CN102824644B - High-stability sustained-release tablet prepared by using hydroxy propyl cellulose - Google Patents
High-stability sustained-release tablet prepared by using hydroxy propyl cellulose Download PDFInfo
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- CN102824644B CN102824644B CN 201210337208 CN201210337208A CN102824644B CN 102824644 B CN102824644 B CN 102824644B CN 201210337208 CN201210337208 CN 201210337208 CN 201210337208 A CN201210337208 A CN 201210337208A CN 102824644 B CN102824644 B CN 102824644B
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Abstract
The invention provides a high-stability sustained-release tablet prepared by using hydroxy propyl cellulose. The sustained-release tablet comprises the following components in parts by weight: 5-40 parts of trimetazidine hydrochloride and 10-85 parts of hydroxy propyl cellulose. A preparation method for the high-stability sustained-release tablet is a common wet granulation tableting process or a powder direct tableting process. According to the trimetazidine hydrochloride sustained-release tablet prepared by using the hydroxy propyl cellulose as a sustained-release material, the problem of low stability of a commercially available trimetazidine hydrochloride sustained-release tablet prepared by using the hydroxy propyl cellulose as a sustained-release material is solved.
Description
Technical field
The invention belongs to the sustained release pharmaceutical formulation field, the slow releasing tablet of specifically using hydroxypropyl cellulose to prepare for slow-release material, it has the stability significantly improved.
Background technology
Trimetazidine Hydrochloride belongs to the antianginal cardiovascular drugs; energy metabolism by Cell protection under anoxia or ischemia; stop the decline of ATP level in cell, thereby guaranteed the normal operation of normal function and the permeable membrane sodium one potassium stream of ionic pump, maintain the stable of intracellular environment.Complementary symptomatic treatment of the clinical prophylactic treatment for angina pectoris attacks of Trimetazidine Hydrochloride, dizzy and tinnitus etc.
Clinical oral administration Trimetazidine Hydrochloride ordinary tablet needs within 1st, to take medicine three times, and this has brought inconvenience to the patient clinical medication.The untoward reaction caused for the fluctuation that reduces Trimetazidine Hydrochloride blood drug level, extend its action time, and a plurality of patents have adopted different technology that it is prepared into to slow releasing preparation.Patent ZL95103558.4 discloses a kind of trimetazidine of slow release and the pharmaceutical composition of officinal salt thereof, and the film that the insoluble polymer by being selected from ethyl cellulose and polymethacrylic acid polymer and the mixture of plasticizer form is controlled the release of trimetazidine.CN 1994280 discloses the slow-release micro-pill of a kind of trimetazidine or its officinal salt, the film-coat layer containing pill core and control drug release, consists of, and main employing is extruded spheronization and prepared the ball core, and fluid bed carries out coating.CN102319225A discloses a kind of trimetazidine hydrochloride sustained-release tablets and preparation method thereof, adopts polyoxyethylene, ethyl cellulose usually to control drug release.Patent ZL00138060.5 discloses can discharge the substrate tablet of trimetazidine after the oral administration for a long time, and the slow release of this substrate tablet is controlled by hypromellose.All patents all do not relate to the degradation problem of Trimetazidine Hydrochloride in the trimetazidine hydrochloride sustained-release preparation.
The major technique of current commercially available trimetazidine hydrochloride sustained-release tablets is that the employing hypromellose is slow-release material.For example Shi Weiya (Tianjin) pharmaceutical Co. Ltd employing hypromellose is that slow-release material is prepared into slow releasing tablet by Trimetazidine Hydrochloride, and the product commodity are called vasorel, the every hydrochloric trimetazidine 35mg of slow releasing tablet.We find through large quantity research, this sustained release tablet products less stable, under the accelerated test condition (40 degree or 30 degree), impurity 4-(2,3,4-trimethoxy benzyl)-1-piperazine aldehyde hydrochlorate all raises rapidly, so is difficult in lay up period guarantee that its related substance meets the quality standard regulation.Therefore, this area, in the urgent need to developing the trimetazidine hydrochloride sustained-release tablets of good stability, to reduce the generation of impurity, reduces untoward reaction, improves drug safety.Develop this trimetazidine hydrochloride sustained-release tablets and will there is good clinical meaning and commercial significance.
