emthylcellulose to be that slow-release material is prepared into substrate tablet, the initial release of medicine is very fast and hold time shorter, this and Trimetazidine Hydrochloride dissolubility cross by force and preparation type relevant.Drug release due to matrix type slow releasing tablet is easily subject to the impact of the gastroenteric environment such as gastrointestinal peristalsis, pH value, especially in gastrointestinal peristalsis situation, substrate is destroyed and loses slow releasing function, the drug level continued during early morning cannot be kept, very high onset risk may be caused.
Still there is another granted patent EP0673649/CN1056057C in Shi Weiya company of France, to obtaining the drug release of long period.That patent describes and use the mixture of ethyl cellulose or polymethacrylic acid polymer and plasticizer to form coating membrane, namely delay trimetazidine release by slow-release micro-pill technology by containment system.This technique comprises that medicine mixes with adjuvant, moistening, extrude, extrudate nodularization, drying, fluidized bed coating, encapsulated or tabletting.Technical process is comparatively complicated, proposes very high requirement to control of product quality.Granule carries out capsule-filling or tabletting owing to adopting granule after fluidized bed coating, and the content difference between preparation is relatively large.In result of study disclosed in this patent, there is sluggishness and the incomplete phenomenon of release of drug release in this preparation, 16 Hours drug Accumulation dissolution are only about 75% in vitro.
CN1931143A discloses a kind of trimetazidine osmotic pump preparation preparation method, comprise double-layer core permeation pump-type and single layer core osmotic pump-type, and disclose the formula composition of double-layer core permeation pump preparation and the Co ntrolled release result to medicine, linear release can be obtained in 16h.Although this application is referred to single layer core osmotic pump preparation, do not provide clear and definite formula composition and can result of implementation.In addition, from its double-layer core permeation pump example of formulations result, this invention preparation only discharges about 10% at 2h, there is the distinctive drug release of osmotic pump preparation " sluggishness " phenomenon.Early morning is cardiovascular disease high incidence period, is also the period that requirement patient takes Trimetazidine Hydrochloride.If slow releasing preparation exists hysteresis phenomenon, can not obtain medicine in time in vivo and supplement after meaning patient consumes, be disadvantageous to performance drug effect; On the other hand, if slow releasing preparation can not Sustainable Control drug release, or drug release time is too short, and the medicine taken before sleeping is to being eliminated completely during early morning in vivo, unfavorable equally to control cardiovascular disease risk at high frequency in early morning.
Therefore, prior art still needs the trimetazidine sustained-release preparation that a kind of technique is simple, releasing effect is desirable, curative effect is good.
Summary of the invention
The invention provides a kind of Trimetazidine Hydrochloride primary osmotic pump preparation, comprise label and release-controlled film clothing layer.Wherein contain Trimetazidine Hydrochloride, filler, penetrating agent, binding agent, lubricant, release regulator in label.Osmotic tablet of the present invention is a kind of elementary osmotic pump sheet (single-layer sheet core osmotic pump tablet), can realize slow, stable drug release at human body.
Particularly, contain in Trimetazidine Hydrochloride osmotic tablet label of the present invention: principal agent 5%-45%, filler 15-65%, penetrating agent 5-50%, binding agent 1-10%, release regulator 1-20% and lubricant 0.1-3%; More preferably, label contains principal agent 10%-40%, filler 20-60%, penetrating agent 10-40%, binding agent 1-8%, release regulator 2-15% and lubricant 0.2-2%.
