WO2015001488A1 - Extended-release tablets of paliperidone and processes of preparation thereof - Google Patents

Abstract

The present invention relates to extended-release tablets of paliperidone. It further relates to processes for the preparation of the extended-release tablets and methods of treating neurological disorders by administering the extended-release tablets of paliperidone.

Description

EXTENDED-RELEASE TABLETS OF PALIPERIDONE AND PROCESSES OF

PREPARATION THEREOF

Field of the Invention

The present invention relates to extended-release tablets of paliperidone. It further relates to processes for the preparation of the extended-release tablets and methods of treating neurological disorders by administering the extended-release tablets of paliperidone.

Background of the Invention

Paliperidone, disclosed in U.S. Patent No. 5,158,952, is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives, and is an active metabolite of risperidone.

Paliperidone is practically insoluble in water. PCT Publication No. WO

2004/010981 discloses the need to have extended-release pharmaceutical compositions of paliperidone instead of immediate-release pharmaceutical compositions.

PCT Publication No. WO 1998/06380 discloses push-pull osmotic dosage forms providing ascending drug-release rates comprising a trilayered core composition, consisting of a first drug layer, a second drug layer, and a push layer.

U.S. Publication No. 2005/0025831 discloses push-pull osmotic dosage forms having one or more drug layers and a push layer wherein the different layers are compressed together to provide a longitudinally compressed capsule shaped tablet.

U.S. Publication No. 2009/0202631 teaches trilayered or capsule shaped osmotic dosage forms of paliperidone comprising a first drug layer, a second drug layer, and a push layer, with the limitation of having an osmagent in the first drug layer and no osmagent in the second drug layer. The addition of osmagent into the first drug layer, but not in the second drug layer, impacts the delivery profile such that a substantially ascending rate of release results for a prolonged period of time.

There still remains a need in the art to develop alternative dosage forms of paliperidone providing a substantially ascending rate of release over a prolonged period of time such that the dosing frequency and side effects are reduced to a minimal extent. The scientists of the present invention have now developed an alternative approach to prepare extended-release tablets of paliperidone providing a substantially ascending rate of release over a prolonged period of time. It has been surprisingly discovered that the desired release profile can be achieved by having osmagent in both of the drug layers or in the seal coating layer present in between the trilayered core and the extended-release coating.

Summary of the Invention

The present invention relates to extended-release tablets of paliperidone which provide the desired ascending rate of release over a prolonged period of time and are bioequivalent to commercially available Invega^® tablets. The present invention includes extended-release tablets of paliperidone comprising a trilayered core comprising two drug layers and a push layer, and an extended-release coating, wherein both of the drug layers comprise osmagents. It further includes extended-release tablets of paliperidone comprising a trilayered core comprising two drug layers and a push layer, a seal coating layer, and an extended-release coating, wherein the seal coating layer comprises an osmagent.

The present invention includes processes for preparing extended-release tablets of paliperidone. It also includes methods of treating and/or preventing neurological disorders by administering the extended-release tablets of paliperidone.

Detailed Description of the Invention

The extended-release tablets of the present invention are designed to be a once-a- day stable dosage form providing the desired in-vitro and in-vivo release profiles. As the drug is relatively insoluble, the first drug layer has a tendency not to mix into the second drug layer. Depending upon the relative viscosity of the first drug layer and second drug layer, different release profiles are obtained. It is imperative to identify the optimum viscosity for each layer. In the present invention, viscosity is modulated by the addition of an osmagent in both drug layers.

A first aspect of the present invention provides an extended-release tablet of paliperidone comprising:

(a) a core comprising: (i) a first drug layer comprising paliperidone, one or more rate-controlling polymers, and one or more osmagents;

(ii) a second drug layer comprising paliperidone, one or more rate- controlling polymers, and one or more osmagents; and

(iii) a push layer comprising one or more fluid-expandable polymers and one or more osmagents;

(b) optionally a seal coating layer comprising one or more film-forming

polymers; and

(c) an extended-release coating comprising one or more semi-permeable

membrane-forming polymers with at least one passageway.

