WO2016050160A1

WO2016050160A1 - Paliperidone oral controlled-release tablet and preparation method thereof

Info

Publication number: WO2016050160A1
Application number: PCT/CN2015/090365
Authority: WO
Inventors: 杜江永; 李巧霞; 施祥杰; 胡李斌; 陈浩; 王红莲; 胡功允
Original assignee: 浙江华海药业股份有限公司
Priority date: 2014-10-01
Filing date: 2015-09-23
Publication date: 2016-04-07
Also published as: CN104257622A; CN104257622B

Abstract

Provided is a paliperidone oral controlled-release tablet, comprising: a single-layer tablet core containing paliperidone, a first coating layer and a second coating layer coating the single-layer tablet core to control release of medication and formed by one or more coating polymers, and a third outer protective coating layer formed by optional one or more coating polymers. Also provided is a preparation method of the paliperidone oral controlled-release tablet. The present invention controls the release of the paliperidone via a method combining two controlled-release mechanisms, namely, a gel framework mechanism and a membrane-controlled coating mechanism, has a simple manufacturing process, and does not utilize an organic solvent in a manufacturing process, thus being environmentally friendly, and facilitating industrial production.

Description

Paclitaxel oral controlled release tablet and preparation method thereof

The present application claims priority from Chinese Patent Application No. 201410543391.1, entitled "A paliperidone controlled release tablet and its preparation method", on October 1, 2014, the entire contents of which are hereby incorporated by reference. Incorporated into this application.

Technical field

The invention relates to a drug controlled release preparation and a preparation method thereof, in particular to a paliperidone oral controlled release tablet and a preparation method thereof.

Background technique

Paclipentone (9-hydroxyrisperidone) is a novel atypical antipsychotic that belongs to the class of benzoisoxazoles and is currently believed to act by blocking dopamine, serotonin and adrenergic receptors. It interferes with the signaling of neurotransmitters in the brain of patients. The oral bioavailability of paliperidone is 28%, the plasma protein binding rate is 74%, the terminal elimination and half-life are about 23 hours, and it is clinically effective for schizophrenia. The structural formula of paliperidone is as follows:

The main problems in the clinical application of drugs for the treatment of nervous system diseases are: large adverse reactions, especially in the early stage of taking the drug, the patient's tolerance is poor, easy to stop in the middle; the initial dose of the common preparation requires dose titration (ie slowly increase the dose) ) to reduce the occurrence of adverse reactions, but inconvenient to take. In order to solve the above clinical application problems, a variety of controlled release technologies have been applied to the nervous system, and controlled release preparations such as those prepared by osmotic pump controlled release technology have been developed, which have the pH of the medium, gastrointestinal motility, food, etc. The influence of factors is small, the individual differences are small, the correlation between the body and the outside is good, the blood medicine is stable, the adverse reactions are small, the number of patients taking the medicine is small, and the compliance is high.

Paliperidone was developed by Johnson & Johnson, Inc., and was made into an osmotic pump controlled release formulation using Alza's osmotic pump technology. Chinese Patent Application No. 03822948.X (invented by the method and dosage form for controlled release of paliperidone) discloses a controlled release formulation of paliperidone. The preparation adopts a three-layer osmotic pump tablet dosage form, and the preparation process is very complicated. The three-layer osmotic pump sheet comprises a propelling layer and two drug-containing layers having different drug ratios. The preparation process of the preparation is as follows: 1) First, the two drug-containing layer particles and the propellant layer particles are respectively granulated by a wet granulation process to obtain two drug-containing layer particles and a propellant layer particle respectively; 2) using a three-layer laminate The tablet machine compresses the two drug-containing layer particles and the propellant layer particles to obtain a pellipidone tri-layer tablet; 3) isolates the paliperidone tri-layer tablet; 4) the pellipidone three-layer tablet The release coating of the sheet is coated with a cellulose acetate and polyethylene glycol for controlled release coating of the osmotic pump sheet, and the cellulose acetate is dissolved in acetone for coating during the coating, and the concentration of the coating liquid is 10 Within 5%; 5) laser perforation of the osmotic pump sheet to provide an outlet for drug release, requiring two laser holes on one side of the peliperone three-layer osmotic pump controlled release sheet; 6) for laser perforated The risperidone osmotic pump sheet is coated with an outer protective layer. The technology has the following disadvantages: 1) the technology requires a special tableting machine, a three-layer tableting machine; 2) a controlled release coating of paliperidone with an organic solvent acetone, which requires not only a large amount of acetone but also At present, the coating equipment lacks the acetone recovery device, so only acetone can be directly discharged into the atmosphere, thereby causing pollution; 3) laser puncturing of the paliperidone tablets is required, and one side needs to be hit two Holes.

Because the three laminates have very high precision requirements on equipment, there are literature improvements in the process of paliperidone controlled release tablets. For example, Chinese Patent Application No. 200910199425.9 (the invention whose name is a controlled release preparation of a benzoisoxazole derivative and a preparation method thereof) discloses a paliperidone double-layer osmotic pump sheet and a preparation method thereof. However, the process still requires a special tableting device, a double laminator, and an organic solvent, acetone, for controlled release coating.

In the preparation process of the currently disclosed paliperidone controlled release tablets, a double laminating machine or a three laminating machine is required to precisely control the tableting process to avoid the problem of excessive content uniformity, so the production cost High, the risk of producing defective films is high. In addition, it is also necessary to dissolve the semipermeable membrane material cellulose acetate in acetone, and it is necessary to use a large amount of organic solvent. At present, the general coating equipment does not have an organic solvent recovery system, so the acetone is directly discharged into the atmosphere, which is not environmentally friendly and pollutes the environment. Even with an organic solvent recovery system, the operating costs are high. In addition, it is necessary to perform laser drilling on the paliperidone osmotic pump sheet, but the domestic laser drilling equipment is not mature, and it is easy to cause leaking and punching depth and insufficient penetration depth. The problem is that the product is easy to have quality problems.

Therefore, it is still necessary to provide a new solution to overcome the above disadvantages, so that the alipenemone oral controlled release tablets have a one-sided appearance and good quality. At the same time, paliperidone has good stability and dissolution behavior, and is inexpensive, which is beneficial to commercial production.

Summary of the invention

In one aspect, the present invention provides a paliperidone oral controlled release tablet comprising: a) a single layer core comprising paliperidone or a pharmaceutically acceptable salt or ester thereof; a first coating layer coated on a single layer core, wherein the first coating layer comprises 0 to 61% by weight of polyvinyl acetate, 22 parts by weight based on the total weight of the first coating layer % to 54% by weight of polyethylene glycol-polyvinyl alcohol copolymer, 12% to 40% by weight of talc and 2% to 7% by weight of triethyl citrate, with respect to single-layer core The weight of the first coating layer is 5% by weight to 20% by weight; c) the second coating layer is coated on the first coating layer, wherein the total weight of the second coating layer is The second coating layer comprises 60.6 wt% to 69 wt% of polyvinyl acetate, 10 wt% to 18.2 wt% of polyethylene glycol-polyvinyl alcohol copolymer, and 12.9% by weight to 20 wt% of talc powder. And 3% by weight to 7% by weight of triethyl citrate, wherein the weight of the second coating layer is 5% by weight to 20% by weight relative to the weight of the single-layer core ; D) optionally a third outer protective coating layer coated on the second coating layer, wherein the third outer protective coating layer is a gastric-coating.

The present inventors have found that alipenemone oral controlled release tablets prepared by using polyoxyethylene as a gel skeleton and polyvinyl acetate as a membrane-control material have an increasing drug release behavior and are substantially consistent in release media of different pH values. The release behavior, that is, the release behavior independent of pH. A paliperidone oral controlled release tablet having such an incremental release behavior is a single layer sheet, which does not require an expensive multi-laminate device; an aqueous dispersion coating does not require the use of an organic solvent; by adjusting the porogen ratio Adjust the release behavior without laser drilling. Therefore, compared with the prior art, the novel peliperone oral controlled release tablet production process is simpler, more environmentally friendly, and easier to industrialize.

In one embodiment, the monolayer core of the paliperidone oral controlled release tablet of the present invention consists of paliperidone, a gel matrix polymeric material, and a lubricant.

In another embodiment, the peliperone oral controlled release tablet of the present invention is in a single layer core The amount of risperidone is from 1 mg to 12 mg.

In yet another embodiment, the monolayer core of the paliperidone oral controlled release tablet of the present invention consists of paliperidone, polyoxyethylene and magnesium stearate or sodium stearyl fumarate.

In another embodiment, the pellipidone oral controlled release tablet of the present invention has a single layer core of from 0.75% by weight to 6.7% by weight of paliperidone, 92% by weight relative to the total weight of the single layer core. 99% by weight of polyoxyethylene and 0.2% by weight to 2% by weight of magnesium stearate or sodium stearyl fumarate.

In one embodiment, the monolayer core of the paliperidone oral controlled release tablet of the present invention has a polyoxyethylene having a molecular weight of 100,000 to 1,000,000 and may be one, two or more polyoxygens of different molecular weights. a mixture of ethylene. A single molecular weight polyoxyethylene is preferred. The polyoxyethylene used in accordance with the present invention may contain from 0 to 3% by weight of silica, based on the total weight of the polyoxyethylene, preferably the product of the company Dow. Because it contains silica, the polyoxyethylene particles have good fluidity, so that the core of the invention can be produced by a direct compression process, thereby avoiding the use of a wet process which has higher energy consumption and has an influence on polyoxyethylene. The pellet process produces a core.

In another aspect, the present invention provides a method for preparing a single layer core of a paliperidone oral controlled release tablet, comprising the steps of:

a) mixing paliperidone and polyoxyethylene, sieving and mixing;

b) adding magnesium stearate or sodium stearyl fumarate to a homogeneous mixture of paliperidone and polyoxyethylene obtained in step a) and continuing to mix;

c) The mixture of the homogeneous paliperidone, polyoxyethylene, magnesium stearate or sodium stearyl fumarate obtained in step b) is tableted to obtain a paliperidone single-layer tablet core.

In still another aspect, the present invention also provides a method for preparing a paliperidone oral controlled release tablet, the preparation method comprising the steps of:

a) mixing paliperidone, polyoxyethylene, magnesium stearate or sodium stearyl fumarate, sieving, mixing, and then directly compressing to prepare a single layer core;

b) coating the single-layer core with a first coating layer, wherein the first coating layer comprises 0 to 61% by weight of polyvinyl acetate, 22% by weight, based on the total weight of the first coating layer ～54% by weight of polyethylene glycol- a polyvinyl alcohol copolymer, 12% to 40% by weight of talc and 2% to 7% by weight of triethyl citrate, wherein the weight of the first coating layer relative to the weight of the single layer core is 5 wt% to 20 wt%;

c) coating the coated tablet obtained in step b) with a second coating layer, wherein the second coating layer comprises from 0.66% by weight to 69% by weight of polyvinyl acetate based on the total weight of the second coating layer Ester, 10% by weight to 18.2% by weight of polyethylene glycol-polyvinyl alcohol copolymer, 12.9% by weight to 20% by weight of talc and 3% by weight to 7% by weight of triethyl citrate, wherein The weight of the ply core: the weight of the second coating layer is 5% by weight to 20% by weight;

d) optionally coating the coated tablet obtained in step c) with a third outer protective coating layer, thereby preparing a paliperidone oral controlled release tablet, wherein the third outer protective coating layer is gastric-soluble Type coating.

In one embodiment of the preparation method of the paliperidone oral controlled release tablet according to the present invention, the peliperone oral controlled release tablet of the present invention can be preferably prepared using a porous pan type coating machine. As an alternative, fluidized bed coaters and spray coaters can also be used.

In another embodiment of the method for preparing a paliperidone oral controlled release tablet according to the present invention, the first coating layer, the second coating layer, and the third outer protective coating layer each use water of the coating polymer. Coating in the form of a dispersion. In particular, the second coating layer which functions as a sustained release, polyvinyl acetate is a film-forming material, and is coated with an aqueous dispersion of the brand name Kollicoat SR30D of BASF, and the sustained release effect can also be obtained without using an organic solvent. The amount of polyvinyl acetate contained was calculated as 30% w/w of the amount of kollicoat SR30D; the polyethylene glycol-polyvinyl alcohol copolymer used the product of the trade name Kollicoat IR of BASF.

DRAWINGS

In order to more clearly illustrate the embodiments of the present invention and the prior art, the following description of the embodiments and the drawings used in the prior art will be briefly described. It is obvious that the drawings in the following description are only Some embodiments of the invention may also be used to obtain other figures from these figures without departing from the art.

Figure 1 shows the release profile of a paliperidone double-layer osmotic pump controlled release tablet prepared according to the prior art (CN200910199425.9) in a release medium of pH 1.2;

Figure 2 shows the release profile of a paliperidone double-layer osmotic pump controlled release tablet prepared according to the prior art (CN200910199425.9) in four different release media at pH 1.2, pH 4.5, pH 6.8 and water;

Figure 3 is a graph showing the release profile of an oral controlled release tablet of paliperidone prepared according to Examples 1-5 of the present invention in a release medium of pH 1.0;

Figure 4 is a graph showing the release profile of alipenemone oral controlled release tablets prepared according to Example 6 of the present invention in a release medium of pH 1.0, pH 4.5 and pH 6.8, respectively;

Figure 5 is a graph showing the release profile of alipenemone orally controlled release tablets prepared according to Example 7 of the present invention in a release medium of pH 1.0, pH 4.5, and pH 6.8, respectively;

Figure 6 is a graph showing the release profile of an oral controlled release tablet of paliperidone prepared according to Examples 8-9 of the present invention in a release medium of pH 1.0.

detailed description

The present invention will be further described in detail below with reference to the accompanying drawings. It is apparent that the described embodiments are only a part of the embodiments of the invention, and not all of the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative efforts are within the scope of the present invention.

In the following examples, polyvinyl acetate was used as an aqueous dispersion of the company KSF's trade name Kollicoat SR30D. Polyethylene glycol-polyvinyl alcohol copolymers are available from the BASF company under the trade name Kollicoat IR. Paliperidone uses products produced by Zhejiang Huahai Pharmaceutical. Polyoxyethylene N80 is commercially available from DOW under the trade name POLYOX WSR N80. Magnesium stearate was purchased from Merck's products. Talc was purchased from IMI Fabi, LLC. Triethyl citrate was purchased from Vertellus Performance Materials Inc.

II coating powder was purchased from Shanghai Kalakang Company. The efficient coating machine was purchased from Manesty, UK.

Example 1:

Remarks: *Kollicoat SR30D is a 30% aqueous dispersion of Kollicoat SR, so when calculating the weight gain of the coating layer, multiplying the amount of Kollicoat SR30D by 30% is the weight gain of Kollicoat SR in the coating layer. with.

The preparation method of Example 1 is:

a) Mix paliperidone and polyoxyethylene N80, sieve and mix.

b) Magnesium stearate is added to a homogeneous mixture of paliperidone and polyoxyethylene N80 obtained in step a) and mixing is continued.

c) a mixture of homogeneous paliperidone, polyoxyethylene N80, magnesium stearate obtained in step b) Tableting, thereby obtaining a peliperone monolayer core.

d) Kollicoat IR, triethyl citrate and talc powder were weighed according to the amount of the first coating layer, and uniformly dispersed in an appropriate amount of purified water, and then the dispersion was added to Kollicoat SR30D, and uniformly stirred to form a coating liquid.

e) placing the paliperidone single-layer tablet core obtained in the step c) in a high-efficiency coating pan, coating with the coating liquid of the step d), obtaining the weight of the target coating and drying, and obtaining the first coating. Layer coated paliperidone coated tablets.

f) Kollicoat IR, triethyl citrate and talc powder were weighed according to the prescribed amount of the second coating layer, and uniformly dispersed in an appropriate amount of purified water, and then the dispersion was added to Kollicoat SR30D, and uniformly stirred to form a coating liquid.

g) The paliperidone coated tablet obtained in step e) is placed in a high-efficiency coating pan, coated with the coating liquid of step f), and the target coating is dried and dried to obtain a first coating layer. And a second coating layer coated paliperidone coated tablet.

h) Weighed according to the prescription of the third outer protective coating layer

II coated powder, and evenly dispersed in an appropriate amount of purified water, stirred to form a coating liquid. The paliperidone coated tablet obtained in the step g) is placed in a high-efficiency coating pan, and the protective coat is wrapped to achieve the weight gain of the target coating and dried, thereby obtaining an oral controlled release tablet of paliperidone.

The release profile of this example is shown in Figure 3. Using the FDA recommended method, using the paddle method, 50 rpm, the release medium is pH 1.0 [NaCl (0.2% w/w) in 0.0825 N HCl], and the volume of the release medium is 500 ml. The release was measured by sampling at 2, 4, 6, 8, 12, 14, 18 and 24 hours.

Example 2:

Preparation process: (same as in Example 1).

Example 3:

Preparation process: (same as in Example 1).

Example 4:

Preparation process: (same as in Example 1).

Example 5:

Preparation process: (same as in Example 1).

Example 6

The preparation process is as follows:

a) Mix paliperidone and polyoxyethylene N80, sieve and mix.

c) The mixture of the homogeneous paliperidone, polyoxyethylene N80, and magnesium stearate obtained in the step b) is tableted to obtain a paliperidone single-layer tablet core.

d) Kollicoat IR, triethyl citrate and talc are weighed according to the amount of the first coating layer, and uniformly dispersed in an appropriate amount of purified water to form a coating liquid.

g) The paliperidone coated tablet obtained in step e) is placed in a high-efficiency coating pan, coated with the coating liquid of step f), and the target coating is dried and dried to obtain a first coating layer. And the second coating layer Palipenone coated tablets.

The release profile for this example is shown in Figure 4. Using the FDA-recommended method, using the paddle method, 50 rpm, the release medium is pH 1.0, pH 4.5, and pH 6.8, and the release medium volume is 500 ml at 1, 2, 4, 6, and 8. The release was measured at 12, 14, 18 and 24 hours.

Example 7

The preparation process was the same as in Example 1.

The release profile of this example is shown in Figure 5. Using the method recommended by the FDA, using the paddle method, 50 rpm, the release medium is pH 1.0, pH 4.5, and pH 6.8 medium, and the volume of the release medium is 500 ml, at 1, 2, 4, 6, The release was measured at 8, 12, 14, 18 and 24 hours.

Example 8

The preparation process was the same as in Example 1.

Example 9

The preparation process was the same as in Example 1.

The release profiles of Examples 8 and 9 are shown in Figure 6. Using the FDA-recommended method, using a paddle method at 50 rpm, the release medium is pH 1.0 [NaCl (0.2% w/w) in 0.0825 N HCl], and the release medium volume is 500 ml. The release was measured at 1, 2, 4, 6, 8, 12, 14, 18 and 24 hours.

Example 10:

The paliperidone oral controlled release tablet of Example 10 was prepared in the same manner as in Example 1 except that sodium stearyl fumarate was used instead of magnesium stearate. Using the method recommended by the FDA, using the paddle method, 50 rpm, the release medium is pH 1.0 [NaCl (0.2% w/w) in 0.0825 N HCl], the volume of the release medium is 500 ml, at 1, 2, 4, 6, 8, 12 Samples of Example 10 were taken at 14, 18 and 24 hours. The release profile of the risperidone oral controlled release tablet was similar to that of the aliskipone oral controlled release tablet of Example 1.

Figure 1 shows the release profile of a paliperidone double-layer osmotic pump controlled release tablet prepared according to the prior art (CN200910199425.9) in a release medium of pH 1.2; Figure 2 shows according to the prior art (CN200910199425) .9) Release profile of the prepared paliperidone double osmotic pump controlled release tablets in four different release media at pH 1.2, pH 4.5, pH 6.8 and water.

The release profile of the aliskipone oral controlled release tablet prepared according to the embodiment 1-10 of the present invention is compared with the release curve of the paliperidone double-layer osmotic pump controlled release tablet prepared according to the prior art. It can be seen that the release profile of the paliperidone oral controlled release tablet according to the present invention in a release medium of pH 1.0 is similar to the release profile of the paliperidone double-layer osmotic pump controlled release tablet according to the prior art, see FIG. And Figure 6 (present invention) and Figure 1 (prior art); release profile of paliperidone oral controlled release tablets according to the invention in a release medium at pH 1.0, pH 4.5 and pH 6.8 and according to the prior art The release profile of paliperidone double osmotic pump controlled release tablets in release media at pH 1.2, pH 4.5 and pH 6.8 was similar, see Figures 4 and 5 (invention) and Figure 2 (prior art). This indicates that the paliperidone oral controlled release tablet according to the present invention can achieve similar drug release behavior as the prior art paliperidone controlled release tablets, and has substantially uniform release behavior in release media of different pH values. However, the preparation process of the paliperidone oral controlled release tablet according to the present invention does not require a multi-laminate device, does not require the use of an organic solvent, and does not require laser drilling. Therefore, the paliperidone oral controlled release tablet production process according to the present invention is simpler, more environmentally friendly, and easier to industrialize than the prior art.

The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalents, improvements, etc., which are made within the spirit and principles of the present invention, should be included in the present invention. Within the scope of protection.

Claims

A paliperidone oral controlled release tablet, characterized in that the oral controlled release tablet comprises:

a) a single layer core comprising paliperidone or a pharmaceutically acceptable salt or ester thereof;

b) a first coating layer coated on a single layer core, wherein the first coating layer comprises 0 to 61% by weight of polyvinyl acetate based on the total weight of the first coating layer, 22% by weight to 54% by weight of polyethylene glycol-polyvinyl alcohol copolymer, 12% by weight to 40% by weight of talc and 2% by weight to 7% by weight of triethyl citrate, with respect to the single The weight of the ply core is 5% by weight to 20% by weight of the first coating layer;

c) a second coating layer coated on the first coating layer, wherein the second coating layer comprises from 0.66% by weight to 69% by weight based on the total weight of the second coating layer Vinyl acetate, 10% by weight to 18.2% by weight of polyethylene glycol-polyvinyl alcohol copolymer, 12.9% by weight to 20% by weight of talc and 3% by weight to 7% by weight of triethyl citrate, wherein The weight of the second coating layer is 5% by weight to 20% by weight based on the weight of the single-layer core;

d) optionally a third outer protective coating layer coated on the second coating layer, wherein the third outer protective coating layer is a gastric soluble coating.
The paliperidone oral controlled release tablet according to claim 1, wherein the single layer core is composed of paliperidone, a gel skeleton polymer material, and a lubricant.
The paliperidone oral controlled release tablet according to claim 1 or 2, wherein the single layer core is composed of paliperidone, polyoxyethylene, and magnesium stearate or sodium stearyl fumarate.
The paliperidone oral controlled release tablet according to any one of claims 1 to 3, wherein the single layer core is from 0.75 wt% to 6.7% by weight of paritimide relative to the total weight of the monolayer core A ketone, 92% to 99% by weight of polyoxyethylene, and 0.5% to 2% by weight of magnesium stearate or sodium stearyl fumarate.
The paliperidone oral controlled release tablet according to any one of claims 1 to 4, wherein the amount of paliperidone in the monolayer core is from 1 mg to 12 mg.
The paliperidone oral controlled release tablet according to claim 3, which is characterized in that a single layer core The polyoxyethylene used has a molecular weight of 100,000 to 1,000,000.
The paliperidone oral controlled release tablet according to claim 3 or 6, wherein the polyoxyethylene used for the single-layer core contains 0 to 3% by weight of silica based on the total weight of the polyoxyethylene.
The paliperidone oral controlled release tablet according to claim 3, wherein the single layer core is prepared by a method comprising the steps of:

a) mixing paliperidone and polyoxyethylene, sieving and mixing;

b) adding magnesium stearate or sodium stearyl fumarate to a homogeneous mixture of paliperidone and polyoxyethylene obtained in step a) and continuing to mix;

c) The mixture of the homogeneous paliperidone, polyoxyethylene, magnesium stearate or sodium stearyl fumarate obtained in step b) is tableted to obtain a paliperidone single-layer tablet core.
A method for preparing a paliperidone oral controlled release tablet according to any one of claims 1-8, which comprises:

a) directly compressing a substance comprising paliperidone or a pharmaceutically acceptable salt or ester thereof to prepare a single layer core;

b) coating the single-layer core with a first coating layer, wherein the first coating layer comprises 0 to 61% by weight of polyvinyl acetate, 22% by weight, based on the total weight of the first coating layer ～54% by weight of polyethylene glycol-polyvinyl alcohol copolymer, 12% by weight to 40% by weight of talc and 2% by weight to 7% by weight of triethyl citrate, wherein the weight relative to the core of the single layer The weight of the first coating layer is 5% by weight to 20% by weight;

c) coating the coated tablet obtained in step b) with a second coating layer, wherein the second coating layer comprises from 0.66% by weight to 69% by weight of polyvinyl acetate based on the total weight of the second coating layer Ester, 10% by weight to 18.2% by weight of polyethylene glycol-polyvinyl alcohol copolymer, 12.9% by weight to 20% by weight of talc and 3% by weight to 7% by weight of triethyl citrate, wherein The weight of the ply core: the weight of the second coating layer is 5% by weight to 20% by weight;

d) optionally coating the coated tablet obtained in step c) with a third outer protective coating layer, thereby preparing a paliperidone oral controlled release tablet, wherein the third outer protective coating layer is gastric-soluble Type coating.
The method for preparing an oral controlled release tablet of paliperidone according to claim 9, wherein the first coating layer, the second coating layer and the third outer protective coating layer are coated with a polymer. Coating in the form of an aqueous dispersion.
The method for preparing a paliperidone oral controlled release tablet according to claim 9 or 10, wherein the single layer core is composed of paliperidone, a gel skeleton polymer material, and a lubricant.
The method for preparing a paliperidone oral controlled release tablet according to any one of claims 9 to 11, wherein the single layer core is composed of paliperidone, polyoxyethylene, and magnesium or calcium stearate. Sodium fumarate composition.
The method for preparing a paliperidone oral controlled release tablet according to any one of claims 9 to 12, wherein the single layer core is from 0.75 wt% to 6.7% by weight based on the total weight of the monolayer core Paclitaxel, 92% to 99% by weight of polyoxyethylene, and 0.5% to 2% by weight of magnesium stearate or sodium stearyl fumarate.
The method for producing a paliperidone oral controlled release tablet according to any one of claims 9 to 13, characterized in that the amount of paliperidone in the single-layer tablet core is from 1.5 mg to 12 mg.
The method of preparing a paliperidone oral controlled release tablet according to claim 12, wherein the polyoxyethylene used in the single layer core has a molecular weight of from 100,000 to 1,000,000.