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

EXTENDED RELEASE PHARMACEUTICAL COMPOSITIONS OF PALIPERIDONE
TECHNICAL FIELD OF THE INVENTION
The present invention relates to the extended release pharmaceutical compositions of Paliperidone. More particularly, the present invention relates to a gastric retentive 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 O with relative molecular weight of 426.49. Its chemical name is (±)-3-
23 27 4 3
[2-[4-(6-fluoro-I, 2-benzisoxazol-3-yI)-l-piperidinyl]ethyl]-6, 7, 8, 9-tetrahydro-9-hydroxy-2-methyl-4Hpyrido[l, 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 increase 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, 3.0, 6.0, 9.0 & 12.0 mg strengths, suspension for parenteral administration of 39mg/0.25ml, 78mg/0.5ml, 117mg/0.75ml, 156mg/ml and 234mg/L5ml 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,

3.0, 6.0 & 9.0 mg strengths in the USA and by Janssen Cilag Ltd. as Invega prolonged release tablets in 1.5, 3.0, 6.0, 9.0 & 12.0 mg strengths in Europe. Extended release suspension for Injection of paliperidone is marketed by Ortho Mcneil Janssen under the brand name Invega Sustenna in 39mg/0.25ml, 78mg/0.5ml, 117mg/0.75m], 156mg/ml and 234mg/1.5ml strengths in the USA. Low oral bioavailability of paliperidone from the innovator formulation of paliperidone i.e., extended/prolonged release tablets which employs push-pull osmotic technology may be due to release of major fraction of the drug in the distal parts of the gastro intestinal tract where it is less absorbed. As paliperidone is having appreciable solubility in the acidic pH and in addition as it get absorbed more preferentially from the proximal parts of the gastro intestinal tract, development of drug delivery systems which can reside in the gastric region for prolonged period of time is a suitable option for enhancing the oral bioavailability of paliperidone.
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 multi-particulate 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 pharmaceutical^ acceptable excipients wherein granules are subject 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 2009/0087487 Al (Michael Fox et al.; April, 2009) discloses pharmaceutical composition for the sustained release of paliperidone, wherein the manufacturing of disclosed pharmaceutical composition utilizes speciality equipment other than conventional manufacturing equipment and ultimately leading to increased manufacturing cost of the final drug product.
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.
Even though many technologies with different compositions are available for oral extended release systems of paliperidone, there is a need for the development of a therapeutically efficient delivery systems for paliperidone because of the low oral bioavailability from these systems.
The present invention relates to novel extended release solid oral pharmaceutical composition, which resides in the gastric region for prolonged period of time, comprising paliperidone or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof and novel method of its manufacture thereof.
OBJECT OF THE INVENTION
The object of the present invention is to provide extended release pharmaceutical compositions of paliperidone or its pharmaceutically acceptable salts, solvates, enantiomers or mixtures thereof.

Another object of the present invention is to provide an extended release
pharmaceutical composition dosage form of paliperidone suitable for oral
administration.
Yet another object of the present invention is to provide various methods of
manufacture of extended release pharmaceutical composition comprising paliperidone
in therapeutically effective amount along with other pharmaceuticaily acceptable
excipients.
Further objective of the present invention is to provide extended release
pharmaceutical compositions of paliperidone useful for the treatment of
Schizophrenia and Schizoaffective disorders.
Still further objective of the present invention is to impart gastric retention property to
the pharmaceutical composition by dry or compression or press coating or film
coating of solid oral dosage form with coating composition containing release
retardant polymers
Still further objective of the present invention is to impart floating property to
pharmaceutical composition by adding gas-generating agents in the dry or
compression or press coating.
SUMMARY OF THE INVENTION
The present invention relates an extended release pharmaceutical composition of paliperidone comprising: a) a core comprising a therapeutically effective amount of paliperidone or its pharmaceuticaily acceptable salts, solvates, enantiomers or mixtures thereof along with pharmaceuticaily acceptable excipients; b) Coating around the said core which comprises of a layer of pharmaceuticaily acceptable release retardant polymers, optionally paliperidone, optionally pharmaceuticaily acceptable excipients.
Further, the coating around the said core comprises of dry or compression or press coating or film coating.
Furthermore, the present invention also provides processes for the preparation of pharmaceutical composition which comprises the steps of
a. Sifting of active pharmaceutical ingredient and pharmaceuticaily acceptable
excipients.
b. Dry mixing or granulation of ingredients.
c. Blending and lubrication.