In one embodiment of the present invention, there is provided an extended-release tablet of paliperidone comprising:

(a) a core comprising:

(i) a first drug layer comprising paliperidone, polyethylene oxide having a molecular weight of about 200,000 to about 5,000,000, and one or more osmagents;

(ii) a second drug layer comprising paliperidone, polyethylene oxide having a molecular weight of about 200,000 to about 5,000,000, and one or more osmagents; and

(iii) a push layer comprising polyethylene oxide having a molecular weight of about 5,000,000 to about 10,000,000 and one or more osmagents;

(b) optionally, a seal coating layer comprising one or more film-forming

polymers; and

(c) an extended-release coating comprising one or more semi-permeable

membrane-forming polymers with at least one passageway.

In another embodiment, the present invention provides an extended-release tablet of paliperidone in which the structure of the tablet consists essentially of or consists of:

(a) a core comprising: (i) a first drug layer comprising paliperidone, one or more rate-controlling polymers, and one or more osmagents;

(ii) a second drug layer comprising paliperidone, one or more rate- controlling polymers, and one or more osmagents; and

(iii) a push layer comprising one or more fluid-expandable polymers and one or more osmagents;

(b) optionally a seal coating layer comprising one or more film-forming

polymers; and

(c) an extended-release coating comprising one or more semi-permeable

membrane-forming polymers with at least one passageway.

A second aspect of the present invention provides an extended-release tablet of paliperidone comprising:

(a) a core comprising:

(i) a first drug layer comprising paliperidone and one or more rate- controlling polymers;

(ii) a second drug layer comprising paliperidone and one or more rate- controlling polymers; and

(iii) a push layer comprising one or more fluid-expandable polymers and one or more osmagents;

(b) a seal coating layer comprising one or more film-forming polymers and one or more osmagents; and

(c) an extended-release coating comprising one or more semi-permeable

membrane-forming polymers with at least one passageway.

In one embodiment of the present invention, there is provided an extended-release tablet of paliperidone comprising:

(a) a core comprising:

(i) a first drug layer comprising paliperidone and polyethylene oxide having a molecular weight of about 200,000 to about 5,000,000; (ii) a second drug layer comprising paliperidone and polyethylene oxide having a molecular weight of about 200,000 to about 5,000,000; and

(iii) a push layer comprising polyethylene oxide having a molecular weight of about 5,000,000 to about 10,000,000, and one or more osmagents;

(b) a seal coating layer comprising one or more film-forming polymers and one or more osmagents; and

(c) an extended-release coating comprising one or more semi-permeable

membrane-forming polymers with at least one passageway.

In another embodiment, the present invention provides an extended-release tablet of paliperidone in which the structure of the tablet consists essentially of or consists of:

(a) a core comprising:

(i) a first drug layer comprising paliperidone and one or more rate- controlling polymers;

(ii) a second drug layer comprising paliperidone and one or more rate- controlling polymers; and

(iii) a push layer comprising one or more fluid-expandable polymers and one or more osmagents;

(b) a seal coating layer comprising one or more film-forming polymers and one or more osmagents; and

(c) an extended-release coating comprising one or more semi-permeable

membrane-forming polymers with at least one passageway.

A third aspect of the present invention provides a process for the preparation of an extended-release tablet of paliperidone, wherein the process comprises the steps of:

(a) blending/granulating one portion of paliperidone with one or more rate- controlling polymers, one or more osmagents, and one or more pharmaceutically inert excipients to form the first drug layer;

(b) blending/granulating another portion of paliperidone with one or more rate- controlling polymers, one or more osmagents, and one or more pharmaceutically inert excipients to form the second drug layer; (c) blending/granulating one or more fluid-expandable polymers with one or more osmagents and one or more pharmaceutically inert excipients to form a push layer;

(d) compressing the blends/granules of steps (a), (b), and (c) into a trilayered tablet core using appropriate tooling;

(e) optionally applying a coating composition comprising a solution or

dispersion of one or more film-forming polymers and other coating additives over the trilayered tablet core of step (d) to form a seal coating layer;

(f) applying a coating composition comprising a solution or dispersion of one or more semi-permeable membrane-forming polymers and other coating additives over the tablet of step (d) or the seal coating layer of step (e) to form an extended-release coating; and

(g) creating at least one passageway in the extended-release coating adjacent to the first drug layer.

