CN102085195A - Metoprolol succinate sustained-release tablets and preparation method thereof - Google Patents

Abstract

The invention provides a stable-release metoprolol succinate sustained-release tablet and a preparation method thereof, the composition includes 100 parts by weight of metoprolol succinate, 200-1000 parts by weight of hypromellose and 5 - 150 parts by weight of carbomer. The hydrophilic gel matrix is used as the slow-release means, and the mixture of hypromellose and carbomer is used as the retarding material, which is suitable for industrial production. Compared with the commercially available sustained-release tablets, the metoprolol succinate sustained-release tablet of the present invention has similar in vitro release characteristics.

Description

Metoprolol succinate sustained-release tablet and preparation method thereof

technical field

The invention belongs to the technical field of medicine, and in particular relates to a metoprolol succinate sustained-release tablet and a preparation method thereof.

Background technique

Metoprolol is a selective β1 receptor blocker, which is one of the commonly used drugs for the treatment of hypertension, coronary heart disease, chronic heart failure and arrhythmia. The common metoprolol tablet widely used in China is metoprolol tartrate, which has a short elimination half-life of about 3-4 hours, so the plasma drug concentration fluctuates greatly, and it needs to be taken 2-4 times a day. In order to overcome these shortcomings, several metoprolol tartrate sustained-release preparations have appeared on the market, but because the solubility of metoprolol tartrate is very large (> 700mg/ml), in order to obtain more slow and sustained release metoprolol Purpose, succinate was used instead of tartrate, so that its solubility in water at 37°C (270mg/ml) was significantly lower than the latter, thereby significantly slowing down the dissolution rate. Metoprolol succinate, the chemical name is 1-isopropylamino-3-[p-(2-methoxyethyl)phenoxy]-2-propanol succinate, and its structural formula is:

It has been proven that metoprolol succinate can effectively reduce the risk of death in patients with chronic heart failure and can effectively treat hypertension. The current clinical dosage form of metoprolol succinate in my country is sustained-release tablets, and the trade name is Betoprolol, which contains the following inactive ingredients in addition to the medicinal active ingredients: silicon dioxide, cellulose compound, sodium stearyl fumarate, Polyethylene glycol, titanium dioxide and paraffin, a microparticle system prepared with silica as the core.

CN1236761C provides a method for preparing metoprolol microparticles. The method includes: providing a granulation liquid medium containing metoprolol as a solid content, and spraying the granulation liquid medium into a fluidized bed to obtain dry and uniform microparticles.

CN101516356A provides a metoprolol succinate composition and a preparation method thereof. The composition comprises a plurality of pellets, each pellet comprising metoprolol succinate and a pharmaceutically acceptable excipient.

The metoprolol succinate composition in CN101516356A comprises a plurality of pellets, and comprises an inert core, an active drug ingredient layer and a controlled release/sustained release coating layer.

A continuous fluidized bed is required in CN1236761C, and the particles are coated. CN101516356A requires the preparation of an inert core, coating the drug on the inert core, and then coating the pellets with a controlled release layer. CN101516356A mainly adopts the method of granulating and tableting after the hydrophobic blocking agent and metoprolol succinate are dissolved or melted together, and then mixed with the gel blocking agent. The above patented process is complicated, and the industrialization cost is relatively high, so it is not suitable for industrialized production.

The metoprolol succinate sustained-release tablet of the present invention does not adopt multi-unit microparticles or pellet systems, and the mixture of hypromellose and carbomer is the slow-release retardation material, and metoprolol succinate and After mixing, it is prepared by conventional wet granulation and tabletting technology. This production process is suitable for industrial production, has good process reproducibility, and can realize the same release characteristics as commercially available sustained-release tablets.

Contents of the invention

The invention invents the metoprolol succinate sustained-release tablet and provides a preparation method thereof.

One aspect of the present invention provides a sustained-release pharmaceutical composition containing metoprolol succinate.

Another aspect of the present invention provides a preparation method of the metoprolol succinate sustained-release tablet.

In a first aspect of the present invention, a kind of metoprolol succinate sustained-release tablet is provided, and the sustained-release tablet comprises the following components:

(a) 100 parts by weight of metoprolol succinate;

(b) Hypromellose 200-1000 parts by weight;

(c) carbomer 5-150 parts by weight;

Wherein the viscosity of hypromellose is 50-100000 centipoise, and the viscosity of carbomer is 20000-80000 centipoise.

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

(a) 100 parts by weight of metoprolol succinate;

(b) hypromellose 300-800 parts by weight;

(c) carbomer 10-80 parts by weight;

In another embodiment of the present invention, the hypromellose is a combination of low viscosity hypromellose with a viscosity of 50-400 centipoise and high viscosity hypromellose with a viscosity of 2000-100000 centipoise. Mixture; preferably, the weight ratio of the low-viscosity hypromellose to the high-viscosity hypromellose is 1:8 to 8:1, more preferably 1:5 to 5:1.

In another embodiment of the present invention, the metoprolol succinate sustained-release tablet also contains one or more pharmaceutically acceptable additives selected from the group consisting of binders, fillers, lubricants .

Another aspect of the present invention provides a method for preparing metoprolol succinate sustained-release tablets, said method comprising the following steps:

(i) mixing 100 parts by weight of metoprolol succinate, 200-1000 parts by weight of hypromellose, 5-150 parts by weight of carbomer and a filler, adding a binder to make a soft material;

(ii) Carrying out granulation, drying and sizing of the soft material, adding a lubricant and pressing it into tablets.

In another preferred example, the hypromellose is a mixture of low viscosity hypromellose with a viscosity of 50-400 centipoise and high viscosity hypromellose with a viscosity of 2000-100000 centipoise.

In another preferred example, the weight ratio of the low-viscosity hypromellose to the high-viscosity hypromellose is 1:8 to 8:1, more preferably 1:5 to 5:1.

The invention adopts a hydrophilic gel-type skeleton as a slow-release means, uses hypromellose and carbomer as slow-release retarding materials, has a simple process, is suitable for industrial production, and simultaneously realizes release curve characteristics similar to commercially available tablets.

Description of drawings

Fig. 1 is that the metoprolol succinate sustained-release tablet prepared by the embodiment of the present invention 1-3 and comparative example 1-3 and the commercially available metoprolol succinate sustained-release tablet measure according to the release test method Release curve graph. Wherein, the abscissa is time (hour), and the ordinate is the percentage (%) of metoprolol succinate released cumulatively. The commercially available sustained-release tablets are metoprolol succinate sustained-release tablets produced by AstraZeneca Pharmaceuticals Co., Ltd., and the trade name is Betoprolol.

Detailed ways

After a lot of groping and in-depth research, the inventors found that using a hydrophilic gel-type framework as a means of sustained release, and using a mixture of hypromellose and carbomer as a retarding material, a drug that can be released slowly at a designed speed can be obtained. Metoprolol succinate extended-release tablets. In addition, the present invention also utilizes hypromellose mixtures with different viscosities and carbomer in the same slow-release system to obtain good slow-release performance and tablet compression performance. Further research shows that the metoprolol succinate sustained-release tablet of the present invention has obvious sustained-release effect.

the term

In the present invention, the terms "metoprolol succinate", "active drug", "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. Thus, the term "consisting essentially of" is 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 retarding material" refers to a substance in aqueous solution, buffer solution or gastrointestinal fluid in animals that can prevent and delay the release of drugs from the preparation. Specifically, the sustained-release retardation material in the present invention refers to hypromellose or a mixture of hypromellose and other cellulose or carbomer.

In the present invention, the term "viscosity of hypromellose" refers to the viscosity of a solution obtained by dissolving 2 grams of hypromellose in 100 ml of distilled water at 25 degrees Celsius.

In the present invention, the term "the viscosity of carbomer" means that at 25 degrees Celsius, take 0.5g of this product, uniformly disperse it in 98ml of water, after fully swelling, mix well, and adjust the pH value to 7.3 with 15% sodium hydroxide solution ~7.8 (tested with precision pH test paper), add water to 100ml, mix (avoid air bubbles), and measure the viscosity obtained according to the law (Method 2 of Appendix VIG of Part Two of the Chinese Pharmacopoeia 2010 Edition).

main component

The main components of the metoprolol succinate slow-release preparation of the present invention are: (a) metoprolol succinate; (b) hypromellose; (c) carbomer.

In the present invention, the active drug metoprolol succinate can be commercially available conventional metoprolol succinate.

In the present invention, the hypromellose used may be commercially available conventional hypromellose. Preferably, the hypromellose used in the present invention has a viscosity of 50-100,000 centipoise. In a preferred embodiment of the present invention, multiple hypromelloses with different viscosities are used simultaneously. In a preferred embodiment of the present invention, a mixture of low viscosity hypromellose with a viscosity of 50-400 centipoise and high viscosity hypromellose with a viscosity of 2000-100000 centipoise is used; preferably, The weight ratio of the low-viscosity hypromellose to the high-viscosity hypromellose is 1:8 to 8:1, more preferably 1:5 to 5:1. The content of hypromellose in the sustained release preparation of the present invention is 200-1000 parts by weight, preferably 250-900 parts by weight, more preferably 300-800 parts by weight.

In the present invention, the viscosity of the carbomer used as the sustained release retardation material is 20000-80000 centipoise. The content is preferably 5-150 parts by weight, preferably 8-100 parts by weight, more preferably 10-80 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 and the like.

The fillers that can be used in the present invention include but are not limited to: lactose, calcium hydrogen phosphate anhydrous or microcrystalline cellulose and the like. Lubricants available in the present invention include but are not limited to: magnesium stearate or micronized silica gel and the like.

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 lactose, anhydrous calcium hydrogen phosphate, microcrystalline cellulose and mixtures thereof. 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 50-500 parts by weight, preferably 60-400 parts by weight, more preferably 80-300 parts by weight.

In the present invention, there is no limitation on the type of pharmaceutically acceptable lubricant, and it may be a lubricant commonly used in the art. In a preferred embodiment of the present invention, the lubricant is selected from one or more of magnesium stearate and micronized silica gel. In another preferred embodiment of the present invention, the lubricant is magnesium stearate. In the present invention, there is no limitation on the usage amount of the lubricant, and it may be a conventional usage amount in this field. In one embodiment of the present invention, the lubricant is used in an amount of 2-20 parts by weight, preferably 3-15 parts by weight.

Metoprolol succinate sustained release formulation

The metoprolol succinate sustained-release tablet of the present invention comprises the following components by weight: (a) 100 parts by weight of metoprolol succinate sustained-release tablet; (b) 200-1000 parts by weight of hypromellose ; (c) a mixture of 5-150 parts by weight of carbomer. The metoprolol succinate sustained-release tablet of the present invention also includes other pharmaceutically acceptable additives as mentioned above.

According to the release assay (Chinese Pharmacopoeia 2010 edition two appendix XD), adopt the release assay (Chinese Pharmacopoeia 2010 edition two appendix XC) second method (slurry method) device, with 500ml phosphate buffer (pH6.8 ) as the medium, the metoprolol succinate sustained-release tablet provided by the present invention can release medicine steadily and slowly at the designed speed.

Preparation Process

The preferred preparation method of metoprolol succinate sustained-release preparation of the present invention comprises the following steps:

(i) mixing 100 parts by weight of metoprolol succinate, 200-1000 parts by weight of hypromellose, 5-150 parts by weight of carbomer and a filler, adding a binder to make a soft material;

(ii) Carrying out granulation, drying and sizing of the soft material, adding a lubricant and pressing it into tablets.

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

Other sustained-release tablet preparation methods known in the art can also be used to prepare the metoprolol succinate sustained-release preparation of the present invention. For example, dry granulation tableting technology or powder direct compression technology can be used.

The main advantages of the present invention are:

1. A sustained-release metoprolol succinate tablet that can be released steadily is provided;

2. The hydrophilic gel-type framework is used as the slow-release means, and the mixture of hypromellose and carbomer is used as the retarding material, which is suitable for industrial production;

3. Compared with the commercially available tablets, the metoprolol succinate sustained-release tablet of the present invention has similar in vitro release characteristics.

4. The sustained-release tablet provided by the present invention only needs to be taken in 24 hours, which improves the convenience of clinical medication and the patient's compliance.

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.

Sustained release retardation material used

hypromellose

Viscosity 100,000 centipoise : METHOCEL ^TM K100M Premium purchased from Shanghai Colorcon Coating Technology Co., Ltd., with a methoxyl content of 19-24%, a hydroxypropoxyl content of 7-12%, and a 2% aqueous solution with a viscosity of 75,000-140,000 centipoise.

Viscosity 15,000 centipoise : METHOCEL ^TM K15M Premium purchased from Shanghai Colorcon Coating Technology Co., Ltd., the content of methoxyl group is 19-24%, the content of hydroxypropoxyl group is 7-12%, and the viscosity of 2% aqueous solution is 13275-24780 centipoise.

Viscosity 4000 centipoise : METHOCEL ^TM K4M Premium purchased from Shanghai Colorcon Coating Technology Co., Ltd., with a methoxyl content of 19-24%, a hydroxypropoxyl content of 7-12%, and a 2% aqueous solution viscosity of 2663-4970 centipoise.

Viscosity 100 centipoise: METHOCEL ^TM K100Premium LVCR purchased from Shanghai Colorcon Coating Technology Co., Ltd., methoxyl content is 19-24%, hydroxypropoxyl content is 7-12%, 2% aqueous solution viscosity is 80-120 centipoise.

Viscosity 50 centipoise: METHOCEL ^TM E50 Premium LV purchased from Shanghai Colorcon Coating Technology Co., Ltd., with a methoxyl content of 28-30%, a hydroxypropoxyl content of 7-12%, and a 2% aqueous solution with a viscosity of 40- 60 centipoise.

Carbomer

Viscosity 40000-80000 centipoise : Carbopol 980 provided by Lubrizol, the neutralized 0.5% aqueous dispersion has a viscosity of 40000-80000 centipoise.

Viscosity 30000-40000 centipoise : Carbopol 974P provided by Lubrizol, the neutralized 0.5% aqueous dispersion has a viscosity of 30000-40000 centipoise.

Viscosity 20000-40000 centipoise : Carbopol 934P provided by Lubrizol, the neutralized 0.5% aqueous dispersion has a viscosity of 20000-40000 centipoise.

Example 1

Prescription for Metoprolol Succinate Extended Release Tablets 1

               

Prescription Dosage per tablet (mg)

               

Metoprolol succinate 47.5

Lactose 45

Carbomer 980 (40000-80000 centipoise) 8

HPMC K15M(15000 centipoise) 170

HPMC K100CR (100 centipoise) 35

Magnesium stearate 3

               

Preparation:

Pass metoprolol succinate, hypromellose (viscosity: 15000 centipoise), hypromellose (viscosity: 100 centipoise) and lactose through 80-mesh sieve respectively. Respectively weigh metoprolol succinate, hypromellose (viscosity: 15000 centipoise), hypromellose (viscosity: 100 centipoise), lactose and carbomer 980 and mix well, add 50 The soft material is made of % ethanol aqueous solution, granulated through 20 mesh, dried at 55 degrees, and granulated with 20 mesh. Add magnesium stearate to the dry granules, mix well, and compress into tablets.

Example 2

Prescription for Metoprolol Succinate Extended Release Tablets 2

               

Prescription Dosage per tablet (mg)

               

Metoprolol succinate 47.5

Calcium hydrogen phosphate anhydrous 60

Carbomer 934P (20000-40000 centipoise) 15

HPMC K100M(100000 centipoise) 110

HPMC E50(50 centipoise) 50

Magnesium stearate 3

               

Preparation:

Pass metoprolol succinate, hypromellose (viscosity: 100,000 centipoise), hypromellose (viscosity: 50 centipoise), and anhydrous calcium hydrogen phosphate through an 80-mesh sieve respectively. Metoprolol succinate, hypromellose (viscosity: 100,000 centipoise), hypromellose (viscosity: 50 centipoise), anhydrous calcium hydrogen phosphate and carbomer 934P were mixed, and 80% Soft material made from ethanol water solution, granulated with 20 mesh, dried at 55 degrees, granulated with 20 mesh. Add magnesium stearate to the dry granules, mix well, and compress into tablets.

Example 3

Prescription for Metoprolol Succinate Extended Release Tablets 3

               

Prescription Dosage per tablet (mg)

               

Metoprolol succinate 23.75

Lactose 80

Carbomer 974P (30000-40000 centipoise) 25

HPMC K4M (4000 centipoise) 220

Magnesium stearate 3

               

Preparation:

Pass metoprolol succinate, hypromellose (viscosity: 4000 centipoise) and lactose through an 80-mesh sieve respectively. Mix metoprolol succinate, HPMC K4M, lactose and carbomer 974P separately, add 80% ethanol aqueous solution to make soft material, granulate through 20 mesh, dry at 55 degrees, and granulate at 20 mesh. Add magnesium stearate to the dry granules, mix well, and compress into tablets.

Comparative Example 1

               

Prescription Dosage per tablet (mg)

               

Metoprolol succinate 47.5

Lactose 45

HPMC K15M(15000 centipoise) 170

HPMC K100CR(100 centipoise) 35

               

Magnesium stearate 3

               

Preparation:

Pass metoprolol succinate, hypromellose (viscosity: 15000 centipoise), hypromellose (viscosity: 100 centipoise) and lactose through 80-mesh sieve respectively. Respectively weigh metoprolol succinate, hypromellose (viscosity: 15,000 centipoise), hypromellose (viscosity: 100 centipoise) and lactose in the prescribed amount and mix well, add 50% ethanol aqueous solution to make soft Wood, granulated with 20 mesh, dried at 55 degrees, granulated with 20 mesh. Add magnesium stearate to the dry granules, mix well, and compress into tablets.

Comparative Example 2

               

Prescription Dosage per tablet (mg)

               

Metoprolol succinate 47.5

Calcium hydrogen phosphate anhydrous 60

HPMC K100M(100000 centipoise) 110

HPMC E50(50 centipoise) 50

Magnesium stearate 3

               

Preparation:

Pass metoprolol succinate, hypromellose (viscosity: 100,000 centipoise), hypromellose (viscosity: 50 centipoise), and anhydrous calcium hydrogen phosphate through an 80-mesh sieve respectively. Mix metoprolol succinate, hypromellose (viscosity: 100,000 centipoise), hypromellose (viscosity: 50 centipoise) and anhydrous calcium hydrogen phosphate respectively, add 80% ethanol aqueous solution to make soft material , through 20-mesh granulation, drying at 55 degrees, and 20-mesh granulation. Add magnesium stearate to the dry granules, mix well, and compress into tablets.

Comparative Example 3

               

Prescription Dosage per tablet (mg)

               

Metoprolol succinate 23.75

Lactose 80

HPMC K4M (4000 centipoise) 220

Magnesium stearate 3

               

Preparation:

Pass metoprolol succinate, hypromellose (viscosity: 4000 centipoise) and lactose through an 80-mesh sieve respectively. Mix metoprolol succinate, HPMC K4M and lactose respectively, add 80% ethanol aqueous solution to make soft material, granulate through 20 mesh, dry at 55 degrees, and granulate at 20 mesh. Add magnesium stearate to the dry granules, mix well, and compress into tablets.

In vitro release test of metoprolol succinate sustained-release tablets

Purpose of the test :

Metoprolol succinate sustained-release tablets prepared in test examples 1-3 and comparative examples 1-3 and commercially available metoprolol succinate sustained-release tablets (trade name: Betoprolol, batch number: LL4241) To evaluate whether the sustained-release formulation of the present invention can release slowly at the designed speed, and whether it has similar release characteristics to commercially available sustained-release tablets.

Test method :

A. Preparation of the test solution:

Each get 6 metoprolol succinate sustained-release tablets prepared in Example 1-3, 6 metoprolol succinate sustained-release tablets prepared in comparative examples 1-3 and commercially available metoprolol succinate Six sustained-release tablets were tested. According to the release assay method (Chinese Pharmacopoeia 2010 edition two appendix XD), adopt the release assay method (Chinese Pharmacopoeia 2010 edition two appendix XC) second method (slurry method) device, with 500ml 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 at 1, 4, 8, and 20 hours, filter through the microporous membrane, take the subsequent filtrate and dilute it appropriately with the release medium as the test solution .

B. Preparation of reference solution:

Accurately weigh the metoprolol succinate reference substance, dissolve and dilute it into a 20 μg/ml solution with a release medium.

C. Sample determination:

The above-mentioned test solution and reference solution were taken respectively, and the release medium was used as a blank control, and the absorbance A was measured at 274 nm, and the cumulative release percentage at each time point was calculated.

Under the same release test conditions, the release standards of USP for metoprolol succinate extended-release tablets are as follows:

             

Time (hours) Cumulative release (%)

             

1 ＜25

4 20-40

8 40-60

20 ＞80

             

test results:

See Table 1 and Figure 1 for the experimental results obtained by the method for measuring the release rate. The results show that the metoprolol succinate sustained-release tablets provided by the present invention can release medicine steadily and slowly at the designed speed.

Table 1 Comparison of in vitro release between Examples 1-3 and Comparative Examples 1-3 and commercially available sustained-release tablets (n=6)

1h 16.17 16.44 15.80 20.17 22.25 23.58 15.35 4h 36.08 37.64 34.96 46.08 48.22 55.36 32.44 8h 55.79 55.99 55.08 63.79 66.02 70.58 53.55 20h 90.68 89.55 92.11 89.35 90.28 95.97 93.04

The results showed that using hypromellose alone as a sustained-release retardation material, the release rate could not meet the USP standard, but after adding an appropriate amount of carbomer to the prescription, the release rate could meet the USP standard.

The similarity of the release curves of the samples of each example and the commercially available sustained-release tablets was compared using the FDA-approved similarity factor method. When the value of the similarity factor (f ₂ ) is in the range of 50-100, two products are considered to have similar release characteristics, and the larger the value of f ₂ , the better the similarity.

Table 2 shows the similarity comparison results of in vitro release between Examples 1-3 and commercially available sustained-release tablets.

Table 2 Comparison results of in vitro release similarity between Examples 1-3 and commercially available sustained-release tablets

Example Example 1 Example 2 Example 3 similarity factor f ₂ 78.68 72.50 86.59

Therefore, compared with the commercially available tablets, the metoprolol succinate sustained-release tablet of the present invention has similar in vitro release characteristics.

Claims (6)

1. a metroprolol succinate sustained-release sheet is characterized in that, described slow releasing tablet comprises:

(a) metroprolol succinate 100 weight portions;

(b) hypromellose 200-1000 weight portion;

(c) CBP 5-150 weight portion;

Wherein the viscosity of hypromellose is the 50-100000 centipoise, and the viscosity of CBP is the 20000-80000 centipoise.

2. metroprolol succinate sustained-release sheet as claimed in claim 1 is characterized in that, described slow releasing tablet comprises:

(a) metroprolol succinate 100 weight portions;

(b) hypromellose 300-800 weight portion;

(c) CBP 10-80 weight portion.

3. metroprolol succinate sustained-release sheet as claimed in claim 1 is characterized in that, described hypromellose is that viscosity is the low viscosity hypromellose of 50-400 centipoise and the mixture of the high viscosity hypromellose that viscosity is the 2000-100000 centipoise; The weight ratio of described low viscosity hypromellose and high viscosity hypromellose is 1: 5 to 5: 1.

4. as each described metroprolol succinate sustained-release sheet among the claim 1-3, it is characterized in that described slow releasing tablet also contains one or more pharmaceutically acceptable additives that are selected from following: binding agent, filler, lubricant.

5. metroprolol succinate sustained-release sheet as claimed in claim 1 is characterized in that, described slow releasing tablet comprises:

The metroprolol succinate of 100 weight portions;

The lactose of 95 weight portions;

The CBP 980 of 17 weight portions (viscosity 40000-80000 centipoise);

The hypromellose of 358 weight portions (viscosity 15000 centipoises);

The hypromellose of 74 weight portions (viscosity 100 centipoises);

The magnesium stearate of 6 weight portions.

6. the preparation method of metroprolol succinate sustained-release sheet as claimed in claim 1 is characterized in that, said method comprising the steps of:

(i), add binding agent and make soft material with metroprolol succinate, hypromellose, CBP and filler mixing;

(ii) to soft material granulate, dry, granulate, add the lubricant tabletting.

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