Wherein, described filler includes but not limited to microcrystalline Cellulose, sodium alginate, arabic gum, guar gum, propylene glycol alginate, food grade sodium polyacrylate (100,000-20 ten thousand), carboxymethyl cellulose, beta-schardinger dextrin-, dextrin, starch etc. or their mixture, wherein preferably microcrystalline cellulose, carboxymethyl cellulose, dextrin, starch, penetrating agent comprises saccharide and/or salt, saccharide comprises mannitol, sorbitol, xylitol, glucose, lactose, fructose, sucrose etc. or their mixture, salt comprises sodium chloride, potassium chloride, calcium chloride, sulfate, phosphate etc. or their mixture, most preferably mannitol, sorbitol, lactose, sucrose, sodium chloride or their mixture, particularly preferably mannitol, sodium chloride or their mixture, binding agent comprises starch, polyvinylpyrrolidone (polyvidone), sodium carboxymethyl cellulose etc. or their mixture, preferably polyethylene ketopyrrolidine, hydroxypropyl methylcellulose or their mixture, lubricant comprises magnesium stearate, stearic acid, calcium stearate, zinc stearate, Polyethylene Glycol, Pulvis Talci, micropowder silica gel, sodium benzoate, sodium lauryl sulfate, sulphuric acid Magnesium dilaurate, sodium acetate, enuatrol, boric acid, paraffin etc. or their mixture, preferred magnesium stearate, Pulvis Talci, stearic acid, release regulator be meet water can the adjuvant of undergoes rapid expansion, in order to increase the release power of medicine, regulating drug discharges, it includes but not limited to it is non-ionic polyalcohol and Ionomer, particularly, include but not limited to polyoxyethylene (polyethylene oxide, PEO), other hypromellose of high viscosity grade, carbomer, carmethose, preferred molecular weight 100,000 ~ 1,000 ten thousand polyoxyethylene, the carbomer of molecular weight 1,000,000 ~ 4,000,000, the hypromellose of molecular weight 10,000 ~ 100,000, the sodium carboxymethyl cellulose of molecular weight 100,000 ~ 700,000, preferred polyoxyethylene molecular weight is 10 ~ 8,000,000, most preferably 10 ~ 5,000,000, particularly preferably 200 ~ 5,000,000, the preferred K100M of oxybenzene methylcellulose.
In Trimetazidine Hydrochloride osmotic tablet of the present invention, controlled release coat film comprises release-controlled film filmogen, plasticizer and/or porogen, wherein, and release-controlled film filmogen 60-90%, plasticizer 0-15%, porogen 5-35%; More preferably, containing release-controlled film filmogen 65-85%, plasticizer 0-10%, porogen 10-30%; The weight of controlled release coat film accounts for 3% ~ 15% of label weight, and preferably 4% ~ 12%, more preferably 5% ~ 10%.
Wherein, release-controlled film filmogen comprises cellulosic polymer, such as, can be cellulose acetate, ethyl cellulose, cellulose diacetate, cellulose triacetate etc. or its mixture, preferred cellulose acetate, ethyl cellulose; Plasticizer can be one or more the mixture in known plasticizer, such as diethyl phthalate, ethyl phthalate, Polyethylene Glycol, glycerol, triethyl citrate, triglyceride etc. or their mixture, preferred diethyl phthalate, triethyl citrate, Polyethylene Glycol or their mixture; Porogen may be a kind of material or multiple mixture, as glycerol, propylene glycol, polyvinyl alcohol, water-soluble inorganic salt, Polyethylene Glycol etc. or their mixture, and preferably glycerine, Polyethylene Glycol or their mixture.
On release-controlled film clothing, the diameter of laser hole is generally 0.2 ~ 1.2mm, preferably 0.3 ~ 1.0mm, more preferably 0.4 ~ 0.8mm.Trimetazidine Hydrochloride osmotic pump tablet of the present invention optionally has one deck outer film coat layer at the outer surface of controlled release coat film; effect attractive in appearance, do not affect osmotic pump tablet release characteristics every protection osmotic pump tablets such as wet protection against the tide can be played; its film material can adopt the coating material thin film coating material of the stomach dissolution type of this area routine, and the determination of coating weight gain amount is also that those skilled in the art just can be obtained by simple experiment.
Should containing in the osmotic pump preparation of semi permeability thin-film material, its semipermeable membrane preferably have at least an expanding channels medicated layer and outside medicine is discharged, this hole adopts laser to get through medicated layer from outside usually, the diameter in hole is generally 0.2 ~ 1.2mm, preferably 0.3 ~ 1.0mm, more preferably 0.4 ~ 0.8mm.