A fourth aspect of the present invention provides a process for the preparation of an extended-release tablet of paliperidone, wherein the process comprises the steps of:

(a) blending/granulating one portion of paliperidone with one or more rate- controlling polymers and one or more pharmaceutically inert excipients to form the first drug layer;

(b) blending/granulating another portion of paliperidone with one or more rate- controlling polymers and one or more pharmaceutically inert excipients to form the second drug layer;

(c) blending/granulating one or more fluid-expandable polymers with one or more osmagents and one or more pharmaceutically inert excipients to form a push layer;

(d) compressing the blends/granules of steps (a), (b), and (c) into a trilayered tablet core using appropriate tooling;

(e) applying a coating composition comprising a solution or dispersion of one or more film-forming polymers, one or more osmagents, and other coating additives over the trilayered tablet core of step (d) to form a seal coating layer;

(f) applying a coating composition comprising a solution or dispersion of one or more semi-permeable membrane-forming polymers and other coating additives over the seal coating layer of step (e) to form an extended-release coating; and

(g) creating at least one passageway in the extended-release coating adjacent to the first drug layer.

A fifth aspect of the present invention provides a method of treating and/or preventing neurological disorders by administering an extended-release tablet of paliperidone comprising:

(a) a core comprising:

(i) a first drug layer comprising paliperidone, one or more rate-controlling polymers, and one or more osmagents;

(ii) a second drug layer comprising paliperidone, one or more rate- controlling polymers, and one or more osmagents; and

(iii) a push layer comprising one or more fluid-expandable polymers and one or more osmagents;

(b) optionally a seal coating layer comprising one or more film-forming

polymers; and

(c) an extended-release coating comprising one or more semi-permeable

membrane-forming polymers with at least one passageway.

A sixth aspect of the present invention provides a method of treating and/or preventing neurological disorders by administering an extended-release tablet of paliperidone comprising:

(a) a core comprising:

(i) a first drug layer comprising paliperidone and one or more rate- controlling polymers;

(ii) a second drug layer comprising paliperidone and one or more rate- controlling polymers; and (iii) a push layer comprising one or more fluid-expandable polymers and one or more osmagents;

(b) a seal coating layer comprising one or more film-forming polymers and one or more osmagents; and

(c) an extended-release coating comprising one or more semi-permeable

membrane-forming polymers with at least one passageway.

In one embodiment of the present invention, there is provided a method of treating and/or preventing neurological disorders by administering an extended-release tablet of paliperidone, wherein the neurological disorders are selected from schizophrenia and bipolar mania.

In another embodiment of the present invention, there is provided a method of treating and/or preventing neurological disorders by administering an extended-release tablet of paliperidone, wherein the method comprises co-administration of additional drugs acting on the central nervous system.

The term "extended-release", as used herein, refers to a dosage form comprising a drug which is formulated in such a way so as to provide a longer duration of

pharmacological response compared to an immediate-release dosage form comprising the same drug in the same amount. In particular, the term "extended-release", as used herein, refers to the release of paliperidone over a prolonged period of time, for example, over a period of 6 hours, 8 hours, 12 hours, 16 hours, or 24 hours.

The term "core", as used herein, refers to a trilayered compact composition comprising two drug layers and a push layer. The trilayered compact composition of the present invention has a defined shape such as tablet, capsule, and the like. In particular, it is capsule shaped.

The extended-release tablet of paliperidone of the present invention provides the desired in-vitro and in-vivo release profile and is bioequivalent to that of the commercially available Invega^® tablet. Bioequivalence is defined to mean the term used by the drug approval agencies, such as the US Food and Drug Administration: "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study." This is typically understood to mean that the reference drug is within +25% and -20% of the reference drug product for AUC and C_maX, for example as explained in the US FDA's various bioequivalence guidance documents for oral tablets and capsules, which are incorporated herein by reference.

The extended-release tablet of paliperidone of the present invention remains stable for a period of at least three months to the time extent necessary for the sale and use of the tablet.