d. Compression of the lubricated blend of step (c) into tablets.
e. Coating of the compressed tablets of step (d).
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: A comparative drug release profile of Example 3 and Invega® 6mg in Modified SGF, pH 1.0 [NaCl (0.2% w/w) in 0.0825N HC1], 500ml, 50RPM, Apparatus II at 37±0.5°C.
Figure 2: A comparative drug release profile of Example 4 and Invega 6mg in Modified SGF, pH 1.0 [NaCl (0.2% w/w) in 0.0825N HC1], 500ml, 50RPM, Apparatus II at 37±0.5°C.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to an extended release pharmaceutical composition of
Paliperidone.
The present invention relates to an extended release pharmaceutical composition in
the form of dry or compression or press coating or film coated tablet systems.
In accordance with the present invention, novel extended release pharmaceutical
composition comprises:
(A) Compressed core, which essentially contains,
1. Active pharmaceutical ingredient,
2. Pharmaceutically acceptable diluents,
3. Pharmaceutically acceptable binders,
4. Pharmaceutically acceptable glidants and lubricants,
5. Optionally pharmaceutically acceptable anti-oxidants,
6. Optionally pharmaceutically acceptable acidulants,
7. Optionally pharmaceutically acceptable disintegrants,
8. Optionally pharmaceutically acceptable colorants &
(B) Dry or compression or press coating around the said core tablet, which comprises of a layer of pharmaceutically acceptable release retardant polymers, optionally active pharmaceutical ingredient, optionally pharmaceutically acceptable excipients like binders, gas generating agents, diluents, colorants, pore forming agents, lubricants and glidants. Or

(C) Film coating around the said core tablet, which comprises of pharmaceutically acceptable release retardant polymers, optionally active pharmaceutical ingredient, optionally pharmaceutically acceptable excipients like pH dependant polymers or pH independent polymers, plasticizers, opacifiers, colorants and antitacking agent.
In accordance with the present invention, manufacturing methods used are one or more of wet granulation technique, dry granulation technique or direct compression of active pharmaceutical ingredient along with one or more of pharmaceutically acceptable excipients.
In accordance with the present invention, coating methods used are one or more of dry or compression or press coating or film coating of immediate release core.
Method of manufacturing by wet granulation method includes, preparation of drug granulates comprising, active pharmaceutical ingredient, one or more of pharmaceutically acceptable excipients by using granulating solution containing binder. Wet granulation method includes, spray granulation using fluidized bed processor or conventional wet granulation using rapid mixer granulator. After drying, milling and sieving, the resulted drug granulates are mixed with one or more of other extra-granular pharmaceutically acceptable excipients, lubricated and then compressed into core tablets. Dry or compression or press coating of the compressed core tablets is by using one or more of pharmaceutically acceptable release retardant polymers, optionally active pharmaceutical ingredient, optionally pharmaceutically acceptable excipients like binders, gas generating agents, diluents, colorants, pore forming agents, lubricants and glidants. Or film coating of the compressed core tablets is by using one or more of pharmaceutically acceptable release retardant polymers, optionally active pharmaceutical ingredient, optionally pharmaceutically acceptable excipients like pH dependant polymers or pH independent polymers, plasticizers, opacifiers, colorants and antitacking agent.
Method of manufacturing by dry granulation method includes, preparation of drug granulates by slugging the uniformly blended mixture of active pharmaceutical ingredient and one or more of pharmaceutically acceptable excipients. After sieving, the resulted drug granulates are mixed with one or more of other extra-granular