Optionally, osmotic tablet of the present invention, on the surface of controlled release coating layer, can also comprise outer film coat layer further.This based calcium only plays a protective role, on the release characteristics of medicine without impact.Wherein, the filmogen of this based calcium is selected from the water miscible polymer with certain viscosity, is selected from cellulose ethers, acrylate copolymer and other water-soluble polymers.Cellulose ethers is selected from hydroxypropyl emthylcellulose (HPMC, the such as Methocel of Dow company, is suitable for viscosity 5 ~ 50cps), hydroxypropyl cellulose (HPC), methylcellulose (MC), hydroxyethyl-cellulose (HEC) or main containing above cellulosic coating pre-mixing agent; Acrylate copolymer is selected from methacrylic acid amido ester copolymer (the acrylic resin IV of such as domestic production or the main pre-mixing agent containing acrylic resin, the Eudragit especially strange E100 of Degussa-Rohm company); Other water-soluble polymers are selected from polyvidone (preferred PVP K30) and copolymerization polyvidone or the main coating pre-mixing agent containing polyvidone and copolymerization polyvidone, polyvinyl alcohol/polyethyleneglycol-graft copolymer or mainly containing coating pre-mixing agent (Kollicoat IR, the Kollicoat IR white of such as BASF BASF AG, Kollicoat IR protect) and the Polyethylene Glycol (PEG) of polyvinyl alcohol/polyethyleneglycol-graft copolymer.Wherein said coating pre-mixing agent refers to commercially available that prepared, easy to use, the main coating intermixture mixed in advance containing above-mentioned film material (also may contain a small amount of plasticizer, antiplastering aid, coloring agent and brightener in addition), the various stomach dissolution type coating pre-mixing agents of the stomach dissolution type Opadry of such as Colocorn company, the Kollicoat IR of above-mentioned BASF AG, Kollicoat IR white and Kollicoat IR protect, domestic corporation's production.
Except above composition, compositions of the present invention optionally can also comprise correctives, aromatic, coloring agent, opacifier etc. further, these can be all the known correctives of pharmaceutical arts, aromatic, coloring agent, opacifier etc., such as, aromatic includes but not limited to menthol, eudesmol, syringyl alcohol etc.; Correctives comprises that A Siba is sweet, vanillin, artificial essence etc.; Coloring agent can be one or more in known coloring agent, such as carmine, sunset yellow, indigo, viride nitens, red ferric oxide, yellow ferric oxide, Black Rouge etc.; Opacifier may be a kind of material or multiple mixture, as titanium dioxide, Pulvis Talci, micropowder silica gel.These optional compositions can join in label, controlled release coating layer and/or outer film coat layer according to actual needs, and this is that those skilled in the art do not need to pay creative work according to known technology and just can complete.
Tablet hardness of the present invention should meet the requirement of pharmacopeia, preferred 50-90N.
Further, applicant is in studying, also surprisingly find, when containing the combination of microcrystalline Cellulose and dextrin in filler, compared with other filleies, the release hysteresis phenomenon of active component in osmotic pump controlled release tablet of the present invention not only can be made obviously to improve, release can also be made more complete, create beyond thought technique effect.Therefore, invention further provides a kind of Trimetazidine Hydrochloride osmotic tablet, wherein contain principal agent 5%-45%, filler 15-65%, penetrating agent 5-50%, binding agent 1-10%, release regulator 1-20% and lubricant 0.1-3% in label; More preferably, label contains principal agent 10%-40%, filler 20-60%, penetrating agent 10-40%, binding agent 1-8%, release regulator 2-15% and lubricant 0.2-2%; Further, filler contains microcrystalline Cellulose and dextrin.
The weight ratio of microcrystalline Cellulose and dextrin can be 1:100-100:1, and be preferably 1: 50-50: 1, being more preferably 1:20-20:1, is most preferably 1:5-5:1, particularly preferably 1:2-2:1.
Controlled release preparation of the present invention, was externally respectively more than 5% ~ 25%, 25% ~ 55%, 55% ~ 80% and 80% of labelled amount at 2 hours, 4 hours, 8 hours with the burst size of 12 hours; Preferably, within 2 hours, 4 hours, 8 hours, more than 10% ~ 25%, 30% ~ 50%, 60% ~ 80% and 85% is respectively with the burst size of 12 hours; Most preferably, within 2 hours, 4 hours, 8 hours, more than 15% ~ 25%, 30% ~ 45%, 65% ~ 76% and 90% is respectively with the burst size of 12 hours.