Summary of the invention
One of purpose of the present invention just is being to provide the slow releasing tablet of the high stability of using hydroxypropyl cellulose to prepare.
Another object of the present invention is to provide the preparation method of the slow releasing tablet of the high stability of using hydroxypropyl cellulose to prepare.
In a first aspect of the present invention, a kind of slow releasing tablet of the high stability of using hydroxypropyl cellulose to prepare is provided, described slow releasing tablet comprises the component of following weight portion:
(a) Trimetazidine Hydrochloride 5～40 weight portions;
(b) hydroxypropyl cellulose 10～85 weight portions;
In an embodiment of the invention, in described trimetazidine hydrochloride sustained-release tablets, the parts by weight of component are as follows:
(a) Trimetazidine Hydrochloride 8～30 weight portions;
(b) hydroxypropyl cellulose 15～70 weight portions.
In another preference, in described mixture, hydroxypropyl cellulose is more than 30 weight portions, presses the total weight of mixture.
In another embodiment of the present invention, the hydroxypropyl cellulose in the slow releasing tablet of high stability prepared by described use hydroxypropyl cellulose has following characteristic:
Viscosity is 20 centipoises～4000 centipoises; Mean diameter is 50 microns～250 microns.
In another preference, the mean diameter of described hydroxypropyl cellulose is 80 microns～210 microns.
In another embodiment of the present invention, the gross weight of described slow releasing tablet is 80mg～500mg/ sheet.
More preferably, the specification of described slow releasing tablet is every 17.5mg, 35mg or 70mg.
In another embodiment of the present invention, the hydroxypropyl cellulose in described slow releasing tablet is the combination of the viscosity low-viscosity hydroxypropylcelluloand that is 20～400 centipoises and the viscosity Klucel EF that is 1000～4000 centipoises; Preferably, the weight ratio of described low-viscosity hydroxypropylcelluloand and Klucel EF is 1: 5 to 5: 1, more preferably 1: 3 to 3: 1.
In another embodiment of the present invention, component in described slow releasing tablet (a) accounts for 20～90% of slow releasing tablet gross weight with the weight sum of component (b).
More preferably, in described slow releasing tablet, component (a) accounts for 30～85% of slow releasing tablet gross weight with the weight sum of component (b).
In another preference, component (a) accounts for 5～40% of slow releasing tablet gross weight, and more preferably 8～30%.
In another preference, component (b) accounts for 10～85% of slow releasing tablet gross weight, and more preferably 15～70%.
In another embodiment of the present invention, the slow releasing tablet of high stability prepared by described use hydroxypropyl cellulose also contains one or more pharmaceutically acceptable additives that are selected from lower group: binding agent, filler, lubricant, fluidizer, sweeting agent or aromatic.
In a second aspect of the present invention, a kind of method of using hydroxypropyl cellulose to prepare the slow releasing tablet of high stability is provided, said method comprising the steps of:
(i) 5～40 weight portion Trimetazidine Hydrochlorides, 10～85 weight portion hydroxypropyl celluloses and filler are mixed, add binding agent, make soft material;
(ii) to described soft material granulated, oven dry, granulate, drying and tabletting, make trimetazidine hydrochloride sustained-release tablets.
In another preference, the invention provides a kind of method of using hydroxypropyl cellulose to prepare the slow releasing tablet of high stability, described method is placed in the container mix homogeneously by each supplementary material, then carries out tabletting.
In another preference, described hydroxypropyl cellulose is the mixture of the viscosity low-viscosity hydroxypropylcelluloand that is 20～400 centipoises and the viscosity Klucel EF that is 1000～4000 centipoises.
In another preference, in described low-viscosity hydroxypropylcelluloand and high viscosity hydroxyl, the cellulosic weight ratio of base is 1: 5 to 5: 1, is more preferably 1: 3 to 3: 1.
