FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION (SECTION 10)
"EXTENDED OSMOTIC RELEASE COMPOSITIONS OF PALIPERIDONE"
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM BHAVAN,
;PRABHAT ESTATE, S. V. ROAD, JOGESHWARI (WEST), MUMBAI - 400 102,
MAHARASTRA, INDIA
The following specification describes the invention and the manner in which it is to be performed.

"EXTENDED OSMOTIC RELEASE COMPOSITIONS OF PALIPERIDONE"
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an extended release pharmaceutical composition of Paliperidone. More particularly, the present invention relates to an oral osmotic push pull extended release solid oral dosage forms of paliperidone and methods for their manufacture thereof, useful for the treatment of Schizophrenia and Schizoaffective disorders.
BACKGROUND OF THE INVENTION
Paliperidone is a white to yellow non-hygroscopic powder. It has a molecular formula of C H FN 0 with relative molecular weight of 426.49. Its chemical name is (±)-3-[2-[4-
(6-fluoro-l, 2-benzisoxazol-3-yl)-l-piperidinyl] ethyl]-6, 7, 8, 9-tetrahydro-9-hydroxy-2-methyl-4ifpyrido [1, 2-a] pyrimidin-4-one. Paliperidone is sparingly soluble in 0.1N HC1 and methylene chloride; practically insoluble in water, 0.1N NaOH, and hexane; and slightly soluble in N,N-dimethylformamide. Paliperidone has one chiral center and is synthesized as a racemic mixture. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. The absolute oral bioavailability of paliperidone from extended release tablets of paliperidone is about 28%. A standard high-fat/high-caloric meal increases mean Cmax and AUC values of paliperidone by 60% and 54%, respectively, compared with administration under fasting conditions. Apparent volume of distribution of paliperidone is 487 L. The plasma protein binding of racemic paliperidone is 74%.
Paliperidone is commercially available as, extended release systems in the form of tablets of 1.5, 3, 6, 9 & 12mg strengths, suspension for parenteral administration of 39mg/0.25ml, 78mg/0.5ml, 117mg/0.75ml, 156mg/ml and 234mg/l.5ml strengths.

Extended release systems of paliperidone in the form of extended, release tablets are currently marketed by Ortho Mcneil Janssen under the brand names of Invega in 1.5, 3, 6. & 9 mg strengths in the USA and by Janssen Cilag Ltd. as Invega prolonged release tablets in 1.5, 3, 6, 9 & 12mg strengths in Europe.
Ortho Mcneil Janssen markets extended release suspension for Injection of paliperidone under the brand name Invega Sustenna in 39mg/0.25ml, 78mg/0.5ml, 117mg/0.75ml, 156mg/ml and 234mg/1.5ml strengths in the USA.
WO 2010/026254 Al (Hudovornik Grega et al.; March 2010) discloses prolonged release multi-particulate pharmaceutical composition of paliperidone wherein the disclosed composition is in the form of pellets (having a maximum diameter of 2 mm or less) comprising a core particle, optionally one or more intermediate coatings, at least one prolonged release coating and optionally one or more outer coatings. As the disclosed multi-particulate pharmaceutical composition of paliperidone utilizes active substance containing core particles manufactured either by melt pelletization or coating of active substance on inert cores or matrix cores and multiple coatings around the pellets, there is a possibility for having variability in the dose. Preparation of core particles containing active substance by melt granulation utilizes special equipment other than conventional equipment used in the regular manufacturing tablets. In addition, the disclosed multiparticulate pharmaceutical composition also utilizes multiple coating around the pellets, which increases the manufacturing time as well as manufacturing cost and hence increases the cost of the final drug product.
WO 2010/044097 A2 (Vijaysinh Vanvirsinh Chauhan et al.; April 2010) discloses extended release solid oral composition comprising a core, inclusive of intra-granular-extra-granular application of matrixing agent, comprising active ingredient and one or more pharmaceutically acceptable excipients wherein granules are subjected to compression followed by non-aqueous functional coat of pH independent polymer. Composition may also be further coated with color coat for aesthetic appeal. The disclosed extended release composition maintains desired therapeutic drug effect over a prolonged period of time and thereby reduces the side effects resulting due to excess plasma drug concentration. The process of non-aqueous coating requires flameproof area,

which increases the manufacturing cost. The disclosed process utilizes more number of unit operations, which increases the manufacturing time and hence manufacturing cost.
US 2004/0092534 Al (Nyomi V Yam et al.; May, 2004) discloses methods and dosage form for controlled delivery of paliperidone, wherein the disclosed pharmaceutical composition of paliperidone is in the form of osmotic systems containing multilayers, which delivers the drug in substantially ascending release rate for prolonged period of time. Manufacturing process involved for the preparation of osmotic systems containing multilayers is complex and in addition it also requires costlier and speciality equipment, which makes the manufacturing process cumbersome and also increases the manufacturing cost.
US2007/0190137(Reyes Iran et al; 2007) discloses an osmotic dosage form comprising : a semipermeable memebrane.; a first and second orifice in the semi-permeable membrane located at opposite ends of the semi permaeble membrane; a controlled release drug layer located adjacent to the first orifice and with in the semipermeable membrane; a fast release drug layer located adjacent to the second orifice and with in the semi permeable membrane ;a push layer located with in the semipermeable membrane and between the controlled release drug layer and the fast release drug layer; a barrier layer slidably located between the push layer and the fast release drug layer and where in an area of the second orifice is greater than or equal to about 7800 mil . Disclosed invention makes use of trilayer layer technology which is expensive, time consuming and requires highly skilled personnel.
U.S.2007/0166381(Iran Reyes et. al.; 2007) discloses an osmotic dosage form comprising a semipermeable membrane; a lubricating subcoat located with in the semipermeable membrane; an orifice in the semi permeable membrane located at an end of the semipermeable membrane; a drug layer located with in the lubricating subcoat; a push layer located with in the lubricating subcoat and on a side of the drug layer opposite from the orifice; where in an area of the orifice is greater than or equal to about 1,600 mil; and where in the drug layer comprises from about 20wt.% to about 90wt% microcrystalline cellulose and less than or equal to about 10 wt.% of a drug, based on the total weight of the drug layer. Disclosed pharmaceutical composition makes use of