Product of the present invention can provide the stable drug controlled release continued, and reduction gastroenteric environment and physiologic factor, on the impact of drug release, well play the drug release characteristic of osmotic pump preparation, at utmost reduce production cost.
Preferably, product of the present invention can also effectively prevent " sluggishness " phenomenon of the usually existing drug release of osmotic pump preparation and end remained the problems such as high, can obtain " Zero order release " of medicine.
Present invention also offers a kind of preparation method of the said goods, comprise the following steps:
1. trimetazidine is mixed with other adjuvant except lubricant contained in label, soft material processed, granulate, wet grain drying, add magnesium stearate lubricant mixing after tabletting namely obtain label;
2. dissolve other the adjuvant in release-controlled film filmogen and release-controlled film clothing layer with coating solvent, obtained semipermeable membrane coating solution;
3. pair label carries out coating, volatilizes the coating solvent in coated tablet, respectively opens a small delivery aperture with laser boring at coated tablet one side or upper and lower surface.
Preferably, preparation method of the present invention comprises the following steps:
1. trimetazidine is mixed with other adjuvant except lubricant contained in label, soft material processed, 30 orders granulate, wet grain drying, granulate, add magnesium stearate lubricant mixing after tabletting namely obtain label;
2. dissolve other the adjuvant in release-controlled film filmogen and release-controlled film clothing layer with coating solvent, obtained semipermeable membrane coating solution;
3. adopt efficient or fluidized bed coating equipment to carry out coating to label, volatilize the coating solvent in coated tablet, respectively open a small delivery aperture with laser boring at coated tablet one side or upper and lower surface;
4. select the film-coating material bag layer protecting film clothing again of commercially available routine, to make it moistureproof, attractive in appearance, obtain Trimetazidine Hydrochloride osmotic pump controlled release tablet.
Accompanying drawing explanation
The different embodiment of Fig. 1 and release profiles schematic diagram.
Fig. 2 comparative example release profiles schematic diagram.
Mean blood plasma concentration-time graph after Fig. 3 single-dose.
Detailed description of the invention
Following embodiment is described in further detail the present invention, but is not limited to the present invention.Those skilled in the art are under the condition grasping main body of the present invention design and spirit, and suitably can adjust technical scheme under the prerequisite of this design, these are all within protection scope of the present invention.In preparation method, suitable preparation method not only comprises following examples, and the technology such as tabletting, coating of this area routine all can be used for the present invention.
embodiment 1
(1) label composition
| Composition | Consumption (mg) |
| Trimetazidine Hydrochloride | 35 |
| Microcrystalline Cellulose | 30 |
| Polyethylene glycol oxide (5,000,000) | 5 |
| Sodium chloride | 45 |
| Lactose | 45 |
| Dextrin | 30 |
| PVP K30 | 10 |
| Magnesium stearate | 1 |
(2) coating solution composition
| Composition | Consumption (mg) |
| Cellulose acetate | 20 |
| Dibutyl phthalate | 0.2 |
| PEG-1500 | 4 |
| Acetone | In right amount |
Preparation method:
(1) after being mixed by supplementary material, use dehydrated alcohol moistening, 30 orders are granulated, 40 DEG C of dryings, control moisture below 3%, 24 mesh sieve granulate.Add recipe quantity magnesium stearate, with φ 8mm scrobicula tabletting, obtain osmotic pumps label.
(2) coating solution configuration: get a certain amount of acetone, cellulose acetate and PEG-1500 are added in acetone soln, is stirred to dissolve; Add plasticizer, stirring and evenly mixing.Coating solution solid content controls 3% ~ 8%.
(3) above-mentioned osmotic pumps label is adopted above-mentioned coating solution coating, control coating weight gain 10% ~ 12%, both obtained Trimetazidine Hydrochloride monolithic core osmotic pump controlled release tablet.
(4) respectively 0.3mm-1.0mm aperture is beaten with laser in the upper and lower both sides of osmotic pump tablet coating membrane.