The term "paliperidone", as used herein, refers to (±)-3-[2-[4-(6-fluoro-l,2- benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrido[l,2-a]pyrimidin-4-one. It further includes salts, polymorphs, enantiomers, hydrates, solvates, metabolites, prodrugs, chelates, and complexes thereof. The present invention comprises paliperidone in an amount of from about 0.1% w/w to about 20% w/w of the total tablet weight. Further, the ratio of the amount of paliperidone in the first drug layer to the amount of paliperidone in the second drug layer ranges from about 0.1 : 1 to about 20: 1, in particular about 1 :3 to about 1 :6.

The term "rate-controlling polymer", as used herein, refers to the agent that helps to control the release of paliperidone from the tablet. Suitable examples of rate- controlling polymers are selected from the group consisting of polyalkylene oxides such as polyethylene oxide, polymethylene oxide, polybutylene oxide, and polyhexylene oxide having average molecular weight of about 100,000 to about 750,000; poly alkali carboxymethylcelluloses such as poly sodium carboxymethylcellulose, poly potassium carboxymethylcellulose, and poly lithium carboxymethylcellulose having an average molecular weight of about 40,000 to about 400,000; or mixtures thereof.

The term "polyethylene oxide", as used herein, is a non-ionic homopolymer of the formula -(-0-CH2-CH2-)_n-, wherein n represents the average number of oxyethylene groups, n generally being from about 2,000 to about 100,000 to 200,000. It is a water- soluble resin which is available as a white powder in several grades having different molecular weights which vary in viscosity profile when dissolved in water (National Formulary XVII, pp. 1963-1964 (1990)), Polyethylene oxide resin is commercially available under the trade name Polyox^®. It is available in various grades depending on its molecular weight, which may range from about 100,000 to about 7,000,000, including from about 200,000 to about 5,000,000. Examples of suitable grades of polyethylene oxide that may be used in the present invention include Polyox , Polyox WSRN-80 (molecular weight of 200,000), Polyox^® WSR N-750 (molecular weight of 300,000), Polyox^® WSR-205 (molecular weight of 600,000), Polyox^® WSR- 1105 (molecular weight of 900,000), Polyox^® WSR N-12K (molecular weight of 1,000,000), Polyox^® WSR N- 60K (molecular weight of 2,000,000), Polyox^® WSR-301 (molecular weight of

4,000,000), Polyox^® WSR Coagulant (molecular weight of 5,000,000). In a preferred embodiment, both drug layers comprise Polyox^® WSRN-80 having a molecular weight of about 200,000. In another preferred embodiment, both drug layers of the present invention comprise rate-controlling polymers in an amount of more than about 30% w/w, and in particular more than about 40% w/w, of the total weight of each drug layer.

The term "fluid-expandable polymer", as used herein, refers to an agent which, after interacting with water and/or aqueous biological fluids, is able to swell or expand. The fluid-expandable polymers are employed in an effective amount that will control the swelling of the push layer. Suitable examples of fluid-expandable polymers are selected from the group consisting of polyethylene oxide having an average molecular weight of about 5,000,000 to about 10,000,000; cellulose derivatives such as methyl cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose; poly(hydroxy alkyl methacrylate); poly(vinyl)alcohol having a low acetal residue; cross-linked agar; alginic acid and its derivatives/salts such as sodium alginate; a water-swellable copolymer produced by forming a dispersion of a finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, butylene or isobutylene; Carbopol^® having a molecular weight of 450,000 to 4,000,000; polyacrylamides; cross-linked water-swellable indane maleic anhydride polymers; Good-Rite^® polyacrylic acid having a molecular weight of 80,000 to 200,000; starch graft copolymers; Aqua Keep^® acrylate polymer;

polysaccharides composed of condensed glucose units such as diester cross-linked polyglucan; or mixtures thereof. In particular, the push layer comprises polyethylene oxide having an average molecular weig ht of about 7,000,000 available as Polyox^® WSR- 303. The push layer of the present invention comprises a fluid-expandable polymer in an amount of more than about 10% w/w based on the total weight of the push layer.

The term "osmagent", as used herein, includes all pharmaceutically acceptable, inert, water-soluble compounds that can imbibe water and/or aqueous biological fluids. Suitable examples of osmagents are selected from the group consisting of water-soluble salts of inorganic acids such as magnesium chloride, magnesium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate; water-soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; carbohydrates such as mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, and raffinose; water-soluble amino acids such as glycine, leucine, alanine, and methionine; urea and urea derivatives; or mixtures thereof.

In one embodiment of the present invention, both drug layers and the push layer comprise osmagent. In another embodiment of the present invention, a seal-coating layer is present in between the trilayered core and the extended-release coating, and both the seal coat and the push layer comprise osmagent. The osmagent in any of the layers is present in an amount of from about 1% w/w to about 40% w/w based on total weight of each layer.

The term "about", as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.

The term "pharmaceutically inert excipients", as used herein, includes all the excipients used in the art of manufacturing osmotic release dosage forms. Specific examples include binders, diluents, surfactants, pH modifiers, lubricants/glidants, stabilizers, and coloring agents.

Specific examples of binders are methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, or mixtures thereof.

Specific examples of diluents are calcium carbonate, calcium dibasic phosphate, calcium tribasic phosphate, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, or mixtures thereof.

Specific examples of surfactants include both non-ionic and ionic (cationic, anionic, and zwitterionic) surfactants suitable for use in pharmaceutical compositions. Specific examples of surfactants polyethoxylated fatty acids and its derivatives such as polyethylene glycol (PEG) 400 distearate, PEG-20 dioleate, PEG 4-150 mono dilaurate, and PEG-20 glyceryl stearate; alcohol-oil transesterification products such as PEG- 6 corn oil; polyglycerized fatty acids such as polygly eery 1-6 pentaoleate; propylene glycol fatty acid esters such as propylene glycol monocaprylate; mono and diglycerides such as glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and their derivatives such as PEG-20 sorbitan monooleate and sorbitan monolaurate; polyethylene glycol alkyl ether or phenols such as PEG-20 cetyl ether and PEG- 10- 100 nonyl phenol; sugar esters such as sucrose monopalmitate; polyoxyethylene-polyoxypropylene block copolymers such as poloxamer; or mixtures thereof.

The pH modifiers are substances which maintain the pH of the local environment surrounding the drug at a value favorable for dissolution of the drug. Specific examples of pH modifiers are dibasic sodium phosphate, sodium ascorbate, meglumine, sodium citrate, trimethanolamine, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium oxide, magnesium hydroxide, ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine, L-lysine, or mixtures thereof.

Specific examples of lubricants/glidants are colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, or mixtures thereof.

Stabilizers include antioxidants, buffers, acids, or mixtures thereof. Suitable antioxidants are selected from the group consisting of butylated hydroxyl anisole, butylated hydroxyl toluene, sodium metabisulfite, ascorbic acid, ascorbyl palmitate, thiourea, acetylcysteine, dithiothreitol, cysteine hydrochloride, propyl gallate, tocopherol, or mixtures thereof.

Coloring agents include any FDA approved colors for oral use, for example, iron red oxide.

The seal-coating layer is applied over the trilayered core and comprises one or more film-forming polymers, one or more osmagents, and coating additives.

Suitable examples of film-forming polymers are selected from the group consisting of hydroxyl ethyl cellulose, ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, waxes such as polyethylene glycol, and methacrylic acid polymers such as Eudragit . Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry^®, may also be used.

The term "extended-release coating", as used herein, refers to a coating which allows movement of water molecules through it but does not allow the contents of the core to pass through. The extended-release coating of the present invention comprises semipermeable membrane -forming polymers, flux enhancers, film-forming polymers, and other coating additives.

Semi-permeable membrane-forming polymers pass through the gastrointestinal tract unchanged and are eliminated in feces. Suitable examples of semi-permeable membrane -forming polymers are selected from the group consisting of cellulose derivatives such as cellulose acetate, ethyl cellulose, cellulose triacetate, agar acetate, amylose acetate, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate

dimethylaminoacetate, cellulose acetate ethyl carbonate, cellulose acetate chioroacetate, cellulose acetate ethyl oxalate, cellulose acetate methyl sulphonate, cellulose acetate butyl sulphonate, cellulose acetate propionate, cellulose acetate diethylamino acetate, cellulose acetate octate, cellulose acetate laurate, cellulose acetate p-toluenesulphonate, and cellulose acetate butyrate; polymeric epoxides; copolymers of alkylene oxides and alkyl glycidyl ethers; polyglycols or polylactic acid derivatives; copolymers of acrylic acid ethyl ester and methacrylic acid methyl ester; or mixtures thereof.

Flux enhancers are water-soluble substances which aid in drawing water from the surrounding media and are thereby helpful in manipulating the semi-permeable membrane permeability. Specific examples of flux enhancers are hydroxymethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, hydroxypropyl cellulose, propylene glycol, povidone, or mixtures thereof.

The term "passageway", as used herein, covers any suitable means for releasing the contents of the core into the surrounding media. The term includes passages, apertures, bores, holes, or openings that are created through the extended-release coating and form a connection between the core and the surrounding media. The passageway may be created by mechanical drilling or laser drilling, or formed in response to osmotic pressure acting on the drug delivery system. Based on the nature of the desired drug- release profile, the number and diameter of the passageways may be adjusted. At least one orifice is drilled through the membrane on the first drug layer end of the capsule-shaped tablet. However, the diameter of the passageway should not be large enough to allow body fluids to enter the drug delivery system by the process of convection.

In the process of preparation of the tablets, the blends may be granulated by conventional techniques known in the art such as wet granulation, dry granulation, extrusion-spheronization, or hot melt extrusion. Wet granulation process involves the use of water or any other suitable granulating fluid. Dry granulation may involve the use of a roller compactor or any suitable technique.

Specific examples of granulating fluids/solvents for coating include acetone, ethanol, isopropyl alcohol, methylene chloride, or combinations thereof.

The trilayered core may be prepared by combining the granule or blend compositions of the drug layers and the push layer using appropriate conventional tooling.

The seal coating layer and/or extended-release coating layer may be applied using conventional coating techniques well known in the art such as spray coating in a conventional coating pan or fluidized bed processor, dip coating, melt coating, or compression coating. In a preferred embodiment of the present invention, a spray coating technique may be used. A further additional non-functional coating layer may be applied over the extended-release coating layer.

The non-functional coating layer comprises one or more film-forming polymers and coating additives.

Coating additives may be selected from the group consisting of plasticizers, coloring agents, and lubricants/glidants.

Examples of plasticizers include polyethylene glycol, triethyl citrate, acetylated triethyl citrate, tributyl citrate, acetylated tributyl citrate, glycerol tributyrate,

monoglyceride, rapeseed oil, olive oil, sesame oil, glycerin sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, or mixtures thereof.

The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. EXAMPLES

Example 1

Procedure:

1. For the first drug layer, paliperidone, povidone, polyoxyethylene oxide (Polyox^® WSR N-80), sodium chloride, and butylated hydroxyl toluene were sifted and blended.

2. The blend of step 1 was granulated with an ethanol and purified water mixture.

3. The granules of step 2 were lubricated with stearic acid.

4. For the second drug layer, paliperidone, povidone, polyoxyethylene oxide (Polyox⁽ WSR N-80), sodium chloride, red iron oxide, and butylated hydroxyl toluene were sifted and blended.

5. The blend of step 4 was granulated with an ethanol and purified water mixture.

6. The granules of step 5 were lubricated with stearic acid.

7. For the push layer, povidone, polyoxyethylene oxide (Polyox^® WSR-303), sodium chloride, and butylated hydroxyl toluene were sifted and blended.

8. The blend of step 7 was lubricated with stearic acid.

9. The granules of step 3, the granules of step 6, and the blend of step 8 were

compressed to form trilayered core tablets using appropriate tooling.

10. Hydroxy ethyl cellulose was dissolved in an ethanol and purified water mixture.

11. The trilayered core tablets of step 9 were coated with the solution of step 10.

12. Cellulose acetate and polyethylene glycol were dissolved in an acetone and water solution.

13. The coated tablets of step 11 were coated with the solution of step 12.

14. The coated tablet of step 13 was drilled using a drilling machine to form one

passageway on the first drug layer side. Example 2

Procedure:

1. For the first drug layer, paliperidone, povidone, polyoxyethylene oxide (Polyox^® WSR N-80), hydroxy propyl methyl cellulose, and butylated hydroxyl toluene are sifted and blended.

2. The blend of step 1 is granulated with an ethanol and purified water mixture.

3. The granules of step 2 are lubricated with magnesium stearate.

4. For the second drug layer, paliperidone, povidone, polyoxyethylene oxide (Polyox^® WSR N-80), hydroxy propyl methyl cellulose, and butylated hydroxyl toluene are sifted and blended.

5. The blend of step 4 is granulated with an ethanol and purified water mixture.

6. The granules of step 5 are lubricated with magnesium stearate.

7. For the push layer, povidone, polyoxyethylene oxide (Polyox^® WSR-303), sodium chloride, butylated hydroxyl toluene, and microcrystalline cellulose are sifted and blended.

8. The blend of step 7 is lubricated with magnesium stearate and mixed with iron oxide red.

9. The granules of step 3, the granules of step 6, and the blend of step 8 are compressed to form trilayered core tablets using appropriate tooling.

10. Hydroxy ethyl cellulose and sodium chloride are dissolved in an ethanol and purified water mixture.

11. The trilayered core tablets of step 9 are coated with the solution of step 10.

12. Cellulose acetate and polyethylene glycol are dissolved in an acetone and purified water solution.

13. The coated tablets of step 11 are coated with solution of step 12.

14. The coated tablet of step 13 is drilled on the first drug layer side to form at least one passageway. In-Vitro Studies

In-vitro drug -release from the tablets, prepared as per Example 1, was determined by the dissolution for paliperidone using USP type II apparatus at 50 rpm, in 500 mL of modified simulated gastric fluid having sodium chloride (0.2% w/w) in 0.0825N HCl having a pH of 1.0. The results of the release studies are represented in Table 1 below.

Table 1: Percentage (%) of In-Vitro Drug-release in USP Type II Apparatus (Media: 500 mL of modified simulated gastric fluid, pH 1.0 at 50 rpm)

Claims

We Claim:

1. An extended-release tablet of paliperidone comprising:

(a) a core comprising:

(i) a first drug layer comprising paliperidone, one or more rate-controlling polymers, and one or more osmagents;

(ii) a second drug layer comprising paliperidone, one or more rate- controlling polymers, and one or more osmagents; and

(iii) a push layer comprising one or more fluid-expandable polymers and one or more osmagents;

(b) optionally a seal coating layer comprising one or more film-forming

polymers; and

(c) an extended-release coating comprising one or more semi-permeable

membrane-forming polymers with at least one passageway.

2. An extended-release tablet of paliperidone comprising:

(a) a core comprising:

(i) a first drug layer comprising paliperidone and one or more rate- controlling polymers;

(ii) a second drug layer comprising paliperidone and one or more rate- controlling polymers; and

(iii) a push layer comprising one or more fluid-expandable polymers and one or more osmagents;

(b) a seal coating layer comprising one or more film-forming polymers and one or more osmagents; and

(c) an extended-release coating comprising one or more semi-permeable

membrane-forming polymers with at least one passageway.

3. The extended-release tablet of paliperidone according to claims 1 and 2, wherein the rate-controlling polymer is polyethylene oxide having a molecular weight of about 200,000 to about 5,000,000.

4. The extended-release tablet of paliperidone according to claims 1 and 2, wherein the fluid-expandable polymer is polyethylene oxide having a molecular weight of about 5,000,000 to about 10,000,000.

5. The extended-release tablet of paliperidone according to claim 1 and claim 2, wherein the osmagents are selected from the group consisting of water soluble salts of inorganic acids such as magnesium chloride, magnesium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate; water-soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; carbohydrates such as mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, and raffinose; water-soluble amino acids such as glycine, leucine, alanine, and methionine; urea and urea derivatives; or mixtures thereof.

6. A process for the preparation of an extended-release tablet of paliperidone, wherein the process comprises the steps of:

(a) blending/granulating one portion of paliperidone with one or more rate- controlling polymers, one or more osmagents, and one or more pharmaceutically inert excipients to form the first drug layer;

(b) blending/granulating another portion of paliperidone with one or more rate- controlling polymers, one or more osmagents, and one or more pharmaceutically inert excipients to form the second drug layer;

(c) blending/granulating one or more fluid-expandable polymers with one or more osmagents and one or more pharmaceutically inert excipients to form a push layer;

(d) compressing the blends/granules of steps (a), (b), and (c) into a trilayered tablet core using appropriate tooling;

(e) optionally applying a coating composition comprising a solution or

dispersion of one or more film-forming polymers and other coating additives over the trilayered tablet core of step (d) to form a seal coating layer; (f) applying a coating composition comprising a solution or dispersion of one or more semi-permeable membrane-forming polymers and other coating additives over the seal coating layer of step (e) to form an extended-release coating; and

(g) creating at least one passageway in the extended-release coating adjacent to the first drug layer.

7. A process for the preparation of an extended-release tablet of paliperidone, wherein the process comprises the steps of:

(a) blending/granulating one portion of paliperidone with one or more rate- controlling polymers and one or more pharmaceutically inert excipients to form the first drug layer;

(b) blending/granulating another portion of paliperidone with one or more rate- controlling polymers and one or more pharmaceutically inert excipients to form the second drug layer;

(c) blending/granulating one or more fluid-expandable polymers with one or more osmagents and one or more pharmaceutically inert excipients to form a push layer;

(d) compressing the blends/granules of steps (a), (b), and (c) into a trilayered tablet core using appropriate tooling;

(e) applying a coating composition comprising a solution or dispersion of one or more film-forming polymers, one or more osmagents, and other coating additives over the trilayered tablet core of step (d) to form a seal coating layer;

(f) applying a coating composition comprising a solution or dispersion of one or more semi-permeable membrane-forming polymers and other coating additives over the seal coating layer of step (e) to form an extended-release coating; and

(g) creating at least one passageway in the extended-release coating adjacent to the first drug layer.

8. A method of treating and/or preventing neurological disorders by administering the extended-release tablet of claim 1.

9. A method of treating and/or preventing neurological disorders by administering the extended-release tablet of claim 2.

10. The extended-release tablet of paliperidone of claim 1, wherein the

the first drug layer comprises paliperidone, the one or more rate-controlling polymers comprises polyoxyethylene oxide, and the one or more osmagents comprise sodium chloride;

the second drug layer comprising paliperidone, the one or more rate-controlling polymers comprises polyoxyethylene oxide, and the one or more osmagents comprise sodium chloride; and

in the push layer the one or more fluid-expandable polymers comprises polyoxyethylene oxide and the one or more osmagents comprises sodium chloride;

in the seal coating layer the one or more film-forming polymers comprising hydroxypropyl cellulose; and

in the extended-release coating the one or more semi-permeable membrane- forming polymers comprising cellulose acetate.

11. The extended-release tablet of paliperidone of claim 10, wherein the first and second drug layers each further comprise povidone, butylated hydroxyl toluene and stearic acid; and the push layer further comprises povidone, butylated hydroxyl toluene and stearic acid.

12. The extended-release tablet of paliperidone of claim 2, wherein the

the first drug layer comprises paliperidone and the one or more rate-controlling polymers comprises polyoxyethylene oxide and hydroxypropylmethyl cellulose;

the second drug layer comprising paliperidone and the one or more rate-controlling polymers comprises polyoxyethylene oxide and hydroxypropylmethyl cellulose; and in the push layer the one or more fluid-expandable polymers comprises polyoxyethylene oxide and the one or more osmagents comprises sodium chloride;

in the seal coating layer the one or more film-forming polymers comprising hydroxyethyl cellulose and the one or more osmagents comprising sodium chloride; and

13. in the extended-release coating the one or more semi-permeable membrane- forming polymers comprising cellulose acetate.

14. The extended-release tablet of paliperidone of claim 12, wherein the first and second drug layers each further comprise povidone, butylated hydroxyl toluene and magnesium stearate or stearic acid; and the push layer further comprises povidone, butylated hydroxyl toluene, and magnesium stearate or stearic acid, and sodium chloride as an osmagent agent.