microcrystalline cellulose which is insoluble filler. This insoluble filler may entrap the active substance and may deposit on the surface of core tablets and thus may not help in attaining the complete release of drug.
WO2010/089775 (Patil A, et. al.;2010) discloses an orally administrable dosage form comprising (1) an inner core comprising (a) one or more pharmaceutical active agent and (b) combination of hydrophilic and hydrophobic polymers, and (2) a permeable membrane covering the inner core. The patent publication further discloses ascending release of pharmaceutically active agent is obtained by using combination of hydrophobic and hydrophilic polymers in inner core and coating layer of the composition.
417/CHE/2010 (Reddy, Anil et. al., 2010) discloses an oral controlled release dosage form in which core comprising of a drug layer and optionally a push layer. Seal coating comprising film forming polymer and one or more pharmaceutical acceptable excipients. A semipermeable membrane coating over the seal coating comprising at least one enteric polymer and one or more pharmaceutical acceptable excipients. The patent application further discloses improved bioavailability of Paliperidone against commercially available Invega. Disclosed pharmaceutical composition of this invention exhibits improved bioavailability. This improved bioavailability of paliperidone may show supra bioavailabilty of drug as compare to Invega or drug product may not be bioequivalent to Invega.
293/CHE/2010 (Reddy, Anil et. al., 2010) discloses an oral osmotic dosage form of paliperidone in which core comprising a drug layer, optionally a push layer and a seal coat layer. A semipermeable membrane having an orifice surrounding said core; wherein said dosage releases paliperidone in a non ascending rate of release, This patent application discloses the non ascending rate of release of drug which may not be in line to commercially available Invega tablets which show ascending rate of release of Paliperidone. Pharmaceutical composition of this disclosed invention may not be bioequivalent to commercially available Invega.
The above various prior art discloses various oral osmotic dosage forms consisting of Paliperidone. Even though, many technologies with different compositions are available for oral extended release systems of paliperidone, there is a need for the development of

therapeutically efficient delivery systems for paliperidone, which is cost effective and shows comparable bioavailability with marketed formulation Invega.
Thus, the present invention relates to novel extended osmotic release solid oral pharmaceutical composition, comprising paliperidone or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof and novel method of manufacture thereof which provides initial slow rate of release of paliperidone followed by increased release at later stages and to provide almost comparable rate of release to that of commercially available Invega in official media as recommended by OGD.
OBJECT OF THE INVENTION
The object of the present invention is to provide therapeutically efficient extended release solid oral pharmaceutical composition for paliperidone or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof which is cost effective and shows comparable bioavailability with marketed formulation Invega.
Another object of the present invention is to provide an extended release solid oral dosage form as an osmotic delivery device.
Yet, another object of the present invention is to provide a process for preparing an extended release solid oral pharmaceutical composition of paliperidone or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof comprising of core, seal coating, semipermeable coating membrane and top coating, wherein seal coating prevents entry of organic solvent in to the tablet core.
Yet, another object of the present invention is to provide an novel bilayer extended release solid oral pharmaceutical composition, comprising paliperidone or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof which provides initial slow rate of release of paliperidone followed by increased release at later stages to provide almost comparable rate of release to that of commercially available trilayer formulation Invega® in official media as recommended by OGD.
Further objective of the present invention is to provide extended release pharmaceutical compositions of Paliperidone or its pharmaceutically acceptable salt, solvate, enantiomers

or mixtures thereof useful for the treatment of Schizophrenia and Schizoaffective disorders.
SUMMARY OF THE INVENTION
In one aspect the present invention provides, the novel extended release pharmaceutical composition in the form of oral osmotic push pull device.
In yet another aspect, the present invention provides novel extended release pharmaceutical composition comprising:
a. compressed core, which essentially comprises of,
i) active pharmaceutical ingredient,
ii) pharmaceutically acceptable diluents,
iii) pharmaceutically acceptable osmogen,
iv) pharmaceutically acceptable swellable polymer,
v) optional ly. pharmaceutical 1 y acceptable anti-o xidants,
vi) optionally pharmaceutically acceptable binders,
vii) optionally pharmaceutically acceptable colorants,
viii) pharmaceutically acceptable glidants and lubricants
b. seal coating comprising of film forming hydrophilic polymer and one or more
pharmaceutical acceptable excipients, wherein seal coating prevents entry of organic
solvent in to the tablet core.
c. semipermeable membrane around the said seal coating, which consists of a layer of
pharmaceutically acceptable release retardant water insoluble polymers> optionally
inactive pharmaceutical ingredient, optionally pharmaceutically acceptable excipients
like pore forming agent or flux enhancing agents, wherein release retardant water
insoluble polymers are not enteric polymers.
d. at least one passageway in the wall communicating with drug layer and exterior of the
device for delivery of paliperidone; and

e. a top coating.
In yet another aspect, the present invention provides a process for preparation of extended release pharmaceutical composition comprising paliperidone or pharmaceutically acceptable salts thereof and one or more pharmaceutical excipients.
BRIEF DESCRIPTION OF THE DRAWING
Fig. 1: Comparative dissolution profile of examples 1, II, III, IV and commercially available Invega (reference) in 500ml of modified SGF for 24 hours having pH of 1 using USP Dissolution Apparatus II with 50 RPM
Fig. 2: Comparative dissolution profile of examples IV and commercially available Invega® (reference) in 250ml of modified SGF for 24 hours having pH of 1 using USP Dissolution Apparatus III with reciprocation rate of 20dpm
Fig. 3: Comparative dissolution profile of examples IV and commercially available Invega® (reference) in 250ml of phosphate buffer for 24 hours having pH of 6.8 using USP Dissolution Apparatus III with reciprocation rate of 20dpm
Fig. 4; Comparative mean plasma concentration vs.Time profile for example 6 (Test) and commercially available Invega® (reference) in fed condition.
Fig. 5: Comparative mean plasma concentration vs.Time profile for example 6 (Test) and commercially available Invega® (reference) in fasting condition
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to controlled release dosage form comprising paliperidone or its pharmaceutically acceptable salts thereof.
In one embodiment, the invention relates to an oral extended release dosage form as an osmotic delivery device for the delivery of paliperidone or pharmaceutically acceptable salts thereof that comprising:
a. a core comprising of drug layer and push layer;

b. seal coating comprising of film forming hydrophilic polymer and one or more
pharmaceutically acceptable excipients, wherein seal coating prevents entry of
organic solvent in to the tablet core.
c. semipermeable membrane around the said seal coating, which consists of a layer
of pharmaceutically acceptable release retardant water insoluble polymers.
optionally inactive pharmaceutical ingredient, optionally pharmaceutically
acceptable excipients like pore forming agent or flux enhancing agents, wherein
release retardant water insoluble polymers are not enteric polymers,
d. at least one passageway in the wall communicating with drug layer and exterior of
the device for delivery of paliperidone; and
e. a top coating.
In yet another embodiment, the invention relates an oral extended release tablet as an osmotic delivery device for the delivery of paliperidone or pharmaceutically acceptable salts thereof comprising;
a. a core comprising of drug layer and push layer;
b. seal coating comprising of film forming hydrophilic polymer and one or more
pharmaceutically acceptable excipients, wherein seal coating prevents entry of
organic solvent in to the tablet core.
c. semipermeable membrane around the said seal coating, which consists of a layer
of pharmaceutically acceptable release retardant water insoluble polymers.
optionally inactive pharmaceutical ingredient, optionally pharmaceutically
acceptable excipients like pore forming agent or flux enhancing agents, wherein
release retardant water insoluble polymers are not enteric polymers.
d. at least one passageway in the wall communicating with drug layer and exterior of
the device for delivery of paliperidone; and
e. a top coating.
The term "extended release" herein refers to any formulation or dosage form that comprises an active drug and which is formulated to provide a longer duration of