pharmaceutically acceptable excipients, lubrication and then compression into core tablets. Dry or compression or press coating of the compressed core tablets is by using one or more of pharmaceutically acceptable release retardant polymers, optionally active pharmaceutical ingredient, optionally pharmaceutically acceptable excipients like binders, gas generating agents, diluents, colorants, lubricants and glidants. Or film coating of the compressed core tablets is by using one or more of pharmaceutically acceptable release retardant polymers, optionally active pharmaceutical ingredient, optionally pharmaceutically acceptable excipients like pH dependant polymers or pH independent polymers, plasticizers, opacifiers, colorants and antitacking agent.
Method of manufacturing by direct compression includes mixing of active pharmaceutical ingredient with other pharmaceutically acceptable excipients, lubrication, and then compression into core tablets. Dry or compression coating of the compressed core tablets is by using one or more of pharmaceutically acceptable release retardant polymers, optionally active pharmaceutical ingredient, optionally pharmaceutically acceptable excipients like binders, gas generating agents, diluents, colorants, lubricants and glidants. Or film coating of the compressed core tablets is by using one or more of pharmaceutically acceptable release retardant polymers, optionally active pharmaceutical ingredient, optionally pharmaceutically acceptable excipients like pH dependant polymers or pH independent polymers, plasticizers, opacifiers, colorants and antitacking agent.
In accordance with the present invention, novel extended release pharmaceutical composition comprises, paliperidone or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof and at least one or more pharmaceutically acceptable excipients like release retardant polymers, diluents, acidulants, anti-oxidants, gas generating agents disintegrants, binders, glidants, lubricants, pore forming agent, plasticizers, antitacking agents, opacifiers, solvents and one or more of coating agents for altering the hydrodynamic properties of the tablet and for controlling the release of the drug from tablet.
Release retardant polymers used in the present invention may be one or more 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; poly (butyl
methacrylate, (2-dimethyl aminomethyl) methacrylate, methyl methacrylate) 1:2:1,
poly (methacrylicacid, methyl methacrylate) 1:1, poly (ethyl acrylate, methacryiic
acid) 1:1, poly (methacryiic acid, methyl methacrylate) 1:2, poly (ethylacrylate,
methyl methacrylate, trimethylammonioethylmethacrylate chloride) 1:2:0.2, poly
(ethylacrylate, methyl methacrylate, trimethylammonioethylmethacrylate chloride)
1:2:0.1, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate,
hydroxypropylmethyl cellulose acetate succinate, dimethyl phthalate, diethyl
phthalate, dibutyl phthalate, and mixture thereof. More preferred release retarding
polymer used in the present invention are at least one or more of the cellulose
derivatives like hydroxyl ethyl cellulose, ethyl cellulose, methyl cellulose,
hydroxypropyl methylcellulose, hydroxypropyl cellulose; polyethylene oxides,
carbopols; natural polysaccharide gums like guar gum, xanthan gum, sodium alginate,
carrageenan, and alginic acid; poly (butyl methacrylate, (2-dimethyl aminomethyl)
methacrylate, methyl methacrylate) 1:2:1, poly (methacrylicacid, methyl
methacrylate) 1:1, poly (ethyl acrylate, methacryiic acid) 1:1, poly (methacryiic acid,
methyl methacrylate) 1:2, poly (ethylacrylate, methyl methacrylate,
trimethylammonioethyl methacrylate chloride) 1:2:0.2, poly (ethylacrylate, methyl
methacrylate, trimethylammonioethylmethacrylate chloride) 1:2:0.1, cellulose acetate
phthalate, hydroxypropylmethyl cellulose phthalate and mixture thereof. Most
preferred release retarding polymer used in the present invention are at least one or
more of the cellulose derivatives like hydroxyl ethyl cellulose, ethyl cellulose, methyl
cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose; polyethylene
oxides, carbopols; poly (methacrylicacid, methyl methacrylate) 1:1, poly (ethyl
acrylate, methacryiic acid) 1:1, poly (methacryiic acid, methyl methacrylate) 1:2, poly
(ethylacrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride)
1:2:0.2, poly (ethylacrylate, methyl methacrylate and
trimethylammonioethylmethacrylate chloride) 1:2:0.1 and mixture thereof.
Diluents used in the present invention are at least one or more of the microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, 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, mannitol, magnesium succinate and potassium acid phosphate. More preferred diluent used in the present invention are at least one or more of the microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, anhydrous lactose, directly compressible lactose, starch 1500, calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, xylitol, dextrose, compressible sugar, dextrin, starch, powdered cellulose, sodium alginate, tragacanth, sodium chloride, potassium chloride and mannitol.
Most preferred diluent used in the present invention are at least one or more of the microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, anhydrous lactose, directly compressible lactose, compressible sugar, powdered cellulose and mannitol.
Acidulants used in the present invention are at least one or more of fumaric acid, citric acid, tartaric acid, maleic acid, anhydrous ascorbic acid, and the like. More preferred acidulant used in the present invention are at least one or more of the citric acid, tartaric acid, malic acid, and anhydrous ascorbic acid. Most preferred acidulant used in the present invention are at least one or more of the citric acid, tartaric acid and malic acid.
Antioxidants used in the present invention are at least one or more of substituted
phenolic compounds such as butylated hydroxyanisole, propyl gallate and butylated
hydroxytoluene (BHT) and ascorbic acid, ascorbyl palmitate, alpha-tocopherol and
biflavonoids
More preferred antioxidant used in the present invention is at least one or more of the
substituted phenolic compounds such as butylated hydroxyanisole, propyl gallate,
butylated hydroxytoluene (BHT) and ascorbic acid.
Most preferred antioxidant used in the present invention is at least one or more of the
substituted phenolic compounds such as butylated hydroxyanisole, butylated
hydroxytoluene (BHT) and ascorbic acid.

Gas generating agents used in the present invention are at least one or more of sodium
bicarbonate, sodium carbonate, calcium carbonate, potassium carbonate, potassium
bicarbonate, sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate
and arginine carbonate,
More preferred gas generating agent of dry or compression coating in the present
invention are at least one or more of the selected from at least on or more of sodium
bicarbonate, sodium carbonate potassium carbonate, potassium bicarbonate, sodium
sesquicarbonate, sodium glycine carbonate and L-lysine carbonate.
Most preferred gas generating agent of dry or compression coating in the present
invention is sodium bicarbonate and sodium carbonate.
Disintegrants used in the present invention may be one or more of the croscarmellose
sodium, crospovidone, sodium starch glycollate, low-substituted hydroxypropyl
cellulose, starch, pregelatinized starch, microcrystalline cellulose, emcosoy (Soya
polysaccharide) and potassium polacrilin.
More preferred disintegrant used in the present invention are at least one or more of
the croscarmellose sodium, crospovidone, sodium starch giycollate, low-substituted
hydroxypropyl cellulose, starch and pregelatinized starch.
Most preferred disintegrant used in the present invention are at least one or more of
the croscarmellose sodium, crospovidone, sodium starch glycollate, low-substituted
hydroxypropyl cellulose and pregelatinized starch.
Binders used in the present invention may be at least one or more of 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 and magnesium aluminum silicate. More preferred binder used in the present invention are at least one or more of the microcrystalline cellulose, povidone, pyrrolidone, co-povidone, acacia gum, guar gum, xanthan gum, gellan gum, gelatin, glucose, sugar, dextrin, sorbitol, maltose,