It is slow-release material that the present invention adopts hydroxypropyl cellulose, and technique is simple, easy to operate, is suitable for suitability for industrialized production, the technique favorable reproducibility.Trimetazidine hydrochloride sustained-release preparation of the present invention, can produce the slow release effect similar to commercially available trimetazidine hydrochloride sustained-release tablets.More main, significantly reduced and used hypromellose for the Trimetazidine Hydrochloride degraded that slow-release material causes, improved product stability, improved the safety of clinical application.
The accompanying drawing explanation
Accompanying drawing is the prepared trimetazidine hydrochloride sustained-release tablets of the embodiment of the present invention 1～4, comparative example and (Shi Weiya (Tianjin) the pharmaceutical Co. Ltd production of commercially available trimetazidine hydrochloride sustained-release tablets, trade name: vasorel, specification: vitro release curve chart 35mg) recorded according to the dissolution test method.Wherein, abscissa be the time (hour), the Trimetazidine Hydrochloride percent (%) that vertical coordinate is cumulative release.
The specific embodiment
Through groping in a large number and furtheing investigate, we find unexpectedly, although hydroxypropyl cellulose and hypromellose belong to the cellulose derivative that structure is close, but the stability of the trimetazidine hydrochloride sustained-release tablets that the present invention uses hydroxypropyl cellulose to make for slow-release material significantly is better than using hypromellose for trimetazidine hydrochloride sustained-release tablets prepared by slow-release material, has improved product stability.Simultaneously can discharge gently Trimetazidine Hydrochloride with the speed of design, reach the slow release effect similar to the commercially available trimetazidine hydrochloride sustained-release tablets that uses hypromellose to prepare for slow-release material.
term
In the present invention, term " Trimetazidine Hydrochloride ", " active medicine ", " active substance " are used interchangeably.
In the present invention, term " contains " and means that various compositions can be applied in mixture of the present invention or compositions together.Therefore, term " mainly by ... form " and " by ... composition " be included in during term " contains ".
In the present invention, term " pharmaceutically acceptable " composition refers to the material that is applicable to people and/or animal and rational benefit/risk ratio is arranged without excessive bad side reaction (as toxicity, stimulation and allergy).
In the present invention, term " slow-release material " refers in the gastro-intestinal Fluid in aqueous solution, buffer or animal body and can stop, delay the material that medicine discharges from preparation.Particularly, the slow-release material in the present invention refers to hydroxypropyl cellulose.
In the present invention, term " viscosity of hydroxypropyl cellulose " is while referring to 20 degrees centigrade, and 2 gram hydroxypropyl celluloses are dissolved in the viscosity of gained solution in 100 ml distilled waters.
key component
Key component in the slow releasing tablet of the high stability that the present invention uses hydroxypropyl cellulose to prepare is: (a) Trimetazidine Hydrochloride; (b) hydroxypropyl cellulose.Wherein said hydroxypropyl cellulose is Klucel EF or its combination that the viscosity low-viscosity hydroxypropylcelluloand that is the 20-400 centipoise and viscosity are 1000-4000.
In the present invention, active medicine Trimetazidine Hydrochloride used can be commercially available regular hydrochloric acid trimetazidine, and its object lesson is the Trimetazidine Hydrochloride that Xianqiang Pharmaceutical Co., Ltd., Guangdong produces.Trimetazidine Hydrochloride content in slow releasing preparation of the present invention is preferably 5～40 weight portions, is more preferably 8～30 weight portions.
In the present invention, hydroxypropyl cellulose used can be commercially available conventional hydroxypropyl cellulose.Preferably, the viscosity of the present invention's hydroxypropyl cellulose used is 20 centipoises～4000 centipoises, and mean diameter is 50 microns～250 microns, preferably 80 microns～210 microns.