(5) bag outer film clothing, shading also increases moisture resistance.
embodiment 2
(1) label composition
| Composition | Consumption (mg) |
| Trimetazidine Hydrochloride | 35 |
| Microcrystalline Cellulose | 80 |
| Hydroxypropyl emthylcellulose (K100M) | 20 |
| Sodium chloride | 30 |
| Dextrin | 25 |
| PVP K30 | 10 |
| Magnesium stearate | 1 |
(2) coating solution composition
| Composition | Consumption (mg) |
| Cellulose acetate | 20 |
| Dibutyl phthalate | 0.2 |
| PEG-1500 | 4 |
| Acetone | In right amount |
Preparation method: with preparation method in embodiment 1, coating weight gain is with embodiment 1.
embodiment 3
(1) label composition:
| Composition | Consumption (mg) |
| Trimetazidine Hydrochloride | 35 |
| Microcrystalline Cellulose | 40 |
| Polyethylene glycol oxide (5,000,000) | 5 |
| Hydroxypropyl emthylcellulose (K100M) | 15 |
| Sodium chloride | 25 |
| Mannitol | 20 |
| Dextrin | 80 |
| PVP K30 | 10 |
| Magnesium stearate | 1 |
(2) coating solution composition:
| Composition | Consumption (mg) |
| Cellulose acetate | 20 |
| PEG-6000 | 5 |
| Acetone | In right amount |
Preparation method: with preparation method in embodiment 1, adopt φ 8.5mm scrobicula tabletting, coating weight gain is with embodiment 1.
embodiment 4
(1) label composition:
| Composition | Consumption (mg) |
| Trimetazidine Hydrochloride | 80 |
| Microcrystalline Cellulose | 75 |
| Polyethylene glycol oxide (5,000,000) | 10 |
| Mannitol | 30 |
| Dextrin | 75 |
| PVP K30 | 12 |
| Magnesium stearate | 1 |
(2) coating solution composition:
| Composition | Consumption (mg) |
| Cellulose acetate | 20 |
| Tributyl 2-acetylcitrate | 2 |
| PEG-6000 | 6 |
| Acetone | In right amount |
Preparation method: with preparation method in embodiment 1, adopt φ 9mm scrobicula tabletting, coating weight gain is with embodiment 1.
embodiment 5
(1) label composition:
| Composition | Consumption (mg) |
| Trimetazidine Hydrochloride | 70 |
| Microcrystalline Cellulose | 70 |
| Polyethylene glycol oxide (5,000,000) | 10 |
| Sodium chloride | 50 |
| Dextrin | 70 |
| PVP K30 | 12 |
| Magnesium stearate | 1 |
(2) coating solution composition: coating solution composition is with embodiment 4.
Preparation method: with preparation method in embodiment 1, adopt φ 9 mm scrobicula tabletting, coating weight gain is with embodiment 1.
embodiment 6
(1) label composition
| Composition | Consumption (mg) |
| Trimetazidine Hydrochloride | 35 |
| Starch | 30 |
| Carbomer (4,000,000) | 5 |
| Sodium chloride | 45 |
| Mannitol | 45 |
| Arabic gum | 30 |
| Hypromellose | 10 |
| Magnesium stearate | 1 |
(2) coating solution composition
| Composition | Consumption (mg) |
| Cellulose acetate | 20 |
| Dibutyl phthalate | 0.2 |
| PEG-1500 | 4 |
| Acetone | In right amount |
Preparation method:
(1) after being mixed by supplementary material, use dehydrated alcohol moistening, 30 orders are granulated, 40 DEG C of dryings, control moisture below 3%, 24 mesh sieve granulate.Add recipe quantity magnesium stearate, with φ 8mm scrobicula tabletting, obtain osmotic pumps label.
(2) coating solution configuration: get a certain amount of acetone, cellulose acetate and PEG-1500 are added in acetone soln, is stirred to dissolve; Add plasticizer, stirring and evenly mixing.Coating solution solid content controls 3% ~ 8%.
(3) above-mentioned osmotic pumps label is adopted above-mentioned coating solution coating, control coating weight gain 10% ~ 12%, both obtained Trimetazidine Hydrochloride monolithic core osmotic pump controlled release tablet.
(4) respectively 0.3mm-1.0mm aperture is beaten with laser in the upper and lower both sides of osmotic pump tablet coating membrane.