pregelatinised starch, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, hyroxyethyl cellulose, carbomers, carrageenan, ceratonia, chitosan and poloxamer.
Most preferred binder used in the present invention are at least one or more of the microcrystalline cellulose, povidone, pyrrolidone, co-povidone, acacia gum, guar gum, xanthan gum, sugar, dextrin, pregelatinised starch, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, hyroxyethyl cellulose and carbomers.
Glidants used in the present invention may be at least one or more of colloidal silicon
dioxide, talc, stearic acid, magnesium stearate, calcium stearate, hydrogenated castor
oil, sodium lauryl sulfate, precipitated silicon dioxide and starch.
More preferred glidant used in the present invention are at least one or more of the
colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate,
precipitated silicon dioxide and starch.
Most preferred glidant used in the present invention are at least one or more of the
colloidal silicon dioxide, talc, magnesium stearate, precipitated silicon dioxide and
starch.
Lubricants used in the present invention are one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, magnesium lauryl sulfate, wax, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, palmitic acid, poloxamer, sodium benzoate and sodium lauryl sulfate. More preferred lubricant used in the present invention are at least one or more of the magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, magnesium lauryl sulfate, glyceryl behenate and glyceryl palmitostearate.
Most preferred lubricant used in the present invention are at least one or more of the magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, magnesium lauryl sulfate and glyceryl behenate.

In accordance with the present invention, the tablet is coated, wherein coating is
applied for altering the hydrodynamics of the tablets and for controlling the release of
the drug. The coating layers over the tablet may be applied as dry or compression or
press coating or film coating.
Pore formers or channeling agents are used in the present invention are at least one or
more of sodium chloride, potassium chloride, magnesium sulfate, magnesium
chloride, sodium sulfate, fructose, sucrose, sorbitol, xylitol, dextrose, urea, inositol,
lactose, mannitol, magnesium succinate, calcium phosphate (dibasic/tribasic), calcium
sulphate, calcium sulphate dihydrate, potassium acid phosphate and povidone and the
like.
More preferred channeling agents used in the present invention are at least one or
more of sodium chloride, potassium chloride, fructose, sucrose, sorbitol, xylitol,
dextrose, inositol, lactose, mannitol, magnesium succinate, calcium phosphate
(dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, potassium acid
phosphate and povidone and the like.
Most preferred channeling agents used in the present invention are at least one or
more of lactose, povidone, and the like.
In accordance with the present invention, multiple coating layers are applied for retarding the drug release from the immediate release core.
In accordance with the present invention, rate controlling or release retarding coating agent comprises release retardant polymer, plasticizers, opacifiers, colorants and antitacking agents.
According to the present invention, pH independent coating agent for controlling the drug release in gastro intestinal tract comprises, pH independent polymer (non-enteric polymer), plasticizer and optionally opacifier and colorant.
According to the present invention, pH independent polymer or release controlling or release retarding fdm forming agent contains one or more of ethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyethylene glycol, polyvinyl alcohol, povidone, chitosan, maltodextrin, isomalt, ammonium alginate, gelatin, carrageen, ethyl lactate, cellulose acetate, poly(ethyl acrylate, methyl methacrylate,

trimethylammonioethyl methacrylate chloride) 1:2:0.2 or Ammonio Methacrylate Copolymer, Type A or 1:2:0.1, poly (ethyl acrylate, methyl methacrylate) 2:1. More preferred release controlling or release retarding film forming agent used in the present invention contains one or more of ethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, povidone, ammonium alginate, gelatin, carrageen, ethyl lactate, and poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 or Ammonio Methacrylate Copolymer, Type A.
Most preferred protective film forming agent used in the present invention contains one or more of ethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol and povidone and poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 or Ammonio Methacrylate Copolymer, Type A.
According to the present invention, pH dependent coating agent for controlling the drug release in gastro intestinal tract comprises, pH dependent polymer (enteric polymer), plasticizer and optionally opacifier and colorant. According to the present invention, pH dependant enteric polymers include one or more of acrylate co-polymers like dimethyl aminoethyl methylmethacrylate, other neutral methacrylic acid esters, methacrylic co-polymer like poly (ethyl acrylate, methyl methacrylate) 2:1, poly (methacrylicacid, methyl methacrylate) 1:1, poly (ethyl acrylate, methacrylic acid) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2, poly (methacrylic acid, methyl methacrylate, methacrylic acid) 7:3:1, poly (ethylaery]ate, methyl methacrylate, trimethylammonioethylmethacrylate chloride) 1:2:0.2, poly (ethylacrylate, methyl methacrylate,
trimethylammonioethylmethacrylate chloride) 1:2:0.1, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polymethacrylates, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, and/or mixture thereof.
More preferably pH dependant polymers used in the present invention are at least one or more of the acrylate co-polymers like dimethyl aminoethyl methylmethacrylate, other neutral methacrylic acid esters, methacrylic co-polymer like poly (ethyl acrylate, methyl methacrylate) 2:1, poly (methacrylicacid, methyl methacrylate) 1:1, poly (ethyl acrylate, methacrylic acid) 1:1, poly (methacrylic acid, methyl methacrylate)