In the preferred embodiment of the present invention, adopted the hydroxypropyl cellulose of multiple different viscosities simultaneously.In a preferred embodiment of the present invention, adopted the mixture of the Klucel EF that low-viscosity hydroxypropylcelluloand that viscosity is 20～400 centipoises and viscosity are 1000～4000 centipoises; Preferably, the weight ratio of described low-viscosity hydroxypropylcelluloand and Klucel EF is 1: 5 to 5: 1, more preferably 1: 3 to 3: 1.
In slow releasing preparation of the present invention, the content of hydroxypropyl cellulose is preferably 10～85 weight portions, is more preferably 15～70 weight portions.
pharmaceutically acceptable additive
In compositions of the present invention, also can comprise other pharmaceutically acceptable additive.
In the present invention, term used " pharmaceutically acceptable additive " refers to the additive of pharmaceutically acceptable reinforcement preparation characteristic.Type for described additive does not have any restriction, and it can be well-known to those skilled in the art, and they include but not limited to: binding agent, filler, lubricant, fluidizer, sweeting agent or aromatic etc.
The present invention can with filler include but not limited to: mannitol, lactose or calcium hydrogen phosphate etc.The present invention can with lubricant and fluidizer include but not limited to: magnesium stearate or micropowder silica gel etc.The present invention can with sweeting agent comprise but be not limited to: A Siba is sweet etc.The present invention can with aromatic include but not limited to: various plant essences etc.
In the present invention, the consumption for other additive does not have any restriction.In a preferred embodiment of the present invention, the content of described additive is 10～80 weight portions.
In the present invention, for the type of pharmaceutically acceptable filler, do not have any restriction, it can be filler commonly used in this area.In a preferred embodiment of the present invention, described filler is selected from mannitol, lactose, calcium hydrogen phosphate and their mixture.In another preferred embodiment of the present invention, described filler is the mixture that calcium hydrogen phosphate and mannitol form.In the present invention, for the consumption of filler, do not have any restriction, it can be the conventional amount used in this area.In an embodiment of the invention, the consumption of described filler is 10～80 weight portions, is preferably 15～70 weight portions.
In the present invention, for the type of pharmaceutically acceptable lubricant and fluidizer, do not have any restriction, it can be lubricant and fluidizer commonly used in this area.In a preferred embodiment of the present invention, described lubricant and fluidizer are selected from one or more in magnesium stearate and micropowder silica gel.In another preferred embodiment of the present invention, described lubricant and fluidizer are magnesium stearate.In the present invention, for the consumption of lubricant and fluidizer, do not have any restriction, it can be the conventional amount used in this area.In an embodiment of the invention, the consumption of described lubricant and fluidizer is 0.5～4 weight portion, is preferably 1～3 weight portion.
In the present invention, for the type of pharmaceutically acceptable sweeting agent, do not have any restriction, it can be sweeting agent commonly used in this area.In a preferred embodiment of the present invention, described sweeting agent is aspartame.In the present invention, for the consumption of sweeting agent, do not have any restriction, it can be the conventional amount used in this area.In an embodiment of the invention, the consumption of described sweeting agent is 0.1～3 weight portion, is preferably 0.4～2 weight portion.
In the present invention, for the type of pharmaceutically acceptable aromatic, do not have any restriction, it can be aromatic commonly used in this area.In a preferred embodiment of the present invention, described aromatic is selected from various plant essences or its mixture.In the present invention, for the consumption of aromatic also without any restriction, as long as it bring certain fragrance can to described compositions.In the preferred embodiment of the present invention, the consumption of described aromatic is 0.05～1 weight portion.
trimetazidine hydrochloride sustained-release tablets
The slow releasing tablet of high stability prepared by use hydroxypropyl cellulose of the present invention comprises the component of following weight portion: (a) 5～40 weight portion Trimetazidine Hydrochlorides; (b) 10～85 weight portion hydroxypropyl celluloses; Wherein said hydroxypropyl cellulose is Klucel EF or its combination that the viscosity low-viscosity hydroxypropylcelluloand that is the 20-400 centipoise and viscosity are 1000-4000.
The slow releasing tablet of high stability prepared by use hydroxypropyl cellulose of the present invention also can comprise other pharmaceutically acceptable additive as above.
The gross weight of the slow releasing tablet of high stability prepared by use hydroxypropyl cellulose of the present invention can be the tablet specification of this area routine, is for example 80mg～500mg/ sheet.In the preferred embodiment of the present invention, the specification of described slow releasing tablet is every 17.5mg, 35mg or 70mg.
According to drug release determination method (two appendix XD of Chinese Pharmacopoeia version in 2010), adopt dissolution method (two appendix XC of Chinese Pharmacopoeia version in the 2010) three therapeutic methods of traditional Chinese medicine (little agar diffusion method) device, the 150ml phosphate buffer (pH 6.8) of take is medium, and trimetazidine hydrochloride sustained-release tablets provided by the present invention can be with the steadily slowly release of speed of design.
Measure related substance according to high-efficient liquid phase technique (two appendix VD of Chinese Pharmacopoeia version in 2010), in trimetazidine hydrochloride sustained-release tablets, 4-(2,3, the content of 4-trimethoxy benzyl)-1-piperazine aldehyde hydrochlorate must not cross 1.0%, other single contaminants must not cross 0.2%, and total impurities must not cross 1.0%.
preparation technology
The preferred preparation method of the slow releasing tablet of the high stability that the present invention uses hydroxypropyl cellulose to prepare comprises two kinds, and the first comprises the following steps:
(i) 5～40 weight portion Trimetazidine Hydrochlorides, 10～85 weight portion hydroxypropyl celluloses and filler are mixed, add binding agent, make soft material,
(ii) to described soft material granulated, oven dry, granulate, drying and tabletting, make trimetazidine hydrochloride sustained-release tablets.
Can adopt the known any method of formulation art to be mixed, prepare soft material and each steps such as the granulation that soft material is carried out, oven dry, granulate, drying or tabletting.
The second preparation method is that each supplementary material is placed in to the container mix homogeneously, then carries out tabletting.
Major advantage of the present invention is:
1. a kind of trimetazidine hydrochloride sustained-release preparation that can steadily discharge is provided;
2. adopting hydroxypropyl cellulose is slow-release material, significantly improves the stability of trimetazidine hydrochloride sustained-release tablets.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only are not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in embodiment, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise defined, the same meaning that all specialties of using in literary composition and scientific words and one skilled in the art are familiar.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.
hydroxypropyl cellulose used
The hydroxypropyl cellulose of viscosity 1000-4000 centipoise: the HPC-H bought from Tso Tat Co., Ltd., Japan, propoxyl content 53.4-77.5%, 2% solution viscosity is the 1000-4000 centipoise, 50 microns to 200 microns of particle diameters.
The hydroxypropyl cellulose of viscosity 150-400 centipoise: the HPC-M bought from Tso Tat Co., Ltd., Japan, propoxyl content 53.4-77.5%, 2% solution viscosity is the 150-400 centipoise, 50 microns to 200 microns of particle diameters.
The hydroxypropyl cellulose of viscosity 20-60 centipoise: the HPC-LM bought from Tso Tat Co., Ltd., Japan, propoxyl content 53.4-77.5%, 2% solution viscosity is the 20-60 centipoise, 50 microns to 200 microns of particle diameters.
Embodiment 1
The preparation of trimetazidine hydrochloride sustained-release tablets 1
1000
preparation method:
The 150-400 centipoise), calcium hydrogen phosphate pulverizes, and crosses 80 mesh sieves by Trimetazidine Hydrochloride, hydroxypropyl cellulose (viscosity:, mix.In stirring, add water to granulate in right amount, dry granulate.By the dried particles after above-mentioned granulate, add magnesium stearate and micropowder silica gel again, put mix homogeneously in mixer.Tabletting, obtain 1000 trimetazidine hydrochloride sustained-release tablets 1.
The preparation of trimetazidine hydrochloride sustained-release tablets 2
1000
preparation method:
The 1000-4000 centipoise), mannitol pulverizes, and crosses 80 mesh sieves by Trimetazidine Hydrochloride, hydroxypropyl cellulose (viscosity:, mix.In stirring, add water to granulate in right amount, dry granulate.By the dried particles after above-mentioned granulate, add magnesium stearate again, put mix homogeneously in mixer.Tabletting, obtain 1000 trimetazidine hydrochloride sustained-release tablets 2.
Embodiment 3
The preparation of trimetazidine hydrochloride sustained-release tablets 3
1000
preparation method:
The 1000-4000 centipoise), hydroxypropyl cellulose (viscosity:, mix the 150-400 centipoise), mannitol pulverizes, and crosses 80 mesh sieves by Trimetazidine Hydrochloride, hydroxypropyl cellulose (viscosity:.In stirring, add water to granulate in right amount, dry granulate.By the dried particles after above-mentioned granulate, add magnesium stearate and micropowder silica gel again, put mix homogeneously in mixer.Tabletting, obtain 1000 trimetazidine hydrochloride sustained-release tablets 3.
The preparation of trimetazidine hydrochloride sustained-release tablets 4
1000
preparation method:
The 1000-4000 centipoise), hydroxypropyl cellulose (viscosity: the 20-60 centipoise), mannitol, calcium hydrogen phosphate, Aspartane, strawberry essence pulverizes by Trimetazidine Hydrochloride, hydroxypropyl cellulose (viscosity:, cross 80 mesh sieves, mix homogeneously, add magnesium stearate and micropowder silica gel, mix homogeneously.Tabletting, obtain 1000 trimetazidine hydrochloride sustained-release tablets 4.
The comparative example
Prepare the comparative example by the method identical with embodiment 3, difference only is to change hydroxypropyl cellulose into hypromellose Methocel
tMk4M (buys Methocel from Shanghai Colorcon Coating Technology Co., Ltd
tM2% solution viscosity of K4M is the 2308-4308 centipoise, and particle diameter is the 50-180 micron) and hypromellose Methocel
tMk100Premium (buys Methocel from Shanghai Colorcon Coating Technology Co., Ltd
tM2% solution viscosity of K100Premium is the 78-117 centipoise, and particle diameter is the 50-180 micron).Comparative example's prescription forms in Table 1.
Table 1 comparative example's prescription forms
1000
preparation method:
The 2308-4308 centipoise), hypromellose (viscosity:, mix the 78-117 centipoise), mannitol pulverizes, and crosses 80 mesh sieves by Trimetazidine Hydrochloride, hypromellose (viscosity:.In stirring, add water to granulate in right amount, dry granulate.By the dried particles after above-mentioned granulate, add magnesium stearate and micropowder silica gel dry powder again, put mix homogeneously in mixer.Tabletting, obtain 1000 trimetazidine hydrochloride sustained-release tablets comparative examples.
The composition of the slow releasing preparation of table 1 embodiment 1～4 and content (unit: g)
Embodiment 5
The vitro release test of trimetazidine hydrochloride sustained-release tablets
test objective:
Test implementation example 1～4, in comparative example 1, (Shi Weiya (Tianjin) pharmaceutical Co. Ltd produces for the trimetazidine hydrochloride sustained-release tablets of preparation and commercially available trimetazidine hydrochloride sustained-release tablets, trade name: vasorel, specification: 35mg, lot number: vitro release 2001199), whether can discharge gently with the speed of design to assess slow releasing preparation of the present invention, whether there is the release profiles similar to commercially available slow releasing tablet.
test method:
A. the preparation of need testing solution:
Respectively get in embodiment 1～5 6 of the trimetazidine hydrochloride sustained-release tablets of preparation, according to drug release determination method (two appendix XD of Chinese Pharmacopoeia version in 2010), adopt dissolution method (two appendix XC of Chinese Pharmacopoeia version in the 2010) three therapeutic methods of traditional Chinese medicine (little agar diffusion method) device, the 150ml phosphate buffer (pH6.8) of take is medium, rotating speed is per minute 50 to turn, operation in accordance with the law, got respectively solution 5ml in the time of 1,2,8 hour, with 0.45 micron microporous filter membrane, filter, subsequent filtrate suitably after dilution as need testing solution.
B. the preparation of reference substance solution:
Precision takes the Trimetazidine Hydrochloride reference substance, adopts phosphate buffer (pH 6.8) to dissolve and be diluted to the solution of 240 μ g/ml.
C. sample determination:
Get respectively above-mentioned need testing solution and reference substance solution, take release medium as blank, measure respectively trap under 267nm and 300nm wavelength, the trap at the trap deduction 300nm wavelength place recorded with 267nm wavelength place during calculating, and then calculate the every burst size at different time.
result of the test:
See accompanying drawing according to drug release determination experimental technique experimental results.Result shows that trimetazidine hydrochloride sustained-release tablets provided by the present invention all can be with the steadily slowly release of speed of design, and to adopt the commercially available product (trade name: vasorel) there is similar release profiles that hypromellose is slow-release material.
Trimetazidine hydrochloride sustained-release tablets stability relatively
test objective:
Test implementation example 1～4, in comparative example 1, (Shi Weiya (Tianjin) pharmaceutical Co. Ltd produces for the trimetazidine hydrochloride sustained-release tablets of preparation and commercially available trimetazidine hydrochloride sustained-release tablets, trade name: vasorel, specification: 35mg, lot number: stability 2001199), whether maintain good stability to assess slow releasing preparation of the present invention, whether more commercially available slow releasing tablet stability is significantly increased.
test method:
A. sample stability test:
Each sample is sealed in respectively in plastic bottle, puts respectively 40 degree (relative humidity 75 ± 5%) and 60 degree lower 10 days.
B. sample treatment:
Get the fine powder appropriate (approximately being equivalent to Trimetazidine Hydrochloride 50mg) under the assay item, accurately weighed, put in the 100ml measuring bottle, add mobile phase and fully vibrate Trimetazidine Hydrochloride is dissolved fully, by mobile phase, be diluted to scale, shake up, filter, get subsequent filtrate as need testing solution.Precision measures 1ml and puts in the 100ml measuring bottle again, by mobile phase, is diluted to scale, shakes up, in contrast solution.Separately with the preparation of mobile phase dissolved dilution, obtain approximately containing in every 1ml the mixing reference substance solution of 4-(2,3,4-trimethoxy benzyl)-1-piperazine aldehyde hydrochlorate (impurity A) 4 μ g and Trimetazidine Hydrochloride 5 μ g.Precision measures contrast solution 20 μ l injection liquid chromatographies, regulate detector sensitivity, the peak height that makes the Trimetazidine Hydrochloride peak is 10～20% of monitor full scale, measure again contrast solution, mix reference substance solution and each 20 μ l of need testing solution, difference injection liquid chromatography, record to main constituent peak retention time 3 times of chromatogram, need testing solution is as aobvious impurity peaks, calculate 4-(2 in test sample with the peak area external standard method, 3, the content of 4-trimethoxy benzyl)-1-piperazine aldehyde hydrochlorate, calculate the content of other unknown impurities by Self-control method.
C. high-efficient liquid phase chromatogram condition:
Chromatograph: Shimadzu high performance liquid chromatograph.
Chromatographic column: InertsilODS post (150 * 4.6mm, 5 μ m);
Mobile phase: water: methanol: acetonitrile: heptanesulfonic acid sodium solution [get anhydrous sodium heptanesulfonate 5.05g, add 3ml phosphoric acid, be diluted with water to 100ml]=67: 33: 10: 1
Column temperature: 30 ℃;
Detect wavelength: 210hm;
Flow velocity: 1ml/ minute
result of the test:in Table 2.
Table 2 embodiment 1-4, the determination of related substances result of comparative example and commercially available slow releasing tablet
Result shows, under 10 days conditions of 40 ℃/75%RH, in 10 days, the impurity 4-in embodiment 1-4 (2,3,4-trimethoxy benzyl)-1-piperazine aldehyde hydrochlorate is without significant change, and comparative example and commercially available slow releasing tablet all have remarkable rising.Embodiment 1-4 also all extremely significantly is better than comparative example and commercially available slow releasing tablet in the stability of high temperature 60 degree.
All documents of mentioning in the present invention are all quoted as a reference in this application, just as each piece of document quoted separately as a reference.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (8)
1. the slow releasing tablet of a high stability of using hydroxypropyl cellulose to prepare, is characterized in that, described slow releasing tablet comprises the component of following weight portion:
(a) Trimetazidine Hydrochloride 5～40 weight portions;
(b) hydroxypropyl cellulose 10～85 weight portions;
The mixture that the Klucel EF that the low-viscosity hydroxypropylcelluloand that the Klucel EF that wherein said hydroxypropyl cellulose is the viscosity low-viscosity hydroxypropylcelluloand that is the 20-400 centipoise, viscosity is 1000-4000 or viscosity are the 20-400 centipoise and viscosity are 1000-4000 mixes according to the ratio of 1: 5 to 5: 1.
2. the slow releasing tablet of the high stability that prepared by use hydroxypropyl cellulose as claimed in claim 1, is characterized in that, the parts by weight of described component are as follows:
(a) Trimetazidine Hydrochloride 8～30 weight portions;
(b) hydroxypropyl cellulose 15～70 weight portions.
3. the slow releasing tablet of the high stability that prepared by use hydroxypropyl cellulose as claimed in claim 1, is characterized in that, the mean diameter of described hydroxypropyl cellulose is 50 microns～250 microns.
4. the slow releasing tablet of the high stability that prepared by use hydroxypropyl cellulose as claimed in claim 1, is characterized in that, the gross weight of described slow releasing tablet is 80mg～500mg/ sheet.
5. the slow releasing tablet of the high stability that prepared by use hydroxypropyl cellulose as claimed in claim 1 is characterized in that the weight ratio of described low-viscosity hydroxypropylcelluloand and Klucel EF is 1: 3 to 3: 1.
6. the slow releasing tablet of the high stability that prepared by use hydroxypropyl cellulose as claimed in claim 1, is characterized in that, component in described slow releasing tablet (a) accounts for 20～90% of slow releasing tablet gross weight with the weight sum of component (b).
7. the slow releasing tablet of the high stability that prepared by use hydroxypropyl cellulose as described as any one in claim 1～6, it is characterized in that, described slow releasing tablet also contains one or more pharmaceutically acceptable additives that are selected from lower group: binding agent, filler, lubricant, fluidizer, sweeting agent and aromatic.
8. the method for making of the slow releasing tablet of the high stability that prepared by use hydroxypropyl cellulose as claimed in claim 1, it is characterized in that, 5～40 weight portion Trimetazidine Hydrochlorides, 10～85 weight portion hydroxypropyl celluloses and filler are mixed, add binding agent to make soft material, to soft material granulated, oven dry, granulate, drying and tabletting; Or each supplementary material is placed in to container mix homogeneously, tabletting.
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| CN109908096A (en) * | 2017-12-12 | 2019-06-21 | 武汉武药科技有限公司 | A kind of trimetazidine hydrochloride sustained-release tablets and preparation method thereof |
| CN109307725B (en) * | 2018-10-31 | 2021-08-17 | 远大医药（中国）有限公司 | Analysis method of trimetazidine hydrochloride |
| CN112315942B (en) * | 2020-11-04 | 2022-08-09 | 南京康川济医药科技有限公司 | Trimetazidine hydrochloride sustained release preparation and preparation method thereof |
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| EP2200591A2 (en) * | 2007-09-11 | 2010-06-30 | Ranbaxy Laboratories Limited | Controlled release pharmaceutical dosage forms of trimetazidine |
| CN102670537B (en) * | 2011-03-10 | 2013-09-11 | 齐鲁制药有限公司 | Trimetazidine dihydrochloride sustained release tablet and preparation method thereof |
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