(5) bag outer film clothing, shading also increases moisture resistance.
embodiment 7
(1) label composition
| Composition | Consumption (mg) |
| Trimetazidine Hydrochloride | 35 |
| Polyethylene glycol oxide (5,000,000) | 5 |
| Sodium chloride | 45 |
| Sorbitol | 45 |
| Microcrystalline Cellulose | 60 |
| PVP K30 | 10 |
| Magnesium stearate | 1 |
(2) coating solution composition: the coating solution with embodiment 6 forms.
Preparation method:
Preparation method: with preparation method in embodiment 6, adopt φ 8 mm scrobicula tabletting, coating weight gain is with embodiment 6.
embodiment 8
(1) label composition
| Composition | Consumption (mg) |
| Trimetazidine Hydrochloride | 35 |
| Polyethylene glycol oxide (5,000,000) | 5 |
| Sodium chloride | 45 |
| Lactose | 45 |
| Dextrin | 60 |
| PVP K30 | 10 |
| Magnesium stearate | 1 |
(2) coating solution composition: the coating solution with embodiment 6 forms.
Preparation method:
Preparation method: with preparation method in embodiment 6, adopt φ 8 mm scrobicula tabletting, coating weight gain is with embodiment 6.
comparative example
(1) label composition
| Composition | Consumption (mg) |
| Trimetazidine Hydrochloride | 35 |
| Hypromellose | 74 |
| Dicalcium phosphate dihydrate | 80.9 |
| Polyvidone | 8.7 |
| Magnesium stearate | 1 |
| Colloidal silica anhydrous | 0.4 |
Preparation method:
(1) by raw material, polyvidone and dicalcium phosphate dihydrate mix homogeneously, add water granulation, and 30 orders are granulated, 60 DEG C of dryings, controls moisture below 3%, 24 mesh sieve granulate.
(2) above-mentioned granule is added hypromellose mix homogeneously, then add magnesium stearate and colloidal silica mixing;
(3) by above-mentioned granule with φ 8mm scrobicula tabletting, control hardness at 40-160N.
Experimental example 1 adopts Chinese Pharmacopoeia 2010 editions pharmacopeia two annex Ⅹ D first methods, adopts dissolution method second subtraction unit, carries out vitro release mensuration to Trimetazidine Hydrochloride controlled release tablet of the present invention.With water 500ml for solvent, rotating speed is 50 revs/min.At stipulated time point sampling 10ml, and instant supplementing is preheated to synthermal same solvent 10ml.Measurement result is as follows.
table 1 Trimetazidine Hydrochloride controlled release tablet embodiment release data
table 2 comparative example release data
| Time, h | 0.5 | 1 | 2 | 3 | 4 | 6 | 8 |
| Release, % | 17.3 | 38.5 | 60.2 | 81.2 | 95.1 | 102.5 | 102.7 |
Embodiment 2 pharmacokinetic
Take the osmotic pump controlled release tablet described by embodiment 1 to 12 beasle dogs, study pharmacokinetic process in its body.And the dual crossing pharmacokinetics comparative study experiment of single dose is carried out with comparative example's (embodiment in CN1166408C patent).
Different embodiment release profiles is shown in Fig. 1, and comparative example's release profiles is shown in Fig. 2, and mean blood plasma concentration is shown in Fig. 3.
With the medicine of comparative example for compared with parameter, of the present invention have peak concentration C
maxreduce, peak time T
maxextend, there is stable blood drug level in 5-12 hour after the tablet has been ingested, in obvious sustained releasing character, and with comparative example's bioequivalence.
Claims (6)
1. a Trimetazidine Hydrochloride osmotic pump controlled release tablet, comprise label, insoluble semipermeable membrane clothing and small delivery aperture, wherein label contains Trimetazidine Hydrochloride 5%-45%, filler 15-65%, penetrating agent 5-50%, binding agent 1-10%, release regulator 1-20% and lubricant 0.1-3%, wherein, described filler contains microcrystalline Cellulose and dextrin, and the ratio of the two is 1:5-5:1; Described penetrating agent is selected from mannitol, sorbitol, xylitol, glucose, lactose, fructose, sucrose, sodium chloride, potassium chloride, calcium chloride, sulfate, phosphate or their mixture; Described binding agent is selected from starch, polyvinylpyrrolidone, sodium carboxymethyl cellulose or their mixture; Described release regulator is selected from polyoxyethylene, hypromellose, carbomer, carmethose or their mixture.
2. controlled release tablet according to claim 1, described lubricant is selected from magnesium stearate, stearic acid, calcium stearate, zinc stearate, Polyethylene Glycol, Pulvis Talci, micropowder silica gel, sodium benzoate, sodium lauryl sulfate, sulphuric acid Magnesium dilaurate, sodium acetate, enuatrol, boric acid, paraffin or their mixture.
3. controlled release tablet according to claim 1, the molecular weight of described ethylene oxide is 20 ten thousand to 800 ten thousand; Hydroxypropyl emthylcellulose is K4M, K15M or K100M.
4. controlled release tablet according to claim 1, described insoluble semipermeable membrane clothing comprises semipermeable membrane clothing material and plasticizer or/and porogen, and wherein semipermeable membrane clothing material is selected from cellulose acetate or ethyl cellulose; Plasticizer be selected from dimethyl phthalate, diethyl phthalate, dibutyl phthalate, tributyl 2-acetylcitrate, Polyethylene Glycol one or more; Porogen is selected from PEG-4000, PEG-4000, one or more in PEG-4000, sucrose, polyvidone.
5. controlled release tablet according to claim 1, containing release-controlled film filmogen 60-90%, plasticizer 0-15%, porogen 5-35% in semipermeable membrane coating, the weight of controlled release coat film accounts for 3% ~ 15% of label weight.
6. the preparation method of controlled release tablet according to the arbitrary claim of 1-5, is characterized in that, comprise the following steps:
(1) trimetazidine is mixed with other adjuvant except lubricant contained in label, soft material processed, granulate, wet grain drying, add lubricant mixing after tabletting namely obtain label;
(2) other the adjuvant in release-controlled film filmogen and release-controlled film clothing layer is dissolved with coating solvent, obtained semipermeable membrane coating solution;
(3) coating is carried out to label, volatilize the coating solvent in coated tablet, respectively open a small delivery aperture with laser boring at coated tablet one side or upper and lower surface.
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| CN201310397342.7A CN103550183B (en) | 2013-09-05 | 2013-09-05 | A kind of Trimetazidine Hydrochloride osmotic pump controlled release tablet and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110882229A (en) * | 2019-12-25 | 2020-03-17 | 中国药科大学 | Trimetazidine hydrochloride single-layer osmotic pump controlled release tablet and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104887639B (en) * | 2015-05-20 | 2018-02-02 | 沈阳药科大学 | Trimetazidine Hydrochloride mono-layer osmotic pump controlled release tablets and preparation method |
| CN108721235B (en) * | 2017-04-18 | 2021-07-02 | 江苏恒瑞医药股份有限公司 | Solid pharmaceutical composition containing trimetazidine or salt thereof and preparation method thereof |
| CN107982231B (en) * | 2018-01-03 | 2021-05-07 | 江苏吴中医药集团有限公司 | Trimetazidine hydrochloride tablet and preparation method thereof |
| CN109966259B (en) * | 2019-03-25 | 2020-12-18 | 山东大学 | Clonidine hydrochloride microporous membrane osmotic pump sustained release tablet and preparation method thereof |
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| CN1931143A (en) * | 2006-10-19 | 2007-03-21 | 广州贝氏药业有限公司 | Orally taken control released trimetazidine medicine composition |
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| CN1931143A (en) * | 2006-10-19 | 2007-03-21 | 广州贝氏药业有限公司 | Orally taken control released trimetazidine medicine composition |
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| 盐酸曲美他嗪渗透泵片的研制及在Beagle犬体内的药动学;赫玉霞等;《中国医药工业杂志》;20111231;第42卷(第10期);第752－756页 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110882229A (en) * | 2019-12-25 | 2020-03-17 | 中国药科大学 | Trimetazidine hydrochloride single-layer osmotic pump controlled release tablet and preparation method thereof |
| CN110882229B (en) * | 2019-12-25 | 2022-10-11 | 中国药科大学 | Trimetazidine hydrochloride single-layer osmotic pump controlled release tablet and preparation method thereof |
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