1:2, poly (methacrylic acid, methyl methacrylate, methacrylic acid) 7:3:1, poly (ethylacrylate, methyl methacrylate, trimethylammonioethylmethacrylate chloride) 1:2:0.2, poly (ethylacrylate, methyl methacrylate,
trimethylammonioethylmethacrylate chloride) 1:2:0.1, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, diethyl phthalate, dibutyl phthalate, and/or mixture thereof.
Most preferably the pH dependant polymers used in the present invention are at least one or more of the acrylate co-polymers like dimethyl aminoethyl methylmethacrylate, other neutral methacrylic acid esters, methacrylic co-polymer like poly (ethyl acrylate, methyl methacrylate) 2:1, poly (rhefhacrylicacid, methyl methacrylate) 1:1, poly (ethyl acrylate, methacrylic acid) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2, poly (methacrylic acid, methyl methacrylate, methacrylic acid) 7:3:1, poly (ethylacrylate, methyl methacrylate,
trimethylammonioethylmethacrylate chloride) 1:2:0.2, poly (ethylacrylate, methyl methacrylate and trimethylamrnonioethylmethacrylate chloride) 1:2:0.1 and/or mixture thereof.
Opacifiers used in the present invention may be one or more of titanium dioxide, silicates such as talc and aluminium silicate, ethylene glycol palmitostearate, acetates such as zinc acetate, carbonates such as magnesium carbonate, calcium carbonate, stearates such as aluminium stearate and zinc stearate, sulfates such as calcium sulfate, oxides such as magnesium oxide and hydroxides such as aluminiuim hydroxides.
More preferred opacifier used in the present invention may be one or more of titanium dioxide, silicates such as talc and aluminium silicate, ethylene glycol carbonates such as magnesium carbonate, calcium carbonate, stearates such as aluminium stearate and zinc stearate.
Most preferred opacifier used in the present invention may be one or more of titanium dioxide, silicates such as talc and aluminium silicate, stearates such as aluminium stearate and zinc stearate.
Plasticizers used in the present invention may be one or more of triethyl citrate, polyethylene glycols, propylene glycol, glycerine, caster oil, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, acetyltributyl citrate, dimethyl phthalate,

diethyl phthalate, dibutyl phthalate, dibutyl sebacate, glyceryl monooleate, glyceryl
monostearate, 2-pyrrolidone, sorbitol, stearic acid, palmitic acid, triacetiii, tributyl
citrate, triethanolamine, lecithin, surfactants like polysorbates, sorbitan esters and
organic acid esters and/or mixtures thereof.
More preferred plasticizers used in the present invention may be one or more of
triethyl citrate, polyethylene glycols, propylene glycol, stearic acid, triacetin and/or
mixtures thereof.
Most preferred plasticizers used in the present invention may be one or more of
triethyl citrate, polyethylene glycols and triacetin.
Anti-tacking agent used in the present invention may be one or more of talc,
magnesium stearate, calcium stearate, stearic acid, calcium carbonate, magnesium
carbonate, ground limestone, magnesium silicate, aluminum silicate, clay, alumina,
titanium oxide, mono-calcium phosphate, di-calcium phosphate, tri-calcium
phosphate and combinations thereof.
More preferred anti-tacking agent used in the present invention may be one or more of
talc, magnesium stearate, calcium stearate, stearic acid, calcium carbonate,
magnesium carbonate, magnesium silicate, aluminum silicate, alumina, titanium oxide
and combinations thereof.
Most preferred anti-tacking agent used in the present invention may be one or more of
talc, magnesium stearate and titanium oxide.
Suitable coloring agents include one or more colors approved by FDA.
Suitable solvents used in the manufacturing of pharmaceutical composition include one or more of water, ethyl acetate, acetone, isopropyl alcohol, n-propanol, ethanol and mixtures thereof.
According to the present invention, novel extended release pharmaceutical composition may contain 0.5 to 30% of active pharmaceutical ingredient, 1 to 90% of diluents, from about 1 to 25% of acidulants, from about 0.01 to 10% of anti-oxidants, from about 0.5 to 15% of disintegrants, from about 0.01 to about 1% of colorants, from about 1 to 25% of binders, from about 0.1 to 5% of glidants, and from about 0.1 to 5% of lubricants and coating agents for dry or compression or press coating ranges