pharmacological response after administration of the dosage form than ordinarily experienced after administration of a corresponding immediate release formulation comprising the same drug in the same amount. Extended release formulations include, inter alia, those formulations described elsewhere as "controlled release", "delayed release", "sustained release", "prolonged release", "programmed release", "time release" and/or "rate controlled" formulations or dosage forms. Further for the purposes of this invention refers to release of an active pharmaceutical agent over a prolonged period of time, such as for example over a period of 8, 12, 16 or 24 hours.
By "pharmaceutically acceptable" is meant to cover a carrier comprised of a material that is not biologically or otherwise undesirable,
The term "paliperidone" as used in the invention is meant to cover Paliperidone in the form of freebase or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof. The term also includes all polymorphic forms, whether crystalline or amorphous.
The term "osmotic device" as used in the invention is meant to cover device which have "osmotically active component i.e. osmogen", "precision laser-drilled orifices" to release active and "semipermeable membrane" that controls the release rate of active.
"Pharmaceutically acceptable salt", as used herein, include those salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt, and. as such, they are the pharmacological equivalents of the bases of the paliperidone. Preferable examples include but are not limited to hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, mandelic, phosphoric, nitric, mucic, isethionic, palmitate, and the like.
Drug "release-rate" refers to the quantity of drug released from a dosage form per unit time, e.g., milligrams of drug released per hour (mg/hr). Drug release-rates from dosage forms are typically measured as an in vitro rate of drug dissolution, i.e., a quantity of drug released from the dosage form per unit time measured under appropriate conditions and in a suitable fluid.

In yet another embodiment, the osmotic delivery device according to the invention provides drug release when measured in 250 ml of modified SGF having 1.0 pH and phosphate buffer of 6.8 pH using USP dissolution apparatus III with reciprocation rate of 20dpm as compared with the commercially available Invega® in such a way that:
(a) about 10 % or more of total paliperidone is released after 2 hours of measurement in said apparatus;
(b) about 30 % or more of total paliperidone is released after 8 hours of measurement in said apparatus;
(c) about 60 % or more of total paliperidone is released after 12 hours of measurement in said apparatus, and;
(d) about 100 % of total paliperidone is released after 24 hour of measurement in said
apparatus.
In yet another embodiment, the controlled release dosage form of the invention provides comparable drug release to the commercially available Invega® for an extended period of time,
"Extended period of time" means a continuous period of time of greater than about 2 hours, preferably, greater than about 4 hours, more preferably, greater than about 6 hours, more preferably greater than about 8 hours, more preferably still, greater than about 18 hours, most preferably, greater than about 18 hours and up to about 24 hours.
The "core" according to the invention may include a single monolithic tablet or a multiple layer tablet comprising a drug layer, a push layer and other suitable layer.
The core comprises about 1-10% w/w of paliperidone of drug layer, and one or more pharmaceutically acceptable excipients such as diluents, binders, surfactants, viscosity enhancers, hydrophilic polymers, antioxidants and lubricants.
Diluents used according to the invention are selected from but not limited to microcrystalline cellulose, silicified microcrystalline cellulose, anhydrous lactose, directly compressible lactose, starch 1500, calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, fructose, sucrose, sorbitol, xylitol, dextrose, compressible sugar, dextrates, dextrin, starch, powdered cellulose, sodium alginate,

tragacanth, sodium chloride, potassium chloride, magnesium sulfate, magnesium chloride, sodium sulfate, lithium sulfate, urea, inositol, lactose, lactose monohydrate, mannitol, magnesium succinate, potassium acid phosphate and the like.
Binders used according to the invention are selected from but not limited to povidone, pyrrolidone, co-povidone, acacia gum, guar gum, xanthan gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, gelatin, glucose, sugar, dextrin, sorbitol, maltose, pregelatinised starch, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hyroxyethyl cellulose, cellulose acetate, agar, alginic acid, sodium alginate, carbomers, carrageenan, ceratonia, chitosan, poloxamer, polyethylene oxide, magnesium aluminum silicate.
Hydrophilic polymers used according to invention are selected from but not limited to a group comprising polyethylene oxide, polymethylene oxide, polybutylene oxide, polyhexylene oxide, polypotassium carboxymethylcellulose, polylithium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, polyvinylpyrrolidone and the like or combinations thereof.
Antioxidants used according to the invention are selected from but not limited to a group comprising, butylated hydroxytoluene, alpha tocopherol, ascorbyl palmitate, ascorbates, isoascorbates, butylated hydroxyanisole and the like or combinations thereof.
Lubricants used according to invention are selected from but not limited to a group comprising magnesium stearate, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and the like or combinations thereof.
In yet another embodiment, the core comprises multiple layers which include a composition comprising a drug layer and a push layer.
The drug layer composition present in multilayered core comprises a pharmaceutic ally active agent, hydrophilic polymer, osmopolymer and one or more pharmaceutically acceptable excipient.
The push layer composition present in bilayered core mainly comprises osmotically active component(s) but without any active ingredients.

The osmotically active component(s) in push layer typically comprises an osmogen and one or more osmopolymer(s) which exhibit swelling as fluid is imbibed and finally it pushes against the drug layer and thereby facilitates release of the drug from the osmotic device.
Osmopolymers used according to the invention are selected from but not limited to a group comprising polyethylene oxide, polymefhylene oxide, xanthan gum, Hydrophilic polymers suitable for the present purpose include poly(hydroxy-alkyl methacrylate) having a molecular weight of from 30,000 to 5,000,000; poly(vinylpyrrolidone) having molecular weight of from 10,000 to 360,000; anionic and cationic hydrogels; polyelectrolyte complexes; polyvinyl alcohol) having a low acetate residual, cross-linked with glyoxal, formaldehyde, or glutaraldehyde and having a degree of polymerization from 200 to 30,000; a mixture of methyl cellulose, cross-linked agar and carboxymethyl cellulose; a mixture of hydroxypropyl methylcellulose and sodium carboxymethylcellulose, hydroxypropyl methylcellulose and sodium carboxymethyl cellulose; a water insoluble, water swellable copolymer reduced by forming a dispersion of finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, butylene or isobutylene cross-linked with from 0.001 to about 0.5 moles of saturated cross-linking agent per mole of maleic anhydride in copolymer; water swellable polymers of N-vinyl lactams; polyoxyethylene-polyoxypropylene gel; polyoxybutylene-polyethylene block copolymer gel; carob gum, polyacrylic gel; polyester gel; polyurea gel; polyether gel; polyamide gel; polyimide gel; polypeptide gel; polyamino acid gel; polycellulosic gel; polygum gel; initially dry hydrogels that generally imbibe and absorb water which penetrates the glassy hydrogel and lowers its glass transition temperature; and the like.
Osmogens used according to the invention are selected from but not limited to a group comprising sodium chloride, potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium acid phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid, raffinose. sucrose, glucose, lactose, sorbitol, inorganic salts, organic salts and carbohydrates and the like or combinations thereof.

In addition to above excipients, the drug layer and push layer may further comprise various excipients such as binders, lubricants, antioxidants and colorants.
Suitable coloring agents include one or more colors approved by FDA such as ferric oxide red.
In yet another embodiment, extended release osmotic delivery device according to present invention is bilayer osmotic delivery device,
In yet another embodiment, the extended release osmotic delivery device according to present invention is prepared by means of any of the conventional manufacturing processes well known to those of skill in the art such as direct compression, dry granulation or wet granulation.
In yet another embodiment, the extended release osmotic delivery device for the delivery of paliperidone further comprises seal coating over the core, wherein seal coating comprises a hydrophilic polymers and optionally plasticizers, optionally flux enhancers, optionally surfactants, optionally anti-tacking agents and pigments.
The seal coating according to the present invention prevents entry of organic solvent in to the tablet core.
It is considered that amount of residual solvents of 50 mg per day or less (corresponding to 5000 ppm) would be acceptable without justification according to ICH topic Q3C (R4) Impurities: Guideline for Residual Solvents.
In yet another embodiment, residual organic solvent present in the final dosage form according to present invention is below 5000 ppm.
Organic solvents used according to the invention are selected from but not limited to a group comprising methanol, ethanol, isopropanol, ethyl acetate, ethyl lactate, acetone, methylene chloride, 1,1,1 -trichloroethane and the like or combinations thereof, more preferably organic solvent used is acetone.
In yet another embodiment, the seal coating is present to achieve initial slow rate of release of paliperidone followed by increased release at later stages and to provide almost comparable rate of release to that of commercially available Invega in official media as recommended by OGD.

Film forming hydrophilic polymers used according to the invention are selected from but not limited to a group comprising cellulose polymers and their derivatives (such as for example, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, and microcrystalline cellulose), polysaccharides and their derivatives, polyalkylene oxides, polyethylene glycols, chitosan, polyvinyl alcohol), xanthan gum, maleic anhydride copolymers, poly( vinyl pyrrolidone), starch and starch- based polymers, poly(2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethane hydrogels, gums, alginates, lectins, carbopol, and combinations comprising one or more of the foregoing polymers, more preferably film forming hydrophilic polymer used is hydroxyethyl cellulose.
Semipermeable membrane around the said seal coating, which consists of a layer of pharmaceutically acceptable release retardant water insoluble, pH independent or polymers, optionally plasticizers, optionally flux enhancers, optionally surfactants, optionally anti-tacking agents and pigments.
Water insoluble polymers are selected from a group consisting of ethyl cellulose, methyl cellulose, cellulose acetate polyvinylchloride, high density polyethylene, and like or combinations thereof; pH independent polymers used according to the invention are selected from but not limited to a group comprising hydroxymethyl cellulose, ethyl cellulose, hydroxy ethyl cellulose and carboxymethyl cellulose and like or combination thereof; release retardant polymers used in accordance with present invention is selected from but not limited to one or more of cellulose derivatives like hydroxy! ethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl mefhylcellulose, hydroxypropyl cellulose; polyvinyl alcohols, polyethylene oxides, carbopols; natural polysaccharide gums like guar gum, xanthan gum, karaya gum, gellan gum, hupu gum, carob gurm caramania gum, sodium alginate, carrageenan, ceratonia, sodium calcium alginate and alginic acid and mixture thereof,
Plasticizers used according to the invention are selected from but not limited to a group comprising polyethylene glycol, triethyl citrate, diethyl phthalate, dibutyl phthalate, cetyl alcohol, triacetin and the like or combinations thereof.

Flux enhancers used according to the invention are selected from but not limited to a group comprising sodium chloride, potassium chloride, sucrose, sorbitol, mannitol. . polyethylene glycol, propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, acrylic polymers, methacrylic acid copolymers or combinations thereof.
Surfactants used according to the invention are selected from but not limited to a group comprising sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbate, Tween and the like or combinations thereof.
Anti-tacking agent and pigments are selected from but not limited to a group consisting of talc, titanium dioxide, colloidal silicon dioxide, bentonites, fumed silica, aluminium lakes and mixtures thereof.
The semi-permeable membrane coating, the seal-coat and optional film coating is applied over the core tablet using conventional coating machines, for example, pan coaters, rotary drum-type coaters, Wurster-type fluidizing coaters and fhiidizing coaters may be employed in said method of the invention.
In accordance with the present invention, osmotic delivery device is further drilled in the centre of drug layer through the semipermeable membrane wall to form the exit orifice, wherein diameter of said passageway is from about 0.2 mm to 0.8 mm, more preferably from 0.4 to 0.6mm.
The term "orifice" according to the invention is defined as a hole or passageway formed through the semi-permeable membrane of the osmotic dosage form.
The "drilling" according to the invention include both mechanical as well as laser drilling. More preferably, the invention uses laser drilling which connect the drug layer with exterior of the dosage form.
In yet another embodiment, the present invention provides an oral extended release tablet as an osmotic delivery device for the delivery of paliperidone or pharmaceutically acceptable salts thereof comprising:

a. a' core comprising of drug layer and push layer, a drug layer comprising
paliperidone, osmopolymer and pharmaceutically acceptable excipients, a push
layer comprising of osmopolymer, osmogen and pharmaceutically acceptable
excipients;
b. a seal coating surrounding a core comprising film forming polymer;
c. a semipermeable membrane permeable to passage of exterior fluid present in the
surrounding and impermeable to passage of paliperidone;
d. at least one passageway in the wall communicating with drug layer and exterior of
the device for delivery of paliperidone; and
e. a film coating surrounding a device.
In yet another embodiment, the present invention provides an oral extended release tablet as an osmotic delivery device for the delivery of paliperidone or pharmaceutically acceptable salts thereof comprising:
a. a core comprising of drug layer and push layer, a drug layer comprising
paliperidone, osmopolymer and pharmaceutically acceptable excipients, a push
layer comprising of osmopolymer, osmogen and pharmaceutically acceptable
excipients;
b. seal coating comprising of film forming hydrophilic polymer and one or more
pharmaceutically acceptable excipients, wherein seal coating prevents entry of
organic solvent in to the tablet core.
c. semipermeable membrane around the said seal coating, which consists of a layer.
of pharmaceutically acceptable release retardant water insoluble polymers,
optionally inactive pharmaceutical ingredient, optionally pharmaceutically
acceptable excipients like pore forming agent or flux enhancing agents, wherein
release retardant water insoluble polymers are not enteric polymers.
d. a semipermeable membrane permeable to passage of exterior fluid present in the
surrounding and impermeable to passage of paliperidone;

e. at least one passageway in the wall communicating with drug layer and exterior of
the device for delivery of paliperidone; and
f. a film coating surrounding a device.
In yet another embodiment the present invention provides the semipermeable coating membrane which is permeable to passage of exterior fluid present in the surrounding and impermeable to passage of paliperidone.
In yet another embodiment the present invention provides osmotic devices for administration of a biologically active substance for extended period of time into a biological environment comprising: a core comprising a first layer (drug layer) containing about 1-10% w/w of paliperidone of drug layer and about 10 to 99 percent by weight of the first layer of hydrophilic polymer carrier, and a second layer (push layer) comprising about 10 to 80 % w/w of osmopolymers of the second layer, and about 5 to 50 % w/w of osmagens of the second layer, a seal coating comprising 10 to 99 % w/w of the hydrophilic polymer of seal coating, 10 to 99 % w/w of the release retarding agent of semipermeable coating.
It has been found that the osmotic delivery device according to the invention is bioequivalent to commercially available Invega formulation of paliperidone.
The plasma drug profile is measured by means of various pharmacokinetic parameters such as AUC72, Cmax, and Tmax.
"Area under the curve" (AUC) is the area as measured under a plasma drug concentration curve, as generally calculated by the trapezoidal rule.
Cmax refers to a maximum plasma concentration obtained following administration of a dosage form which can be obtained directly from the experimental data.
Similarly Tmax refers to time of maximum measured plasma concentration obtained.
In yet another embodiment, an extended release dosage form of present invention upon oral administration to the human provides a mean plasma concentration of paliperidone not more than 25ng/ml.

In yet another embodiment, process for preparing novel extended release osmotic device includes;
1. Preparation of pull layer:
a. Sift osmopolymer, through ASTM mesh #60.
b. Mix active agent with diluent and cosift through ASTM mesh #60.
c. Sift hydrophilic polymer through #60 and add to step lb.
d. Cosift the material of step 1 a and step 1 c through #60.
e. Prepare the binder solution by dissolving binder in solvent.
f. Mix the blend of step 1d for 10 minutes and granulate using binder solution
of step le.
g. Sift dried granules of Step 1 f through ASTM mesh #30.
h. Sift lubricant through ASTM mesh #60 and add to the blend of Step lg and then mix.
2. Preparation of push layer:
a. Sift osmopolymer, osmogen, and binder through ASTM mesh #30.
b. Sift colorant through ASTM mesh #100 and add to the blend of Step 2a
c. Mix the blend of step 2b for 10 minutes and granulate using organic solvent.
d. Sift dried granules of step 2c through ASTM mesh #30.
e. Sift lubricant through ASTM mesh #60 and add to the blend of Step 2d and
then mix.
3. Compress the lubricated blend into bi-layer core tablets using suitable punch tooling fitted to bilayer compression machine.
4. Prepare seal coating solution by dissolving hydrophilic polymer and one or more pharmaceutically acceptable excipient and coat the core tablets of Step 3.

5. Prepare the non-aqueous solution/dispersion of semi-permeable membrane by dissolving release retarding polymer in mixture of solvents and coat the core tablets of Step 4 and dry the coated tablets for about 24 hours at 40 °C.
6. Drill the holes on the coated tablets of Step 5 using orifice diameter of 0.5 mm and using Laser Drill machine.
7. Prepare opadry dispersion for performing top coating and coat the tablets of step 6 in auto coater.
The extended release pharmaceutical composition of the present invention may be administered to the mammals. Preferably the mammal is a human, and the composition is administered as extended release osmotic tablet. Preferably, the pharmaceutical composition of present invention containing paliperidone or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof may be used in the treatment of Schizophrenia and Schizoaffective disorders. The amount of the paliperidone in the extended release pharmaceutical composition of present invention is preferably an amount that provides a therapeutically effective amount of paliperidone.
Although the present invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
The following examples illustrate specific aspects and embodiments of the invention. The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims
Example I

Sr. No. Ingredients Qty./tab (mg)
Pull layer
1 Paliperidone 6.00

2 Lactose Monohydrate 22,0
3 Polyethylene oxide (low viscosity) 123.5
4. Hydroxy propyl methyl cellulose 5.0
5 Povidone 10
6 Isopropyl alcohol q.s.
7 Magnesium stearate 0,5
Push layer
8 Polyethylene oxide (high viscosity) 54.5
9 Sodium Chloride 23.0
10 Povidone 4.4
11 Isopropyl alcohol q.s.
12 Ferric oxide red 0.6
13 Magnesium Stearate 0.5
Semi-permeable coating
34 Cellulose acetate 398-10NF 32.55
15 Polyethylene glycol 3350 2.45
16 Acetone q.s.
17 Water q.s.
Top coating
18 Opadry 15
19 Water q.s.
Total we ight 300.00
Brief Manufacturing Procedure: Pull layer:
1. Paliperidone, Poylehthylene oxide, Lactose, hydroxyl propyl methyl cellulose were sifted and dry mixed.
2. Binder solution was prepared by dissolving Povidone in Isopropyl alcohol.

3. Blend of step (1) was granulated using binder solution of step (2).
4. The granules obtained in step-3 were dried.
5. The step-4 dry granules were sifted.
6. Magnesium stearate was sifted and blended with step-5 blend. Push Layer:
7. Polyethylene oxide, Povidone, Sodium chloride, and Ferric oxide red were sifted and
dry mixed.

8. Above blend was granulated using Isopropyl alcohol.
9. The granules obtained in step-8 were dried.
10. The step-9 dry granules were sifted.
11. Magnesium stearate was sifted and blended extra granularly with step-10 blend.
12. The step-6& 11 lubricated blends were compressed to form bilayer tablet.
13. Semi permeable membrane coating composition was prepared by dissolving cellulose acetate and polyethylene glycol in a mixture of acetone and water.
14. The semi permeable membrane coating composition of step 13 was coated over core tablet of step 12 to form osmotic tablet.
15. Semipermeble membrane coated tablet of step -14 was drilled mechanically .

16. Opadry was dispersed in water to make top coating composition.
17. Tablet of step -15 was coated by using opadry dispersion of step -16.
Example II

Sr. No. Ingredients Qty./tab (nig)
Pull layer 6.00
1 Paliperidone

2 Lactose Monohydrate 22.0
3 Polyethylene oxide (low viscosity) 123.5
4. Hydroxy propyl methyl cellulose 5.0
5 Povidone 10
6 Isopropyl alcohol q.s.
7 Magnesium stearate 0.5
Push layer
8 Polyethylene oxide (high viscosity) 54.5
9 Sodium Chloride 23.0
10 Povidone 4.4
11 Isopropyl alcohol q.s.
12
13 Ferric oxide red 0.6

Magnesium stearate 0.5
Seal coating
14 Hydroxy Ethyl cellulose 5.63
15 Propylene glycol 1.87
16 Isopropyl alcohol q.s.

17 1 Water q.s.
Semi-permeable coating
18 Cellulose acetate 398-10NF 33.50
19 Polyethylene glycol 4000 2.5
20 Acetone q.s.
21 Water q.s.
Top coating
22 | Opadry 14.5
23 Water q.s.
Total weight 308.00
Brief Manufacturing Procedure: Pull layer:
1. Paliperidone, Polyethylene oxide, Lactose, hydroxyl propyl methyl cellulose & BHT were sifted and dry mixed.
2. Binder solution was prepared by dissolving Povidone in Isopropyl alcohol.
3. Blend of step (1) was granulated using binder solution of step (2).
4. The granules obtained in step-3 were dried.
5. The step-4 dry granules were sifted.
6. Magnesium stearate was sifted and blended with step-5 blend.
Push Layer:
7. Polyethylene oxide. Povidone, Sodium chloride, BHT and Ferric oxide red were sifted and dry mixed.
8. Above blend was granulated using Isopropyl alcohol.
9. The granules obtained in step-8 were dried.
10. The step-9 dried granules were sifted.
] 1. Magnesium Stearate was sifted and blended extra granularly with step-10 blend.
12. The step-6 & 11 lubricated blends were compressed to form bilayer tablet
13. Ethyl cellulose and Polyethylene Glycol were dissolved in a mixture of isopropyl alcohol and acetone to form seal coating composition.

14. Bilayered tablet of step 12 was coated with seal coating composition of step 13 to form a seal coated tablet.
15. Semi permeable membrane coating composition was prepared by dissolving cellulose acetate and polyethylene glycol in a mixture of acetone and water.
16. The semi permeable membrane coating composition of step 15 was coated over seal coated tablet of step 15 to form osmotic tablet.
17. Semipermeble membrane coated tablet of step -16 was drilled mechanically.
18. Opadry was dispersed in water to make top coating composition.
19. Tablet of step -17 was coated by using opadry dispersion of step -18.
Example HI

Sr. No. Ingredients Qty./tab (mg)
Pull layer
1 Paliperidone 6.00
2 Lactose Monohydrate 22.0
3 Polyethylene oxide (Low viscosity) 123.3
4. Hydroxy propyl methyl cellulose 5.0
5. Povidone 10
6 Isopropyl alcohol 0.5
7 Magnesium stearate q.s,
Push layer
8 Polyethylene oxide (High Viscosity) 54.5
9 Sodium Chloride 23.0
10 Povidone 4.4
11 Isopropyl alcohol 0.3
12 Ferric oxide red 0.6
13 Magnesium Stearate q.s.
Seal coating
14 Ethyl cellulose 5.63
15 Polyethylene glycol 1.87
16 Isopropyl alcohol q.s.
17 Acetone q.s.
Semi-permeable coating
18 Cellulose acetate 398-1ONF 33.50
19 Polyethylene glycol 4000 2.5

20 Acetone q.s.
21 Water
Top coating
22 Opadry 14.5
23 Water q.s
Total weight 308.00
Brief Manufacturing Procedure: Pull layer:
1. Paliperidone, Polyethylene oxide, Lactose, hydroxyl propyl methyl cellulose & were sifted and dry mixed.
2. Binder solution was prepared by dissolving Povidone in Isopropyl alcohol.

3. Blend of step (1) was granulated using binder solution of step (2).
4. The granules obtained in step-3 were dried.
5. The step-4 dry granules were sifted.
6. Magnesium stearate was sifted and blended with step-5 blend. Push Layer:

7. Polyethylene oxide, Povidone, Sodium chloride, BHT and Ferric oxide red were sifted and dry mixed.
8. Above blend was granulated using Isopropyl alcohol.
9. The granules obtained in step-8 were dried.
10. The step-9 dried granules were sifted.
11. Magnesium Stearate was sifted and blended extra granularly with step-10 blend.
12. The step-6 & 11 lubricated blends were compressed to form bilayer tablet
13. Hydroxyethyl cellulose and Polyethylene Glycol were dissolved in a purified water to form seal coating composition.
14. Bilayered tablet of step 12 was coated with seal coating composition of step 13 to form a seal coated tablet.

15. Semi permeable membrane coating composition was prepared by dissolving cellulose acetate and polyethylene glycol in a mixture of acetone and water.
16. The semi permeable membrane coating composition of step 15 was coated over seal coated tablet of stepl 5 to form osmotic tablet.
17. Semipermeble membrane coated tablet of step -16 was drilled mechanically.

18. Opadry was dispersed in water to make top coating composition.
19. Tablet of step -17 was coated by using opadry dispersion of step -18.
Example IV

Sr. No. Ingredients Qty./tab (mg)
Pull Layer
1 Paliperidone 6.00
2 Lactose monohydrate 16.98
Polyox (Low Viscosity) 100.31
4. Hydroxy propyl methyl cellulose 4.07
5. Povidone (K29/K32) 8.14
6 Isopropyl alcohol q.s.
7 Stearic acid 1.500
Push Layer
8 Polvox (High Viscosity) 85.37
9 Sodium Chloride 36.02
10 Povidone (K29/K32) 6.470
11 Ferric oxide red 0.94
12 Isopropyl alcohol q.s.
13 Stearic Acid 1.200
Seal Coa tine
14 Hydroxy ethyl cellulose 9.61
15 Propylene Glycol 1.07
16 Purified water q.s.
Semipermeable Coating
17 Opadry CA Clear (CA:PEG3350-90:10) 58.74
18 Acetone q.s.
19 Water q.s.
Top Coating

20 Opadry Yellow 31.58
21 Water q.s.
Total weight of the Tablet 348
Brief Manufacturing Procedure: Pull layer:
1. Paliperidone, Polyethylene oxide, Lactose, hydroxyl propyl methyl cellulose & were sifted and dry mixed.
2. Binder solution was prepared by dissolving Povidone in Isopropyl alcohol.

3. Blend of step (1) was granulated using binder solution of step (2).
4. The granules obtained in step-3 were dried.
5. The step-4 dry granules were sifted.
6. Stearic Acid was sifted and blended with step-5 blend. Push Layer:

7. Polyethylene oxide, Povidone, Sodium chloride, BHT and Ferric oxide red were sifted and dry mixed.
8. Above blend was granulated using Isopropyl alcohol.
9. The granules obtained in step-8 were dried.
10. The step-9 dried granules were sifted.
11. Stearic Acid was sifted and blended extra granularly with step-10 blend.
12. The step-6 & 11 lubricated blends were compressed to form bilayer tablet
13. Hydroxyethyl cellulose and Polyethylene Glycol were dissolved in a purified water to form seal coating composition.
14. Bilayered tablet of step 12 was coated with seat coating composition of step 13 to form a seal coated tablet.
15. Semi permeable membrane coating composition was prepared by dissolving
cellulose acetate and polyethylene glycol in a mixture of acetone and water.

16. The semi permeable membrane coating composition of step 15 was coated over seal coated tablet of step 15 to form osmotic tablet.
17. Semipermeble membrane coated tablet of step -16 was drilled mechanically.

18. Opadry was dispersed in water to make top coating composition.
19. Tablet of step -17 was coated by using opadry dispersion of step -18.
Example V

Sr. No. Ingredients Qty./tab (mg)
Pull layer
1 Paliperidone 6.00
2 Lactose Monohydrate 22.0
3 Polyethylene oxide (Low viscosity) 123.3
4. Hydroxy propyl methyl cellulose 5.0
5 Povidone 10
6 Isopropyl alcohol q.s.
7 Butylated hydroxytoluene 0.20
8 Magnesium stearate 0.5
Push lay er
9 Polyethylene oxide (High Viscosity) 54.5
10 Sodium Chloride 23.0
11 Povidone 4.4
12 Isopropyl alcohol q.s.
13 Butylated hydroxytoluene 0.20
14 Ferric oxide red 0.6
15 Magnesium stearate 0.5
Seal coating
16 Hydroxy Ethyl cellulose 11.70
17 Propylene glycol 1.30
18 Isopropyl alcohol q.s.
19 Water q.s.
Semi-permeable coating
20 Cellulose acetate 398-1ONF 37.8

21 Polyethylene glycol 4000 4.2
22 Acetone q.s.
23 Water q.s.
Top coating
24 Opadry 15
25 Water q.s.
Total weight 320.00
Brief Manufacturing Procedure: Pull layer:
1. Paliperidone, Poylehthylene oxide, Lactose, hydroxyl propyl methyl celluliose &
BHT were sifted and dry mixed.
2. Binder solution was prepared by dissolving Povidone in Isopropyl alcohol.
. 3. Blend of step (1) was granulated using binder solution of step (2).
4. The granules obtained in step-3 were dried.
5. The step-4 dry granules were sifted.
6. Magnesium stearate was sifted and blended with step-5 blend. Push Layer:

7. Polyethylene oxide, Povidone, Sodium chloride, BHT and Ferric oxide red were sifted and dry mixed.
8. Above blend was granulated using Isopropyl alcohol.
9. The granules obtained in step-8 were dried.
10. The step-9 dry granules were sifted.
11. Magnesium stearate was sifted and blended extra granularly with step-10 blend.
12. The step-6& 11 lubricated blends were compressed to form bilayer tablet.
13. Hydroxy ethyl cellulose and Propylene Glycol were dissolved in a mixture of isopropyl alcohol and water to form seal coating composition.

14. Bilayered tablet of step 12 was coated with seal coating composition of step 13 to form a seal coated tablet,
15. Semi permeable membrane coating composition was prepared by dissolving cellulose acetate and polyethylene glycol in a mixture of acetone and water.
16. The semi permeable membrane coating composition of step 15 was coated over seal coated tablet of step 14 to form osmotic tablet.
17. Semipermeble membrane coated tablet of step -16 was drilled.

18. Opadry was dispersed in water to make top coating composition.
19. Tablet of step -17 was coated by using opadry dispersion of step -18.
Example VI

Sr. No. Ingredients Qty./tab (mg)
Pull layer
1 Paliperidone 6.00
2 Lactose Monohydrate 22.0
3 Polyethylene oxide (Low viscosity) 123,3
4. Hydroxy propyl methyl cellulose 5.0
5. Povidone 10
6 Isopropyl alcohol 0.5
7 Butylated hydroxytoluene 0.20
8 Magnesium stearate q.s.
Push layer
9 Polyethylene oxide (High Viscosity) 54.5
10 Sodium Chloride 23.0
11 Povidone 4.4
12 Isopropyl alcohol 0.3
13 Butylated hydroxytoluene 0.20
14 Ferric oxide red 0.6
15 Magnesium stearate q.s.
Seal coating
16 Ethyl cellulose 11.70
17 Polyethylene glycol 1.30

18 Isopropyl alcohol q.s.
19 Acetone q.s.
Semi-permeable coating
20 Cellulose acetate 398-10NF 37.8
21 Polyethylene glycol 4000 4.2
22 Acetone q.s.
23 Water
Top coating
24 Opadry 15
25 Water q.s
Total weight 320.00
Brief Manufacturing Procedure: Pull layer:
1. Paliperidone, Polyethylene oxide, Lactose, hydroxyl propyl methyl cellulose & BHT were sifted and dry mixed.
2. Binder solution was prepared by dissolving Povidone in Isopropyl alcohol.

3. Blend of step (1) was granulated using binder solution of step (2).
4. The granules obtained in step-3 were dried.
5. The step-4 dry granules were sifted.
6. Magnesium stearate was sifted and blended with step-5 blend. Push Layer:

7. Polyethylene oxide, Povidone, Sodium chloride, BHT and Ferric oxide red were sifted and dry mixed.
8. Above blend was granulated using Isopropyl alcohol.
9. The granules obtained in step-8 were dried.
10. The step-9 dried granules were sifted.
11. Magnesium stearate was sifted and blended extra granular})' with step-10 blend.

12. The step-6 & 11 lubricated blends were compressed to form bilayer tablet
13. Ethyl cellulose and Polyethylene Glycol were dissolved in a mixture of isopropyl alcohol and acetone to form seal coating composition.
14. Bilayered tablet of step 12 was coated with seal coating composition of step 14 to form a seal coated tablet.
15. Semi permeable membrane coating composition was prepared by dissolving cellulose acetate and polyethylene glycol in a mixture of acetone and water.
16. The semi permeable membrane coating composition of step 15 was coated over seal coated tablet of step 14 to form osmotic tablet.
17. Semipermeble membrane coated tablet of step -16 was drilled.

18. Opadry was dispersed in water to make top coating composition.
19. Tablet of step -17 was coated by using opadry dispersion of step -18.
Dissolution study:
The osmotic tablets of paliperidone according to the invention and commercially available Invega® (reference) were tested for a drug release in 500ml of modified SGF for 24 hours having pH of 1.0 using USP Dissolution Apparatus 11 with 50 RPM. The samples were periodically withdrawn and analyzed for paliperidone content. The comparative dissolution profile of examples I, II. III, IV and commercially available Invega® (reference) is given in table-1
Table-1

Apparatus: USP II, Media: Modified SGF pH 1.0, RPM: 50, Volume: 500mL
Time Points Reference Product (Invega 6mg) Example I Example II Example HI Example IV

% Cumulative drug release
0 0 0 0 0 0
4 4.3 13.5 14.2 1.7 0.6
6 9.7 26.4 26.2 11.4 5.6
8 17.6 39.2 37.9 20.8 20.1

12 37.2 '63.5 59.5 49.0 45.7
16 60.2 74.5 76.5 68.3 70.6
18 71.6 82.4 82.1 75.2 83.6
20 84.5 88.5 87.8 80.6 93.3
22 95.6 92.2 91.5 84.8 100.0
24 102.7 96.8 94.1 87.9 100.7
The paliperidone osmotic tablets of example 4 and commercially available Invega (reference) were tested for a drug release in 250ml of modified SGF for 24 hours having pH of 1.0 using USP Dissolution Apparatus III with reciprocation rate of 20dpm. The samples were periodically withdrawn and analyzed for paliperidone content. The comparative dissolution profile of examples IV and commercially available Invega (reference) is given in table-2
Table-2

Apparatus: USP III, Media: Modified SGF pH 1.0, Amplitude: 10cm, Reciprocation Rate: 20dpm, Volume: 250mL
Reference Formulation (6mg) Unichem Formulation (6mg)
Time points(hrs) % Cumulative drug release % Cumulative drug release
0 0 0
2 1.9 0.3
8 23.2 18.2
12 45.2 45.9
14 57.4 58.7
18 82.7 84.2
24 102.2 100.6
The paliperidone osmotic tablets of example 4 and commercially available Invega (reference) were tested for a drug release in 250ml of phosphate buffer for 24 hours having pH of 6.8 using USP Dissolution Apparatus III with reciprocation rate of 20dpm. The samples were periodically withdrawn and analyzed for paliperidone content. The comparative dissolution profile of examples IV and commercially available Invega® (reference) is given in table-3

Table-3

Apparatus: USP III, Media: phosphate buffer pH6.8, Amplitude: 10cm, Reciprocation Rate: 20dpm, Volume: 250mL
Reference Formulation ( 6mg) Unichem Formulation (6mg)
Time points(hrs) % Cumulative drug release % Cumulative drug release
0 0 0
2 1.8 0.5
8 22.9 17.8
12 47.0 46.6
14 61.0 60.1
18 90.2 85.6
24 101.9 98.8
Bio study:
The pharmacokinetics study to determine the concentration-time plasma profile was done on healthy subjects. The study, on example IV as sample and innovator formulation Invega® as test 6mg, was conducted using full replicate design on 16 volunteers in fasting and fed condition.
Mean pharmacokinetic data of example IV and commercially available Invega® (reference) in fasting condition is given in table-4
Table-4

Treatment Test Cmax AUC72 T max
Test Mean 13.255 431.353 23.37

%CV 36.4 39.2 10.5
Reference Mean 14.105 469.479 24.10

%CV 26.8 27.7 9.4
Geometric least square mean of example IV (Test) and commercially available Invega® (reference) in fasting condition is given in table-5

Tabie-5

Geometric least square mean
Treatment Ln AUC 72 (ng.hr.ml-1)
Ln Cmax(ng.ml-1)

Test 398.685 12.387
Reference 453.902 13.630
T/R ratio forAUC 87.83% 90.88
Mean pharmacokinetic data of example IV (Test) and commercially available Invega® (reference) in fed condition is given in table-6
TabIe-6

Treatment Test Cmax AUC72 Tmax
Test Mean 16.976 550.053 22.42

%cv 62.1 72.0 16.3
Reference Mean 16.018 492.452 J 23.45
%CV 50.6 43.4 6.7
Geometric least square mean of example IV (Test) and commercially available Invega® (reference) in fed condition is given in table-7
Table-7

Geometric least square mean
Treatment Ln AUC 72 Ln Cmax(ng.ml-1) (ng.hr.ml-1)

Test 350.788 12.253
Reference 399.918 12.839
T/R ratio for AUC 87.72% 95.44%

We claim
1. An oral extended release dosage form as an osmotic delivery device for the delivery
of paliperidone or pharmaceutical!)' acceptable salts thereof that comprising:
a. a core comprising of drug layer and push layer;
b. seal coating comprising of film forming hydrophilic polymer and one or more
pharmaceutically acceptable excipients, wherein seal coating prevents entry of
organic solvent in to the tablet core,
c. semipermeable membrane around the said seal coating, which consists of a layer
of pharmaceutically acceptable release retardant water insoluble polymers,
optionally inactive pharmaceutical ingredient, optionally pharmaceutically
acceptable excipients like pore forming agent or flux enhancing agents, wherein
release retardant water insoluble polymers are not enteric polymers.
d. at least one passageway in the wall communicating with drug layer and exterior of
the device for delivery of paliperidone; and
e. a film coating surrounding a device.
2. The oral extended release dosage form according to claim 1, wherein the semipermeable membrane is permeable to passage of exterior fluid present in the surrounding and impermeable to passage of paliperidone.
3. The oral extended release dosage form according to claim 1 wherein said osmopolymer is selected from a group comprising of polyethylene oxide, polymethylene oxide, carboxymethyl cellulose, hydroxpropyl methyl cellulose and xanthan gum.

4. The oral extended release dosage form according to claim 1 wherein said osmogen is selected from a group comprising of sodium chloride, potassium chloride, lithium chloride, magnesium sulfate, magnesium chloride, mannitol, glucose, lactose, sorbitol, organic salts and carbohydrates and the combination's thereof.
5. The oral extended release dosage form according to claim 1 wherein said organic solvent is acetone,

6. The oral extended release dosage form according to claim 1 wherein film forming
hydrophilic polymers used in seal coating is selected from group comprising of
. cellulose polymers and their derivatives , polysaccharides and their derivatives, polyalkylene oxides, polyethylene glycols, chitosan, poly(vinyl alcohol), xanthan gum, maleic anhydride copolymers, poly( vinyl pyrrolidone), starch and starch- based polymers, poly(2-ethyl-2-oxazoline), poly(ethyieneimine), polyurethane hydrogels, gums, alginates, lectins, carbopol, and combinations comprising one or more of the foregoing polymers.
7. The oral extended release dosage form according to claim 1, wherein film forming hydrophilic polymer used in seal coating is selected from cellulose and derivatives thereof.
8. The oral extended release dosage form according to claim 1, wherein film forming hydrophilic polymer used in seal coating is selected from cellulose such as micro crystalline cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropy cellulose, methylcellulose, ethylcellulose, hydroxyefhylmethylcellulose, ethylhydroxy-ethylcellulose, and carboxymethylcellulose.

9. The oral extended release dosage form according to claim 1, wherein film forming hydrophilic polymer is hydroxyethyl cellulose.
10. The oral extended release dosage form according to claim 1, wherein semipermeable polymer is selected from group comprising of cellulose derivatives like hydroxyl ethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose. hydroxypropyl cellulose; polyvinyl alcohols, polyethylene oxides, carbopols; natural polysaccharide gums like guar gum, xanthan gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, sodium alginate, carrageenan, ceratonia, sodium calcium alginate and alginic acid and mixture thereof.
11. The oral extended release dosage form according to claim 1 wherein said first and second layers each further comprise a lubricant, a glidant, a colorant and one or more pharmaceutically acceptable excipients.

12. The oral extended release dosage form according to claim 1 wherein diameter of said passageway is from about 0.2 mm to 0.8 mm.
13. The oral extended release dosage form according to claim 1 upon oral administration to the human provides a mean plasma concentration of paliperidone not more than
25ng/ml.