CN111419813A

CN111419813A - Metoprolol succinate sustained-release tablet and preparation method thereof

Info

Publication number: CN111419813A
Application number: CN202010385897.XA
Authority: CN
Inventors: 克里斯蒂安·山多夫
Original assignee: Shenzhen Daokesi Pharmaceutical Co ltd
Current assignee: Wuxi daokesen Pharmaceutical Co.,Ltd.
Priority date: 2020-05-09
Filing date: 2020-05-09
Publication date: 2020-07-17

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a metoprolol succinate sustained-release tablet and a preparation method thereof.

Description

Metoprolol succinate sustained-release tablet and preparation method thereof

Technical Field

Background

Metoprolol tartrate is a selective β 1 adrenoceptor blocker and is provided in the form of tartrate and succinate for the treatment of the cardiovascular system, especially hypertension.

Metoprolol has a very low melting point, around 120 ℃ for tartaric acid and around 136 ℃ for succinic acid. Thus, metoprolol is always produced in a salt-based solution because low melting drugs are difficult to work in a production environment. Metoprolol free base is present as a waxy white solid, tartrate is a relatively fine crystalline material. Metoprolol succinate is a white crystalline powder with molecular weight of 652.8.

Metoprolol succinate is classified as a BCS (biopharmaceutical classification system) class 1 drug with high solubility, high permeability and good absorption with higher absorption rate than excreta. Is easily soluble in water; dissolving in methanol; slightly soluble in ethanol; slightly soluble in dichloromethane and 2-propanol; practically insoluble in ethyl acetate, acetone, diethyl ether and heptane.

Metoprolol is metabolized in the liver as an inactive metabolite and undergoes a-hydroxylation and O-demethylation as a substrate for cytochrome liver enzyme CYP2D6, while a small amount is metabolized by CYP3a 4.

In the United states, metoprolol succinate is available under the trademark metoprolol succinate

Is a sustained release tablet, and is administered once a day. The tablet comprises a multiple unit system comprising metoprolol succinate in a plurality of controlled release pellets. Each pill acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over a dosage interval. Tablets contained 23.75, 47.5, 95 and 190mg of metoprolol succinate, respectively, corresponding to 25, 50, 100 and 200mg of metoprolol tartrate, respectively.

The inactive ingredients in (1) include silicon dioxide, sodium stearyl fumarate, polyethylene glycol, titanium dioxide, paraffin and hydroxymethyl cellulose.

U.S. patent No. 4,927,640 describes a composition that requires beads selected from glass and silica and that are insoluble in water, physiological fluids and liquids commonly used for intravenous infusion. The beads are covered by one or more pharmaceutically active compounds and a controlled release polymer film covering the active layer.

U.S. patent No. 4,957,745 describes a controlled release formulation comprising a plurality of beads having a soluble component comprising at least 95 wt%/wt of a metoprolol salt. The control polymer film is described as consisting essentially of ethyl cellulose or a mixture of ethyl cellulose and hydroxypropyl-methyl cellulose. This patent illustrates a metoprolol salt applied to silica microbeads having a size of between 150 μm and 250 μm.

U.S. patent No. 5,081,154 relates to metoprolol succinate in an oral composition coated with an anionic polymer soluble at pH above 5.5 and a water insoluble quaternary ammonium to replace the acrylic polymer.

U.S. patent No. 5,246,714 describes compositions and methods for preparing beads containing a pharmaceutically active ingredient that are compressed into tablets.

U.S. patent No. 8,815,285 describes a sustained release dosage form of metoprolol succinate comprising an inert core comprising microcrystalline cellulose spheres coated with one or more water insoluble pharmaceutically acceptable polymers, the inert core further comprising one or more coatings having one or more pharmaceutical activities. The ingredients and other pharmaceutically acceptable excipients may optionally be coated with one or more controlled release polymers.

U.S. patent No. 9,561,187 describes a sustained release pharmaceutical composition comprising a monolithic matrix tablet comprising granules containing metoprolol and additional granule excipients, wherein the granules comprise about: 20-30% of metoprolol selected from the group consisting of metoprolol succinate and metoprolol tartrate; 5-10% of calcium hydrogen phosphate; 5-10% lactose monohydrate; 5-10% acetic acid pregelatinized starch; 1-5% hydroxyethyl cellulose; wherein the additional particulate excipients comprise about: 5-15% carbomer homopolymer; and 5-15% polyethylene oxide; 10-20% hypromellose; and 5-10% of methacrylic acid copolymer.

US2007/0053983a1 describes an oral composition comprising: a therapeutically effective amount of metoprolol succinate and a hydrophilic polymer matrix consisting of a gelling agent comprising at least one hydrophilic polymer with one or more gums or gum derivatives and pharmaceutically acceptable excipients, whereby the composition provides a sustained or modified release of metoprolol succinate or a pharmaceutically acceptable derivative thereof.

US2007/0202172 describes a pharmaceutical composition for extended release comprising pellets coated with an active pharmaceutical ingredient, wherein each coated pellet comprises: a) an inert core comprising at least about 50% (w/w) soluble species; b) a drug layer comprising an active pharmaceutical ingredient, the layer overlying the inert core; c) the controlled release layer thereon does not use inherently toxic solvents. Ideally, the primer layer covers the initial core/sphere forming the inert core.

US2009/0324717 describes slow release coated granules comprising granules with a particle size of 0.2 to 2mm and a friability of less than or equal to 1% and comprising metoprolol succinate as active ingredient in an amount of 10 to 75%. A weight of granules and at least one binder selected from one or both of microcrystalline cellulose and methylcellulose, said granules being coated with a film-forming agent.

EP2255791a1 describes a process for the preparation of a sustained release pharmaceutical composition comprising granules containing metoprolol succinate and at least two pharmaceutically acceptable excipients, wherein one pharmaceutically acceptable excipient is a sustained release agent; the second pharmaceutically acceptable adjuvant is selected from the group consisting of binders, diluents and mixtures thereof; metoprolol succinate in crystalline form, D thereof₅₀Is 5 to 16 μm, D₉₀Below 50 microns, wherein the final granules or spheronized granules are further mixed with at least one pharmaceutically acceptable excipient and compressed into tablets, ideally coated.

WO2005/084636a2 describes an oral controlled release pharmaceutical composition of metoprolol succinate comprising a plurality of beads comprising: a) a water-soluble, water-swellable or water-insoluble inert core; b) one or more drug layers comprising metoprolol; c) one or more polymeric coating layers surrounding one or more drug layers.

WO2012/052834a2 describes a sustained release composition comprising metoprolol or a pharmaceutically acceptable salt thereof, wherein the composition comprises sustained release pellets comprising: a) a water-soluble or water-swellable inert core; b) coating a drug layer consisting of metoprolol or a pharmaceutically acceptable salt thereof on the core to obtain drug particles; c) an extended release polymer layer comprising at least one water insoluble polymer selected from polymethacrylates, cellulose ethers, cellulose esters, or mixtures thereof, to form extended release particles; a tablet excipient comprising at least two grades of microcrystalline cellulose, wherein the dissolution rate of the sustained release pellets is substantially unaffected when compressed into a tablet.

The main problems associated with sustained release tablets of metoprolol succinate are the consistency of dissolution and the rupture of the sustained release coating layer during compression.

Disclosure of Invention

In view of the problems of the prior art, the main object of the present invention is to provide a sustained release tablet of metoprolol succinate which is bioequivalent to a commercially available tablet, prepared using a simple and commercially available process.

The present invention provides an oral extended release tablet of metoprolol succinate comprising:

a) an inert core comprising at least about 10 to 20% (w/w) of the mass of the tablet;

b) coating a drug layer comprising metoprolol succinate on the inert core to obtain drug loaded pellets;

c) coating an extended release polymer layer comprising at least one water insoluble polymer and a binder on the drug loaded pellets to form extended release granules;

d) coating a buffer layer on the extended release particles;

e) mixing with at least one other tablet excipient.

The present invention provides an oral sustained release tablet of metoprolol succinate prepared by a process comprising the use of a fluidized bed process/granulation and a high shear mixing granulator.

Certain ranges are provided herein, with values preceded by the term "about". The term "about" is used herein to provide literal support for the exact number following it, as well as numbers that are near or similar to the number following the term.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this method belongs.

Where a range of values is provided, it is understood that each intervening value, between the upper and lower limit of that range and any other stated or intervening value in that range is encompassed within the methods and compositions of the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also limited by the methods and compositions, subject to any specifically excluded upper limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the methods and compositions.

It is to be understood that certain components or features, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Note that as used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

Note that as used herein, the terms "solid dosage form" or "tablet dosage form" are interchangeable.

As used herein, the term "comprising" allows for the presence of one or more additional components in the composition.

As used herein, "relative standard deviation" or "RSD" refers to the accuracy of each measurement of blend uniformity or content uniformity, i.e., the accuracy of each individual element deviation from the group.

As used herein, "mixing uniformity" refers to the uniformity of the granules comprising metoprolol succinate prior to tablet preparation and may represent the average of one sample or more than one sample.

The tablets of the invention have a content uniformity of between 95% and 115% and a mixing uniformity of between 95% and 105% and a relative standard deviation of the mixing uniformity of less than 2%.

The present invention provides an oral extended release tablet of metoprolol succinate comprising preparing drug loaded release pellets using a fluid bed processor and applying a buffer layer using a high shear mixing granulator followed by compressing the pellets into a tablet.

As used herein, the term "inert core" refers to a pharmaceutically acceptable core that is inert and commercially available and may be water insoluble, such as silicon dioxide, water swellable, such as microcrystalline cellulose spheres, or water soluble, such as lactose beads. The inert core may be modified by, for example, applying a primer coating over the core.

Suitable water-insoluble polymers for preparing the extended release coated pellets according to the invention are selected from the group consisting of ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl acetate succinate, cellulose acetate, poly (methacrylic acid, ethyl acrylate) 1: 1, poly (ethyl acrylate, methyl methacrylate) 2: 1, poly (ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate) 1: 2: 0.2, poly (ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate) 1: 2: 0.1, methyl methacrylate) 1: 1, poly (methacrylic acid, methyl methacrylate) 1: 2, etc. or mixtures thereof. The water-insoluble polymer is present in an amount of about 5 to 15% w/w of the tablet.

The extended release polymer layer comprises a binder selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, povidone, and the like, or mixtures thereof. The extended release polymer layer may further comprise plasticizers such as acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, dibutyl sebacate, propylene glycol, polyethylene glycol, and the like.

The drug layer and the extended release coating may be applied to the inert core by spraying in a conventional coating pan, or a fluid bed processor, or dip coating. The inert core is coated by spraying a drug solution or suspension prepared by dissolving or dispersing metoprolol succinate and a binder (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, povidone, etc.) or a mixture thereof in a solvent (e.g., dichloromethane, isopropanol, acetone, methanol, ethanol, water, etc. or a mixture thereof).

By dissolving or dispersing at least one water-insoluble polymer and a binder in a solvent such as methylene, isopropyl chloride, acetone, methanol, ethanol, water, or the like, or mixtures thereof.

The present invention comprises converting a polymer sustained release coated pellet of metoprolol succinate into a homogeneous granule under shear conditions that do not degrade the pellet. For the purposes of the present invention, the application of shear conditions under the buffer layer to polymer coated sustained release particles is generally described as a set of conditions, including a combination of temperature and mechanical force, that allows the formation of buffer layers and homogeneous particles without collapsing during compression. The buffer layer was processed using a Rapid Mixer Granulator (RMG). The RMG machine also has various key terms in the industry, such as high shear granulator, dry powder granulator, wet granulator, PharmaSaizoner granulator, high shear mixer granulator, fast mixer granulator.

In one aspect, the buffer layer applied on the delayed release pellets or the delayed release polymer coated pellets comprises a water soluble polymer selected from the group consisting of polyethylene glycol, e.g. polyethylene glycol (Macrogol), such as polyethylene glycol 3350, polyethylene glycol 4000 or polyethylene glycol 6000; binders such as hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, and the like or mixtures thereof. The water soluble polymer and binder are present in an amount of about 5 to 15% w/w of the tablet.

In another aspect, the sustained release pellets or sustained release polymer coated pellets are mixed with one or more excipients, such as diluents, disintegrants selected from microcrystalline cellulose (MCC), lactose, crospovidone, sodium starch glycolate, croscarmellose sodium or mixtures thereof and the like, prior to administration of the buffer layer. The amount of excipients to be mixed with the extended release coated pellets may be 20 to 30% w/w of the tablet.

In another aspect, the present invention provides for determining the blending uniformity of particles. The compression of the particles covered with the buffer layer is only carried out when the blending homogeneity of the particles meets a predetermined criterion.

The present invention provides an oral sustained release solid dosage form of metoprolol succinate comprising:

a) at least about 10 to 20% (w/w) of an inert core comprising a solid dosage form;

d) 20% to 35% w/w by mass of the tablet of a buffer layer comprising polyethylene glycol and a binder, in a high shear mixing granulator and coating the buffer layer with extended release granules,

e) mixing with at least one other tablet excipient.

In one aspect of the invention, an inert core is coated with a solution or suspension comprising metoprolol succinate, Opadry (Opadry) and a suitable solvent in a fluidized bed processor with optimal parameters. The drug layer was coated with the sustained release coating in a fluid bed processor at optimized parameters. And the breaker layer was applied using a rapid mix granulator.

In another embodiment, the present invention provides an oral extended release solid dosage form of metoprolol succinate prepared by a process comprising the steps of:

a) applying a drug layer comprising metoprolol succinate in a solid dosage form of at least about 10% to 20% (w/w) on an inert core, obtaining drug-loaded pellets in a fluidized bed process,

b) applying a sustained release polymer layer comprising at least one water insoluble polymer using a fluid bed processor to form sustained release granules on the drug-loaded pellets,

c) applying a buffer layer on the sustained-release granules by using a high-shear mixing granulator,

d) mixing the granulate obtained in step (c) with at least one further tablet excipient and,

e) adding a lubricant, mixing with the blend obtained in step (d), and compressing to obtain the sustained release solid dosage form.

Suitable tablet excipients include diluents, disintegrants, binders, glidants, lubricants and the like, suitable diluents are selected from lactose, microcrystalline cellulose, mannitol, starch, modified starch, (spray-dried compounds consisting of 85% α -lactose monohydrate and 15% corn starch dry matter available from Meggle corporation) or mixtures thereof, disintegrants are selected from microcrystalline cellulose, crospovidone, sodium starch glycolate and the like, lubricants are selected from magnesium stearate, stearic acid, sodium stearyl fumarate, docosanoate, talc, zinc stearate, silicon dioxide and the like.

In a preferred aspect, the present invention provides an oral sustained release tablet of metoprolol succinate comprising:

a) an inert core of microcrystalline cellulose spheres comprising at least about 10% to 20% (w/w) of the mass of the oral sustained release tablet;

b) a drug layer comprising metoprolol succinate and a binder selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose or povidone coated on the inert core to obtain drug-loaded pellets;

c) coating the drug-loaded pellets with a sustained release polymer layer comprising at least one water-insoluble polymer and a binder in an amount of about 5 to 15% w/w of the tablet to form sustained release granules;

d) coating the sustained release granules with a buffer layer comprising polyethylene glycol and a binder in an amount of 20% to 35% w/w of the mass of the tablet using a high shear mixing granulator,

e) mixing with at least one other tablet excipient.

In yet another preferred aspect, the present invention provides an oral extended release tablet of metoprolol succinate comprising:

a) an inert core of microcrystalline cellulose spheres comprising at least about 10% to 20% (w/w) of the tablet by mass;

b) applying a drug layer comprising metoprolol succinate and hydroxypropyl methylcellulose on the inert core to obtain drug-loaded pellets;

c) coating the drug-loaded pellets with a sustained release polymer layer comprising ethylcellulose and hypromellose in an amount of 5% to 15% w/w of the tablet mass to form sustained release pellets;

d) forming a buffer layer comprising polyethylene glycol, hypromellose, microcrystalline cellulose and crospovidone in an amount of 20-35% w/w of the tablet using a high shear mixer granulator, coating the sustained release pellets,

e) mixing with at least one other tablet excipient comprising microcrystalline cellulose, crospovidone, colloidal silicon dioxide and sodium stearyl fumarate.

In one embodiment, the extended release tablet optimally has a dissolution profile such that about 20% to about 50% of the drug is dissolved after 8 hours when a sample corresponding to the desired dose is tested using USP apparatus type 1. The method comprises the following steps: stirring (50rpm medium: 500ml 0.05M, phosphate buffer USP pH-6.8 and temperature at 37 ℃).

The present invention also provides an oral sustained release solid dosage form of metoprolol succinate prepared by a process comprising the use of a combination of fluidized bed process/granulation and high shear mixing granulator.

In the pharmaceutical composition of the present invention, the inert core of each pellet comprises from about 50% to about 100% (by weight) of a water-swellable or water-insoluble material. Preferred inert cores of the invention comprise sugar spheres, microcrystalline cellulose spheres or silica beads. The sugar spheres used in pharmaceutical compositions typically contain no more than 92% sucrose, calculated in the dry state, with the remainder consisting of corn starch. Inert cores having a size of about 50 μm to about 500 μm, preferably about 100 to about 400 μm, and more preferably about 250 μm to about 350 μm are generally used.

In the present invention, the inert core may comprise an initial core/sphere which is initially coated with a layer of plasticized film coating polymer. The primer layer provides physical strength to the inert core. The film coating polymer may be a hydrophobic or hydrophilic polymer, or a combination thereof may be a cellulose polymer or a polymethacrylate polymer, and includes a plasticizer, such as acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, polyethylene glycol, dibutyl sebacate, and dibutyl phthalate, to plasticize the film coating polymer. The base coat is mixed with a solvent selected from the group consisting of ethanol, isopropanol, acetone and purified water prior to application to the inert core.

The buffer layer according to the invention is applied on the extended release layer using a high shear fast mix granulator (RMG) without affecting the strength of the granules. This is simple, reliable and easy to copy. The extended release coated pellets are mixed with diluents and disintegrants (e.g., microcrystalline cellulose and crospovidone) to create a buffer action between the extended release coating and the buffer layer.

The present invention provides an oral sustained release solid dosage form of metoprolol succinate prepared by a process comprising the use of a fluidized bed process/granulation and a high shear mixing granulator.

The sustained-release tablet can be coated with a commercially available tablet film coating agent such as Opadry

And performing appearance coating.

The beneficial effects of the invention compared with the prior art comprise:

(1) the particles obtained according to the invention are stable and robust, the process is simple and cost-effective;

(2) according to the present invention there is provided a tablet which is bioequivalent to commercially available tablets.

Detailed Description

Reference is made to the following examples which are provided to illustrate the invention, but are for illustrative purposes only, and should not be construed as limiting the scope of the invention.

Example 1 metoprolol succinate sustained Release tablets

Manufacturing process

The drug loading process is as follows:

1. hypromellose was added with stirring.

2. Metoprolol succinate was added to the above solution with stirring.

3. The core microcrystalline cellulose drug granules were loaded into a fluidized bed unit (FBE) and coated with the metoprolol succinate solution prepared above, and the coated granules were then dried.

Polymer coatings

1. Hydroxypropyl cellulose was dissolved in isopropanol with stirring until the lumps dissolved.

2. Dichloromethane and ethyl cellulose were added to the above solution, followed by purified water.

3. The drug loaded pellets are loaded into a fluidized bed apparatus (FBE) and coated with a polymer coating solution and the polymer coating solution is sprayed onto the drug loaded pellets.

Buffer layer coating

1. PEG-6000 and hypromellose were dissolved in purified water with stirring.

2. The polymer coated particles are added to microcrystalline cellulose and crospovidone.

3. The polymer-coated granules were loaded into a Rapid Mix Granulator (RMG) and the granules were granulated using a PEG coating solution.

4. After granulation, the granules were wet milled, dried and sieved using ASTM # 12.

Mixing and lubricating

1. Sieving colloidal silicon dioxide and microcrystalline cellulose

2. The granulated PEG granules are mixed with additional granular colloidal silicon dioxide, crospovidone and microcrystalline cellulose in an octagonal mixture,

3. the milled granules were lubricated with sodium stearyl fumarate.

Tabletting and coating process

1. Compressing the lubricated granules into tablets, and then

2. The compressed tablets were film coated with Opadry (Opadry White).

Example 2 metoprolol succinate extended Release tablet 25 mg

Tablets contained 23.75 mg of metoprolol succinate, equivalent to 25 mg of metoprolol tartrate USP. This tablet was prepared using a method similar to that described in example one.

Example 3 metoprolol succinate extended Release tablet 50 mg

Tablets contained 47.5 mg of metoprolol succinate, corresponding to 50 mg of metoprolol tartrate USP. This tablet was prepared using a method similar to that described in example one.

Example 4 metoprolol succinate extended Release tablet 100 mg

Tablets contained 95 mg of metoprolol succinate, corresponding to 100 mg of metoprolol tartrate USP. This tablet was prepared using a method similar to that described in example one.

Example 5 metoprolol succinate extended Release tablets 200mg

Tablets contained 190mg of metoprolol succinate, corresponding to 200mg of metoprolol tartrate USP. This tablet was prepared using a method similar to that described in example one.

Example 6 dissolution determination

Dissolution profiles of metoprolol succinate sustained release tablets prepared above were compared to a reference formulation using USP II apparatus, 500m L pH 6.8 medium and 50 revolutions (rpm)

A comparison is made.

Dissolution curve comparison of 25 mg strength of test formulation to reference formulation

Dissolution curve comparison of 50 mg strength of test formulation to reference formulation

Dissolution curve comparison of 100 mg strength of test formulation to reference formulation

Dissolution Curve comparison of 200mg Strength of test formulation with reference formulation

Example 7 stability assay

Tablets prepared according to the invention were found to be stable when stored at 40 ℃/75% RH and 25 ℃/60% RH. The table below shows the stability data for the tablets of the invention.

Example 8, mixing uniformity and content uniformity

By taking 10 samples that can represent the upper, middle and lower layers (before tableting) of each batch of the final mixture, an HP L C assay was performed to measure the amount of active ingredient in the samples and compare the active ingredient content in each sample to the labeled active ingredient content.

The content uniformity of the tablets was determined by performing an HP L C assay to measure the amount of active ingredient in each tablet and comparing the amount of active ingredient in each tablet with the amount of labeled active ingredient, using 10 random tablets the content uniformity of the tested batches ranged from 99.5% to 106.9% the RSD (relative standard deviation, expressed as a percentage of the mean) was less than 2.0% for all batches of tablets, indicating that the uniformity of the tablets was high despite the low amount of active ingredient in each tablet.

Example 9 consistency of dosage units

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims

1. An oral sustained release tablet of metoprolol succinate, characterized in that it comprises:

d) coating a buffer layer on the extended release particles;

e) mixing with at least one other tablet excipient.

2. The extended release tablet of claim 1, wherein the inert core is selected from the group consisting of water-insoluble substances, such as silicon dioxide; and swellable aqueous materials such as microcrystalline cellulose or lactose.

3. The sustained-release tablet according to claim 1, wherein the water-insoluble polymer is selected from the group consisting of ethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, hydroxypropylmethyl acetate succinate, cellulose acetate, poly (methacrylic acid, ethyl acrylate) 1: 1, poly (ethyl acrylate, methyl methacrylate) 2: 1, poly (ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate) 1: 2: 0.2, poly (ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate) 1: 2: 0.1, methyl methacrylate) 1: 1, poly (methacrylic acid, methyl methacrylate) 1: 2, etc. or mixtures thereof.

4. The extended release tablet of claim 1, wherein said water insoluble polymer is present in an amount ranging from about 5 to 15% w/w of said tablet.

5. The sustained release tablet of claim 1, wherein the binder is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, povidone, or mixtures thereof.

6. The sustained-release tablet of claim 1, wherein the drug layer and the extended-release polymer layer are applied to the inert core by spray coating in a conventional coating pan, or a fluid bed processor, or dip coating.

7. The sustained-release tablet of claim 1, wherein said buffer layer is coated using a high shear mixer granulator.

8. The extended release tablet of claim 1, wherein the buffer layer comprises a water soluble polymer selected from polyethylene glycol, for example as commercially available polyethylene glycol (Macrogol), such as polyethylene glycol 3350, polyethylene glycol 4000 or polyethylene glycol 6000; and one or more binders, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, or mixtures thereof.

9. The sustained-release tablet according to claim 1, wherein after coating the buffer layer, the extended-release granules are mixed with one or more excipients such as diluents, disintegrants selected from microcrystalline cellulose, lactose, crospovidone, sodium starch glycolate, croscarmellose sodium or mixtures thereof.

10. The sustained-release tablet according to claim 1, wherein the tablet excipient is selected from a diluent, a disintegrant, and a lubricant, wherein the diluent is selected from lactose, microcrystalline cellulose, mannitol, starch, and modified starch，

Or a mixture thereof, the disintegrant is selected from microcrystalline cellulose, crospovidone, sodium starch glycolate; the lubricant is selected from magnesium stearate, stearic acid, sodium stearyl fumarate, docosanol ester, pulvis Talci, zinc stearate, and silicon dioxide.

11. The sustained-release tablet of claim 1, wherein the content uniformity of the tablet is between 95% and 115%, and the mixing uniformity is between 95% and 105%, and the relative standard deviation of the mixing uniformity is less than 2%.

12. The sustained-release tablet according to claim 1, characterized by comprising:

d) coating a buffer layer of 20% to 35% (w/w) of the tablet mass to the extended release granules using a high shear mixing granulator;

e) mixing with at least one other tablet excipient.

13. The sustained-release tablet according to claim 1, characterized by comprising:

c) coating the pellets with an extended release polymer layer comprising at least one water insoluble polymer of about 5 to 15% w/w of the tablet and a binder to form a sustained release granule;

d) 20% to 35% w/w of the tablet dosage, a buffer layer comprising polyethylene glycol and hypromellose, coated on the slow release granules using a high shear mixing granulator;

e) mixing with at least one other tablet excipient.

14. The sustained-release tablet according to claim 1, which is prepared by a method comprising the steps of:

a) coating a drug layer comprising metoprolol succinate on an inert core using a fluidized bed process, the drug layer having a mass of at least about 10% to 20% (w/w) of the tablet to obtain drug loaded pellets;

b) applying a sustained-release polymer layer comprising at least one water-insoluble polymer and a binder on pellets of the drug using a fluidized bed processor to form sustained-release granules;

c) coating a buffer layer containing polyethylene glycol and hypromellose on the sustained release granules using a high shear mixing granulator;

e) compressing the blend obtained in step (d) to obtain a sustained release tablet.

15. The sustained-release tablet according to claim 1, characterized by comprising:

c) a sustained release polymer layer comprising 5% to 15% w/w ethylcellulose and hypromellose to form sustained release granules;

d) a buffer layer comprising polyethylene glycol, microcrystalline cellulose, crospovidone and hypromellose, in an amount of 20% to 35% w/w of the mass of the tablet, the buffer layer being coated on the sustained release granules, and,

16. The sustained-release tablet according to claim 1, which is prepared by using a combination of a fluidized bed method/granulation and a high shear mixing granulator.