from 2 to 10 times of core composition and film coating ranges from 1 to 40% of core composition.
According to the present invention, novel extended release pharmaceutical composition is in the form of a coated tablet which contains a sparingly soluble paliperidone.
According to the present invention, novel extended release pharmaceutical composition may contain about 0.5 to 30% of the total paliperidone in the core and about 0.2 to 5% of the total paliperidone in the dry or compression or press coated tablet, and coating agent ranges from 2 to 10 times of core composition.
According to the present invention, novel extended release pharmaceutical composition may containing about 0.5 to 30% of the total paliperidone in the core and about 0.2 to 25% of the total paliperidone in the film coated tablet and coating agent ranges form 1 to 40%,
According to the present invention, novel extended release pharmaceutical composition may contain paliperidone in the core as crystalline or amorphous form and having a maximum mean particle size of 5 to 40 um.
According to the present invention, novel extended release pharmaceutical composition may contain about 10 to 80% of the total coat weight is a release retarding polymer.
According to the present invention, novel extended release pharmaceutical
composition may contain ethylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose, as the release retarding polymer.
According to the present invention, novel extended release pharmaceutical composition may contain paliperidone in crystalline form or amorphous form.
According to the present invention, novel extended release pharmaceutical composition wherein solid dosage form suitable for oral administration is selected

from tablets, minitablets, capsules, granules and pellets, preferably tablet dosage form.
According to the present invention, novel extended release pharmaceutical
composition may contains film coated tablet, wherein about 5 to 30% of the total coat
weight is a water insoluble swellable polymer or pH independent or pH dependant
polymer.
According to the present invention, novel extended release, pharmaceutical
composition may be a film coated tablet, wherein the coat contains ethylcellulose,
Poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate
chloride) 1:2:0.2 or Ammonio Methacrylate Copolymer, Type A.
Extended release pharmaceutical composition of the present invention contains the
active ingredient in the range of from about 1.5 to about 12 mg. The 'active
ingredient' refers to paliperidone.
In one embodiment, process for preparing novel extended release system includes:
1. Sifting of active pharmaceutical ingredient, anti-oxidant & acidulant and dry mixing.
2. Preparation of binder solution by dissolving povidone in purified water.
3. Granulation of step-1 dry mix using step-2 binder solution.
4. Drying of step-3 granules.
5. Sifting of step-4 dried granules.
6. Sifting of diluent, disintegrant and then mixing with step-5 granules in a blender.
7. Sifting of glidant and part of lubricant and blending with step-6 blend.
8. Compression of the step-7 lubricated blend to form tablets.
9. Sifting of release retardant polymers, diluent & binder and dry mixing.
10. Sifting of part of lubricant and blending with step-9 blend.
11. Dry or compression coating of step-8 tablets with step-10 dry mix.
In another embodiment, process for forming an extended release system includes:
1. Sifting of one part of active pharmaceutical ingredient, one part of anti-oxidant & acidulant and dry mixing.
2. Preparation of binder solution by dissolving povidone in purified water.

3. Granulation of step-1 dry mix using step-2 binder solution.
4. Drying of step-3 granules.
5. Sifting of step-4 dried granules.
6. Sifting of diluent and mixing with step-5 granules in a blender.
7. Sifting of glidant and lubricant and blending with step-6 blend.
8. Compression of the step-7 lubricated blend to form tablets.
9. Sifting of second part of active pharmaceutical ingredient, second part of antioxidant release retardant polymers, gas generating agent, diluent, binder and dry mixing.
10. Sifting of part of lubricant and mixing with step-9 blend.
11. Dry or compression coating of step-8 tablets with step-10 dry mix.
In another embodiment, process for forming a novel extended release system includes:
1. Sifting of active pharmaceutical ingredient, anti-oxidant & acidulant and dry mixing.
2. Preparation of binder solution by dissolving binder in purified water.
3. Granulation of step-1 dry mix using step-2 binder solution.
4. Drying of step-3 granules.
5. Sifting of step-4 dried granules.
6. Sifting of diluent and mixing with step-5 granules in a blender.
7. Sifting of glidant and lubricant and blending with step-6 blend.
8. Compression of the step-7 lubricated blend to form tablets.
9. Sifting of release retardant polymers, gas generating agent, diluent, binder and dry mixing.
10. Sifting of part of lubricant and mixing with step-9 blend.
11. Dry or compression coating of step-8 tablets with step-10 dry mix.
In another embodiment, process for forming a novel extended release system includes:

1. Sifting of active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients (anti-oxidant, acidulants, diluents, binders & first one third part of lubricants etc.) and dry mixing.
2. Slugging of step-1 dry mix.
3. Milling and sifting of step-2 slugs.
4. Sifting of glidant and second one third part of lubricant and blending with milled slugs of step-3.
5. Compression of the step-4 lubricated blend to form core tablets.
6. Sifting of release retardant polymers, gas generating agent, diluent, binder and dry mixing.
7. Sifting of remaining one third part lubricant and mixing with step-6 blend.
8. Dry or compression coating of step-5 tablets with step-7 dry mix.
In another embodiment, process for forming a novel extended release system includes:
1. Sifting of active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients (anti-oxidant, acidulants, diluents & binder) and dry mixing.
2. Sifting of glidant and half the quantity of lubricant and blending with step-1 dry mix.
3. Compression of the step-2 lubricated blend to form core tablets.
4. Sifting of release retardant polymers, gas generating agent, diluent, binder and dry mixing.
5. Sifting of remaining half quantity of lubricant and mixing with step-4 blend.
6. Dry or compression coating of step-3 core tablets with step-5 dry mix.
In another embodiment, process for forming a novel extended release system includes:
1. Sifting of active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients (anti-oxidant, acidulants, diluents, binders & first one third part of lubricants etc.) and dry mixing.
2. Slugging of step-1 dry mix.
3. Milling and sifting of step-2 slugs.
4. Sifting of glidant and second one third part of lubricant and blending with milled slugs of step-3.

5. Compression of the step-4 lubricated blend to form core tablets.
6. Preparation of coating dispersion by dispersing the pH dependant or pH independent polymer with or without plasticizer and anti-tacking agent and film coating of step-5 tablets.
According to the present invention process for the preparation of pH dependent extended release pharmaceutical composition comprises the steps of
1. Sifting of active pharmaceutical ingredient and one or more pharmaceutically acceptable intra-granular excipients (antioxidant, acidulants, diluents & binders etc.) and dry mixing.
2. Preparing the aqueous solution of acidulant.
3. Granulating the step-1 dry mix with step 2 solution.
4. Drying and milling the granulates
5. Mixing milled granules of step 4 with extra-granular excipeints (diluents, glidant and lubricant).
6. Compression of the step-5 lubricated blend to form core tablets.
7. Preparation of the aqueous or hydroalcoholic coating dispersion by dispersing water insoluble polymer, binder or pore former and plasticizer.
8. Coating of core tablets of step 6 using aqueous dispersion of step 7 using coating machine.
According to the present invention process for the preparation of pH independent extended release pharmaceutical composition comprises the steps of
1. Sifting of active pharmaceutical ingredient and one or more pharmaceutically acceptable intra-granular excipients (anti-oxidant, acidulants, diluents & binders etc.) and dry mixing.
2. Preparing the aqueous solution of acidulant.
3. Granulating the step-1 dry mix with step 2 solution.
4. Drying and milling the granulates
5. Mixing milled granules of step 4 with extra-granular excipeints (diluents, glidant and lubricant).
6. Compression of the step-5 lubricated blend to form core tablets.
7. Preparation of the aqueous or hydro-alcoholic or non-aqueous solution containing water soluble polymer so as to form a protective barrier or seal coat against environmental conditions.

8. Preparation of the aqueous or hydro-alcoholic or non-aqueous solution containing pH independent polymer so as to control the release of the drug in gastro intestinal tract.
9. Coating of core tablets of step 6 using aqueous dispersion of step 7 using coating machine.
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 tablet. Preferably, the pharmaceutical composition of present invention containing paliperidone 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.
EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims

Example 1

S.No. Ingredients Qty./tab (mg)
Core: Ingredients
1. Paliperidone 6.000
2. Lactose monohydrate 35.000
3. Povidone 3.000
4. Malic acid 0.600
5. Microcrystalline cellulose 15.000
6. Colloidal silicon dioxide 0.100
7. Magnesium stearate 0.300
8. Purified water q.s.
Weight of Core Tablet (mg) 60.000
Coating Composition: Excipients
9. Hydroxypropyl methyl cellulose 143.000
10. Lactose monohydrate 153.700
11. Talc 1.600
12. Magnesium stearate 1.700
Weight of Coated Tablet (mg) 360.000
Brief Manufacturing Procedure:
1. Paliperidone, lactose monohydrate, povidone were sifted and dry mixed.
2. Malic acid solution was prepared by dissolving malic acid in purified water.
3. Granulation of step-1 dry mix was done using step-2 binder solution.
4. The granules obtained in step-3 were dried.
5. The step-4 dry granules were sifted.
6. Microcrystalline cellulose was sifted and mixed with step-5 granules in a blender.
7. Colloidal silicon dioxide and magnesium stearate were sifted and blended with step-6 blend.
8. The step-7 lubricated blend was compressed to form tablets.
9. Hydroxypropylmethyl cellulose and lactose monohydrate were sifted and dry mixed.
10. Talc and magnesium stearate were sifted and blended with step-9 blend.
11. The step-8 tablets were dry or compression coated with step-10 dry mix.

Example 2

S.No. Ingredients Qty./tab (mg)
Core: Ingredients
1. Paliperidone 6.000
2. Lactose monohydrate 35.000
3. Povidone 3.000
4. Malic acid 0.600
5. Microcrystalline cellulose 15.000
6. Colloidal silicon dioxide 0.100
7. Magnesium stearate 0.300
8. Purified water q.s.
Weight of Core Tablet (nig) 60.000
Coating Composition: Excipients
9. Hydroxypropyl methyl cellulose 178.000
10. Lactose monohydrate 118.700
11. Talc 1.600
12. Magnesium stearate 1.700
Weight of Coated Tablet (nig) 360.000
Brief Manufacturing Procedure:
1. Paliperidone, lactose monohydrate, povidone were sifted and dry mixed.
2. Malic acid solution was prepared by dissolving malic acid in purified water.
3. Granulation of step-1 dry mix was done using step-2 binder solution.
4. The granules obtained in step-3 were dried.
5. The step-4 dry granules were sifted.
6. Microcrystalline cellulose was sifted and mixed with step-5 granules in a blender.
7. Colloidal silicon dioxide and magnesium stearate were sifted and blended with step-6 blend.
8. The step-7 lubricated blend was compressed to form tablets.
9. Hydroxypropylmethyl cellulose and lactose monohydrate were sifted and dry mixed.
10. Talc and Magnesium stearate were sifted and blended with step-9 blend.
11. The step-8 tablets were dry or compression coated with step-10 dry mix.

Example 3

S.No. Ingredients Qty./tab (mg)
Core: Ingredients
1. Paliperidone 6.000
2. Lactose monohydrate 35.000
3. Povidone 3.000
4. Malic acid 0.600
5. Microcrystalline cellulose 15.000
6. Colloidal silicon dioxide 0.100
7. Magnesium stearate 0.300
8. Purified water q.s.
Weight of Core Tablet (mg) 60.000
Coating Composition: Excipients
9. Carbapol 143.000
10. Lactose monohydrate 153.700
11. Talc 1.600
12. Magnesium stearate 1.700
Weight of Coated Tablet (mg) 360.000
Brief Manufacturing Procedure:
1. Paliperidone, lactose monohydrate, povidone were sifted and dry mixed.
2. Malic acid solution was prepared by dissolving malic acid in purified water.
3. Granulation of step-1 dry mix was done using step-2 binder solution.
4. The granules obtained in step-3 were dried.
5. The step-4 dry granules were sifted.
6. Microcrystalline cellulose was sifted and mixed with step-5 granules in a blender.
7. Colloidal silicon dioxide and magnesium stearate were sifted and blended with step-6 blend.
8. The step-7 lubricated blend was compressed to form tablets.
9. Carbopol and lactose monohydrate were sifted and dry mixed.
10. Talc and Magnesium stearate were sifted and blended with step-9 blend.
11. The step-8 tablets were dry or compression coated with step-10 dry mix.

Example 4

S.No. Ingredients Qty./tab (mg)
Core: Ingredients
1. Paliperidone 6.000
2. Lactose monohydrate 35.000
3. Povidone 3.000
4. Malic acid 0.600
5. Macrocrystalline cellulose 15.000
6. Colloidal silicon dioxide 0.100
7. Magnesium stearate 0.300
8. Purified water q.s.
Weight of Core Tablet (mg) 60.000
Coating Composition: Excipients
9. Carbapol 118.700
10. Lactose monohydrate 178.000
11. Talc 1.600
12. Magnesium stearate 1.700
Weight of Coated Tablet (mg) 360.000
Brief Manufacturing Procedure:
1. Paliperidone, lactose monohydrate, povidone were sifted and dry mixed.
2. Malic acid solution was prepared by dissolving Malic acid in purified water.
3. Granulation of step-1 dry mix was done using step-2 binder solution.
4. The granules obtained in step-3 were dried.
5. The step-4 dry granules were sifted.
6. Microcrystalline cellulose was sifted and mixed with step-5 granules in a blender.
7. Colloidal silicon dioxide and magnesium stearate were sifted and blended with step-6 blend.
8. The step-7 lubricated blend was compressed to form tablets.
9. Carbopol and lactose monohydrate were sifted and dry mixed.
10. Talc and Magnesium stearate were sifted and blended with step-9 blend.
11. The step-8 tablets were dry or compression coated with step-10 dry mix.

Example 5

S.No. Ingredients Qty./tab (mg)
Core: Ingredients
I. ] Paliperidone 6.000
2. Lactose monohydrate 35.000
3. Povidone 3.000
4. Malic acid 0.600
5. Microcrystalline cellulose 15.000
6. Colloidal silicon dioxide 0.100
7. Magnesium stearate 0.300
8. Purified water q.s.
Weight of Core Tablet (mg) 60.000
Coating Composition: Excipients
9. Ethyl cellulose (Used as 30% dispersion) 4.800
10. Povidone 0.480
11. Triethyl citrate 0.720
12. Purified water q.s.
Weight of Coated Tablet (mg) 66.000
Brief Manufacturing Procedure:
1. Paliperidone, lactose monohydrate, povidone were sifted and dry mixed.
2. Malic acid solution was prepared by dissolving malic acid in purified water.
3. Granulation of step-1 dry mix was done using step-2 binder solution.
4. The granules obtained in step-3 were dried.
5. The step-4 dry granules were sifted.
6. