CN102824644B - High-stability sustained-release tablet prepared by using hydroxy propyl cellulose - Google Patents

Abstract

The invention provides a sustained-release tablet which uses hydroxypropyl cellulose as a sustained-release material to improve stability. The slow-release tablet comprises 5-40 parts by weight of trimetazidine hydrochloride and 10-85 parts by weight of hydroxypropyl cellulose. Its preparation method is a common wet granulation tableting process or a powder direct tableting process. The present invention uses hydroxypropyl cellulose as the trimetazidine hydrochloride sustained-release tablet prepared by the sustained-release material to solve the problem of poor stability of the commercially available trimetazidine hydrochloride sustained-release tablet prepared from hypromellose question.

Description

Sustained-release tablets with high stability prepared from hydroxypropyl cellulose

technical field

The invention belongs to the field of sustained-release pharmaceutical preparations, in particular to a sustained-release tablet prepared by using hydroxypropyl cellulose as a sustained-release material, which has significantly improved stability.

Background technique

Trimetazidine hydrochloride is an anti-angina cardiovascular drug. By protecting the energy metabolism of cells under hypoxic or ischemic conditions, it prevents the decline of intracellular ATP levels, thereby ensuring the normal function of the ion pump and the transmembrane sodium-potassium flow. normal operation and maintain the stability of the intracellular environment. Trimetazidine hydrochloride is clinically used for preventive treatment of angina pectoris attack, auxiliary symptomatic treatment of vertigo and tinnitus, etc.

Clinical oral trimetazidine hydrochloride common tablet needs to take medicine three times a day, and this brings inconvenience to patient's clinical medication. In order to reduce the adverse reactions caused by fluctuations in plasma concentration of trimetazidine hydrochloride and prolong its action time, several patents have adopted different technologies to prepare it into sustained-release preparations. Patent ZL95103558.4 discloses a pharmaceutical composition of sustained-release trimetazidine and its pharmaceutically acceptable salts, through the preparation of water-insoluble polymers and plasticizers selected from ethyl cellulose and polymethacrylic acid polymers The mixture forms a film to control the release of trimetazidine. CN 1994280 discloses a sustained-release pellet of trimetazidine or a pharmaceutically acceptable salt thereof, which is composed of a pill core and a film coating layer for controlling drug release. The pellet core is mainly prepared by extrusion spheronization, and the fluidized bed coating. CN102319225A discloses a trimetazidine hydrochloride sustained-release tablet and a preparation method thereof, using polyoxyethylene and ethyl cellulose to control drug release. Patent ZL00138060.5 discloses a matrix tablet capable of releasing trimetazidine for a long time after oral administration, and the sustained release of the matrix tablet is controlled by hypromellose. All patents are not related to the degradation of trimetazidine hydrochloride in the trimetazidine hydrochloride sustained-release preparation.

The main technology of currently commercially available trimetazidine hydrochloride sustained-release tablets is to adopt hypromellose as the sustained-release material. For example, Servier (Tianjin) Pharmaceutical Co., Ltd. uses hypromellose as a sustained-release material to prepare trimetazidine hydrochloride into sustained-release tablets. The product name is Wanshuangli, and each sustained-release tablet contains trimetazidine hydrochloride. Zine 35mg. After a lot of research, we found that the sustained-release tablet product has poor stability. Hydrochloride all rises rapidly, so it is difficult to ensure that its related substances meet the quality standards during storage. Therefore, there is an urgent need in this area to develop trimetazidine hydrochloride sustained-release tablets with good stability, so as to reduce the generation of impurities, reduce adverse reactions, and improve drug safety. The development of this trimetazidine hydrochloride sustained-release tablet will have good clinical and commercial significance.

Contents of the invention

One of the objects of the present invention is to provide a highly stable sustained-release tablet prepared using hydroxypropyl cellulose.

Another object of the present invention is to provide a method for preparing a highly stable sustained-release tablet prepared by using hydroxypropyl cellulose.

In a first aspect of the present invention, a high-stability sustained-release tablet prepared using hydroxypropyl cellulose is provided, and the sustained-release tablet includes the following components in parts by weight:

(a) 5-40 parts by weight of trimetazidine hydrochloride;

(b) 10-85 parts by weight of hydroxypropyl cellulose;

In one embodiment of the present invention, the parts by weight of the components in the trimetazidine hydrochloride sustained-release tablet are as follows:

(a) 8-30 parts by weight of trimetazidine hydrochloride;

(b) 15-70 parts by weight of hydroxypropyl cellulose.

In another preferred example, the hydroxypropyl cellulose in the mixture is more than 30 parts by weight, calculated based on the total weight of the mixture.

In another embodiment of the present invention, the hydroxypropyl cellulose in the high-stability sustained-release tablet prepared by using hydroxypropyl cellulose has the following characteristics:

The viscosity is 20 centipoise to 4000 centipoise; the average particle size is 50 microns to 250 microns.

In another preferred example, the average particle diameter of the hydroxypropyl cellulose is 80 microns to 210 microns.

In another embodiment of the present invention, the total weight of the sustained-release tablet is 80mg-500mg/tablet.

More preferably, the specifications of the sustained-release tablets are 17.5 mg, 35 mg or 70 mg per tablet.

In another embodiment of the present invention, the hydroxypropyl cellulose in the sustained-release tablet is low-viscosity hydroxypropyl cellulose with a viscosity of 20-400 centipoise and high-viscosity hydroxypropyl cellulose with a viscosity of 1000-4000 centipoise. The combination of propyl cellulose; preferably, the weight ratio of described low viscosity hydroxypropyl cellulose and high viscosity hydroxypropyl cellulose is 1:5 to 5:1, more preferably 1:3 to 3: 1.

In another embodiment of the present invention, the weight sum of component (a) and component (b) in the sustained-release tablet accounts for 20-90% of the total weight of the sustained-release tablet.

More preferably, in the sustained-release tablet, the weight sum of component (a) and component (b) accounts for 30-85% of the total weight of the sustained-release tablet.

In another preferred example, component (a) accounts for 5-40% of the total weight of the sustained-release tablet, more preferably 8-30%.

In another preferred example, component (b) accounts for 10-85% of the total weight of the sustained-release tablet, more preferably 15-70%.

In another embodiment of the present invention, the high-stability sustained-release tablet prepared by using hydroxypropyl cellulose also contains one or more pharmaceutically acceptable additives selected from the following group: binder , fillers, lubricants, glidants, sweeteners or flavoring agents.

In a second aspect of the present invention, there is provided a method of using hydroxypropyl cellulose to prepare a highly stable sustained-release tablet, the method comprising the following steps:

(i) mixing 5 to 40 parts by weight of trimetazidine hydrochloride, 10 to 85 parts by weight of hydroxypropyl cellulose and a filler, and adding a binder to make a soft material;

(ii) granulating, drying, sizing, drying and tableting the soft material to prepare trimetazidine hydrochloride sustained-release tablets.

In another preferred example, the present invention provides a method for preparing high-stability sustained-release tablets using hydroxypropyl cellulose. In the method, all raw and auxiliary materials are placed in a container and mixed uniformly, and then compressed into tablets.

In another preferred example, the hydroxypropyl cellulose is a mixture of low-viscosity hydroxypropyl cellulose with a viscosity of 20-400 centipoise and high-viscosity hydroxypropyl cellulose with a viscosity of 1000-4000 centipoise.

In another preferred example, the weight ratio of the low-viscosity hydroxypropyl cellulose to the high-viscosity hydroxylactyl cellulose is 1:5 to 5:1, more preferably 1:3 to 3:1.

The invention adopts hydroxypropyl cellulose as the slow-release material, has simple process, convenient operation, is suitable for industrial production, and has good process reproducibility. The trimetazidine hydrochloride sustained-release preparation of the present invention can produce similar sustained-release effects as the commercially available trimetazidine hydrochloride sustained-release tablets. More importantly, it significantly reduces the degradation of trimetazidine hydrochloride caused by using hypromellose as a sustained-release material, improves product stability, and improves the safety of clinical medication.

Description of drawings

Accompanying drawing is the trimetazidine hydrochloride slow-release tablet prepared by the embodiment of the present invention 1～4, comparative example and the commercially available trimetazidine hydrochloride slow-release tablet (servier (Tianjin) Pharmaceutical Co., Ltd. production, trade name : Wanshuangli, specification: 35mg) in vitro release curve measured according to the release test method. Wherein, the abscissa is time (hour), and the ordinate is the percentage (%) of trimetazidine hydrochloride released cumulatively.

Detailed ways

After a lot of groping and in-depth research, we unexpectedly found that although hydroxypropyl cellulose and hypromellose belong to cellulose derivatives with similar structures, the present invention uses hydroxypropyl cellulose as a slow-release material to prepare The stability of the trimetazidine hydrochloride sustained-release tablet is significantly better than that of the trimetazidine hydrochloride sustained-release tablet prepared using hypromellose as the sustained-release material, which improves product stability. At the same time, the trimetazidine hydrochloride can be released slowly at the designed speed, achieving a sustained release effect similar to that of the commercially available trimetazidine hydrochloride sustained-release tablets prepared using hypromellose as the sustained-release material.

the term

In the present invention, the terms "trimetazidine hydrochloride", "active drug", and "active substance" are used interchangeably.

In the present invention, the term "comprising" means that various components can be used together in the mixture or composition of the present invention. Accordingly, the terms "consisting essentially of" and "consisting of" are included in the term "comprising".

In the present invention, the term "pharmaceutically acceptable" ingredient refers to a substance suitable for human and/or animal without undue adverse side effects (such as toxicity, irritation and allergic reaction), ie having a reasonable benefit/risk ratio.

In the present invention, the term "sustained-release material" refers to a substance that can prevent and delay the release of the drug from the preparation in aqueous solution, buffer solution or gastrointestinal fluid in animals. Specifically, the slow-release material in the present invention refers to hydroxypropyl cellulose.

In the present invention, the term "viscosity of hydroxypropyl cellulose" refers to the viscosity of a solution obtained by dissolving 2 grams of hydroxypropyl cellulose in 100 milliliters of distilled water at 20 degrees Celsius.

main component

The main components in the highly stable sustained-release tablet prepared by using hydroxypropyl cellulose in the present invention are: (a) trimetazidine hydrochloride; (b) hydroxypropyl cellulose. Wherein said hydroxypropyl cellulose is a low viscosity hydroxypropyl cellulose with a viscosity of 20-400 centipoise, a high viscosity hydroxypropyl cellulose with a viscosity of 1000-4000 or a combination thereof.

In the present invention, the active drug trimetazidine hydrochloride used may be commercially available conventional trimetazidine hydrochloride, a specific example of which is trimetazidine hydrochloride produced by Guangdong Xianqiang Pharmaceutical Co., Ltd. The content of trimetazidine hydrochloride in the sustained-release preparation of the present invention is preferably 5-40 parts by weight, more preferably 8-30 parts by weight.

In the present invention, the hydroxypropyl cellulose used may be commercially available conventional hydroxypropyl cellulose. Preferably, the viscosity of the hydroxypropyl cellulose used in the present invention is 20 centipoise to 4000 centipoise, and the average particle size is 50 microns to 250 microns, preferably 80 microns to 210 microns.

In a preferred embodiment of the present invention, multiple hydroxypropyl celluloses with different viscosities are used simultaneously. In a preferred embodiment of the present invention, a mixture of low-viscosity hydroxypropyl cellulose with a viscosity of 20 to 400 centipoise and high-viscosity hydroxypropyl cellulose with a viscosity of 1000 to 4000 centipoise is used; preferably, The weight ratio of the low viscosity hydroxypropyl cellulose to the high viscosity hydroxypropyl cellulose is 1:5 to 5:1, more preferably 1:3 to 3:1.

The content of hydroxypropyl cellulose in the sustained-release preparation of the present invention is preferably 10-85 parts by weight, more preferably 15-70 parts by weight.

pharmaceutically acceptable additives

In the composition of the present invention, other pharmaceutically acceptable additives may also be included.

In the present invention, the term "pharmaceutically acceptable additive" used refers to a pharmaceutically acceptable additive that enhances the properties of the preparation. There is no limitation on the types of the additives, which may be well known to those skilled in the art, and they include but not limited to: binders, fillers, lubricants, glidants, sweeteners or fragrances and the like.

The fillers that can be used in the present invention include but are not limited to: mannitol, lactose or calcium hydrogen phosphate and the like. Lubricants and glidants that can be used in the present invention include but are not limited to: magnesium stearate or micronized silica gel and the like. Sweeteners that can be used in the present invention include but are not limited to: aspartame and the like. Fragrances available in the present invention include, but are not limited to: various plant essences and the like.

In the present invention, there is no limitation on the amount of other additives used. In a preferred embodiment of the present invention, the content of the additive is 10-80 parts by weight.

In the present invention, there is no limitation on the type of the pharmaceutically acceptable filler, and it may be a filler commonly used in this field. In a preferred embodiment of the present invention, the filler is selected from mannitol, lactose, calcium hydrogen phosphate and mixtures thereof. In another preferred embodiment of the present invention, the filler is a mixture of calcium hydrogen phosphate and mannitol. In the present invention, there is no limitation on the amount of the filler, and it can be a conventional amount in the art. In one embodiment of the present invention, the filler is used in an amount of 10-80 parts by weight, preferably 15-70 parts by weight.

In the present invention, there is no limitation on the types of pharmaceutically acceptable lubricants and glidants, which may be commonly used lubricants and glidants in this field. In a preferred embodiment of the present invention, the lubricant and glidant are selected from one or more of magnesium stearate and micronized silica gel. In another preferred embodiment of the present invention, the lubricant and glidant are magnesium stearate. In the present invention, there is no limitation on the amount of lubricant and glidant, which can be the conventional amount in this field. In one embodiment of the present invention, the lubricant and glidant are used in an amount of 0.5-4 parts by weight, preferably 1-3 parts by weight.

In the present invention, there is no limitation on the type of the pharmaceutically acceptable sweetener, and it may be a sweetener commonly used in the art. In a preferred embodiment of the present invention, the sweetener is aspartame. In the present invention, there is no limitation on the amount of sweetener used, and it can be a conventional amount used in the art. In one embodiment of the present invention, the sweetener is used in an amount of 0.1-3 parts by weight, preferably 0.4-2 parts by weight.

In the present invention, there is no limitation on the type of pharmaceutically acceptable fragrance, and it may be a fragrance commonly used in this field. In a preferred embodiment of the present invention, the fragrance agent is selected from various plant essences or mixtures thereof. In the present invention, there is no limitation on the amount of fragrance as long as it can bring a certain fragrance to the composition. In a preferred embodiment of the present invention, the fragrance is used in an amount of 0.05-1 part by weight.

Trimetazidine Hydrochloride Sustained Release Tablets

The high-stability sustained-release tablet prepared by using hydroxypropyl cellulose of the present invention comprises the following components by weight: (a) 5-40 parts by weight of trimetazidine hydrochloride; (b) 10-85 parts by weight of hydroxypropyl cellulose Base cellulose; wherein said hydroxypropyl cellulose is a low viscosity hydroxypropyl cellulose with a viscosity of 20-400 centipoise and a high viscosity hydroxypropyl cellulose with a viscosity of 1000-4000 or a combination thereof.

The high-stability sustained-release tablet prepared by using hydroxypropyl cellulose of the present invention may also include other pharmaceutically acceptable additives as mentioned above.

The total weight of the high-stability sustained-release tablet prepared by using hydroxypropyl cellulose of the present invention can be a conventional tablet specification in the field, for example, 80mg-500mg/tablet. In a preferred embodiment of the present invention, the specifications of the sustained-release tablets are 17.5 mg, 35 mg or 70 mg per tablet.

According to the release assay (Chinese Pharmacopoeia 2010 edition two appendix XD), adopt the dissolution assay (Chinese Pharmacopoeia 2010 edition two appendix XC) third method (small cup method) device, with 150ml phosphate buffer (pH 6.8 ) as the medium, the trimetazidine hydrochloride sustained-release tablet provided by the present invention can release medicine steadily and slowly at the designed speed.

Determination of related substances according to the HPLC method (Chinese Pharmacopoeia 2010 edition two appendix VD), 4-(2,3,4-trimethoxybenzyl)-1-piperazinaldehyde hydrochloride in trimetazidine hydrochloride sustained-release tablets The content of salt shall not exceed 1.0%, other single impurities shall not exceed 0.2%, and total impurities shall not exceed 1.0%.

Preparation Process

The preferred preparation method of the high-stability sustained-release tablet prepared by the present invention using hydroxypropyl cellulose comprises two kinds, and the first comprises the following steps:

(i) Mix 5-40 parts by weight of trimetazidine hydrochloride, 10-85 parts by weight of hydroxypropyl cellulose and a filler, add a binder, and make a soft material,

(ii) granulating, drying, sizing, drying and tableting the soft material to prepare trimetazidine hydrochloride sustained-release tablets.

Any method known in the field of formulation can be used to carry out the steps of mixing, preparing the soft material, granulating, drying, sizing, drying or tableting the soft material.

The second preparation method is to put all the raw and auxiliary materials in a container, mix them uniformly, and then perform tablet compression.

The main advantages of the present invention are:

1. A steady-release trimetazidine hydrochloride sustained-release preparation is provided;

2. Hydroxypropyl cellulose is used as the sustained-release material to significantly improve the stability of trimetazidine hydrochloride sustained-release tablets.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods that do not specify specific conditions in the examples, usually follow the conventional conditions or the conditions suggested by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention.

Hydroxypropyl cellulose used

Hydroxypropyl cellulose with a viscosity of 1000-4000 centipoise: HPC-H purchased from Nippon Soda Co., Ltd., with a hydroxypropoxyl content of 53.4-77.5%, a 2% aqueous solution with a viscosity of 1000-4000 centipoise, and a particle size of 50 microns to 200 microns.

Hydroxypropyl cellulose with a viscosity of 150-400 centipoise: HPC-M purchased from Nippon Soda Co., Ltd., with a hydroxypropoxyl content of 53.4-77.5%, a 2% aqueous solution with a viscosity of 150-400 centipoise, and a particle size of 50 microns to 200 microns.

Hydroxypropyl cellulose with a viscosity of 20-60 centipoise: HPC-LM purchased from Nippon Soda Co., Ltd., with a hydroxypropoxyl content of 53.4-77.5%, a 2% aqueous solution with a viscosity of 20-60 centipoise, and a particle size of 50 microns to 200 microns.

Example 1

Preparation of Trimetazidine Hydrochloride Sustained Release Tablet 1

1000 pieces

Preparation:

Grind trimetazidine hydrochloride, hydroxypropyl cellulose (viscosity: 150-400 centipoise), and calcium hydrogen phosphate, pass through an 80-mesh sieve, and mix well. Add appropriate amount of water during stirring to granulate, dry and granulate. Then, add magnesium stearate and micropowder silica gel to the dry granules after granulation, put them in a mixer and mix them evenly. Tablet, get 1000 trimetazidine hydrochloride sustained-release tablets 1.

Example 2

Preparation of Trimetazidine Hydrochloride Sustained Release Tablet 2

1000 pieces

Preparation:

Grind trimetazidine hydrochloride, hydroxypropyl cellulose (viscosity: 1000-4000 centipoise) and mannitol, pass through an 80-mesh sieve, and mix well. Add appropriate amount of water during stirring to granulate, dry and granulate. Add magnesium stearate to the above-mentioned dry granules after granulation, and put them in a mixer to mix evenly. Tablet, get 1000 trimetazidine hydrochloride sustained-release tablets 2.

Example 3

Preparation of Trimetazidine Hydrochloride Sustained Release Tablet 3

1000 pieces

Preparation:

Grind trimetazidine hydrochloride, hydroxypropyl cellulose (viscosity: 1000-4000 centipoise), hydroxypropyl cellulose (viscosity: 150-400 centipoise), and mannitol, pass through an 80-mesh sieve, and mix well. Add appropriate amount of water during stirring to granulate, dry and granulate. Then, add magnesium stearate and micropowder silica gel to the dry granules after granulation, put them in a mixer and mix them evenly. Tablet, get 1000 trimetazidine hydrochloride sustained-release tablets 3.

Example 4

Preparation of Trimetazidine Hydrochloride Sustained Release Tablet 4

1000 pieces

Preparation:

Trimetazidine hydrochloride, hydroxypropyl cellulose (viscosity: 1000-4000 centipoise), hydroxypropyl cellulose (viscosity: 20-60 centipoise), mannitol, calcium hydrogen phosphate, aspartame, strawberry The essence is pulverized, passed through an 80-mesh sieve, and mixed evenly. Add magnesium stearate and micronized silica gel, and mix evenly. Tablet, get 1000 trimetazidine hydrochloride sustained-release tablets 4.

comparative example

Prepare comparative example with the same method as embodiment 3, and difference is only to change hydroxypropyl cellulose into hypromellose Methocel ^™ K4M (purchasing from Shanghai Color Kang Coating Technology Co., Ltd., Methocel ^™ K4M 2% aqueous solution viscosity is 2308-4308 centipoise, and particle diameter is 50-180 micron) and hypromellose Methocel ^™ K100Premium (purchase from Shanghai Color Kang Coating Technology Co., Ltd., the 2% aqueous solution viscosity of Methocel ^™ K100Premium is 78-117 centipoise, the particle size is 50-180 microns). The prescription composition of comparative example is shown in Table 1.

The prescription composition of table 1 comparative example

1000 pieces

Preparation:

Grind trimetazidine hydrochloride, hypromellose (viscosity: 2308-4308 centipoise), hypromellose (viscosity: 78-117 centipoise), and mannitol, pass through an 80-mesh sieve, and mix well. Add appropriate amount of water during stirring to granulate, dry and granulate. Add magnesium stearate and micronized silica gel dry powder to the above-mentioned dry granules after granulation, and put them in a mixer to mix evenly. Tablet, get 1000 pieces of trimetazidine hydrochloride sustained-release tablets comparative example.

The composition and content (unit: g) of the slow release preparation of table 1 embodiment 1～4

Example 5

In Vitro Release Test of Trimetazidine Hydrochloride Sustained Release Tablets

Test purposes:

Test Examples 1 to 4, the trimetazidine hydrochloride sustained-release tablets prepared in comparative example 1 and the commercially available trimetazidine hydrochloride sustained-release tablets (produced by Servier (Tianjin) Pharmaceutical Co., Ltd., trade name: Wanshuang Force, specification: 35mg, batch number: 2001199) in vitro release rate, to evaluate whether the sustained-release preparation of the present invention can release slowly at the speed designed, whether it has a release profile similar to that of commercially available sustained-release tablets.

experiment method:

A. Preparation of the test solution:

Respectively get 6 pieces of trimetazidine hydrochloride sustained-release tablets prepared in Examples 1 to 5, according to the release assay method (two appendix XD of the Chinese Pharmacopoeia version in 2010), adopt the dissolution assay method (two appendix XD of the Chinese Pharmacopoeia version in 2010) XC) The third method (small cup method) device, with 150ml phosphate buffer (pH6.8) as the medium, the rotating speed is 50 revolutions per minute, operate according to the law, take 5ml of the solution respectively in 1, 2, and 8 hours, and Filter through a 0.45 micron microporous membrane, and then dilute the filtrate appropriately as the test solution.

B. Preparation of reference solution:

Accurately weigh the trimetazidine hydrochloride reference substance, dissolve it with phosphate buffer (pH 6.8) and dilute it into a solution of 240 μg/ml.

C. Sample determination:

Take the above-mentioned need testing solution and the reference substance solution respectively, take the release medium as the blank control, measure the absorbance at 267nm and 300nm wavelength respectively, subtract the absorbance at 300nm wavelength from the absorbance at 267nm wavelength during calculation, and then Then calculate the release amount of each tablet at different times.

test results:

The experimental results obtained according to the method for measuring the release rate are shown in the accompanying drawings. The result shows that the trimetazidine hydrochloride sustained-release tablet provided by the present invention can release medicine steadily and slowly with the speed designed, and adopts hypromellose as the commercially available product (trade name: Wanshuangli) of sustained-release material have similar release profiles.

Example 6

Comparison of Stability of Trimetazidine Hydrochloride Sustained-release Tablets

Test purposes:

Test Examples 1 to 4, the trimetazidine hydrochloride sustained-release tablets prepared in comparative example 1 and the commercially available trimetazidine hydrochloride sustained-release tablets (produced by Servier (Tianjin) Pharmaceutical Co., Ltd., trade name: Wanshuang strength, specification: 35mg, batch number: 2001199), to evaluate whether the sustained-release preparation of the present invention maintains good stability, and whether it is significantly improved compared with the stability of commercially available sustained-release tablets.

experiment method:

A. Sample stability test:

Each sample was sealed in a plastic bottle, respectively, and placed at 40 degrees (relative humidity 75±5%) and 60 degrees for 10 days.

B. Sample handling:

Get an appropriate amount of fine powder (approximately equivalent to trimetazidine hydrochloride 50mg) under the content determination item, accurately weighed, put in a 100ml measuring bottle, add mobile phase and fully shake to make trimetazidine hydrochloride dissolve completely, dilute to scale, shake well, filter, and take the continued filtrate as the test solution. Then accurately measure 1ml and put it in a 100ml measuring bottle, dilute to the mark with mobile phase, shake well, and use it as a control solution. In addition, dissolve and dilute with mobile phase to obtain a mixture containing 4 μg of 4-(2,3,4-trimethoxybenzyl)-1-piperazinaldehyde hydrochloride (impurity A) and 5 μg of trimetazidine hydrochloride in every 1 ml. Reference substance solution. Precisely measure 20 μl of the control solution and inject it into the liquid chromatograph, adjust the sensitivity of the detector so that the peak height of the trimetazidine hydrochloride peak is 10-20% of the full scale of the recorder, then measure the control solution, mixed reference solution and supply Each 20 μ l of the test solution is injected into the liquid chromatograph respectively, and the chromatogram is recorded to 3 times of the retention time of the main component peak. If there is an impurity peak in the test solution, calculate the 4-(2 , 3,4-trimethoxybenzyl)-1-piperazinaldehyde hydrochloride content, calculate the content of other unknown impurities according to the self-control method.

C. High performance liquid chromatography conditions:

Chromatography: Shimadzu high performance liquid chromatography.

Chromatographic column: Inertsil ODS column (150×4.6mm, 5μm);

Mobile phase: water: methanol: acetonitrile: sodium heptanesulfonate solution [take 5.05g of anhydrous sodium heptanesulfonate, add 3ml of phosphoric acid, dilute to 100ml with water] = 67:33:10:1

Column temperature: 30°C;

Detection wavelength: 210hm;

Flow rate: 1ml/min

Test results: see Table 2.

Table 2 embodiment 1-4, the related substance determination result of comparative example and commercially available sustained-release tablet

The result shows that, in 10 days under 40 ℃/75%RH 10 days condition, the impurity 4-(2,3,4-trimethoxybenzyl)-1-piperazinaldehyde hydrochloride in embodiment 1-4 has no obvious Changes, while comparative examples and commercially available sustained-release tablets all have a significant increase. The stability of Examples 1-4 at a high temperature of 60 degrees is also significantly better than that of Comparative Examples and commercially available sustained-release tablets.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

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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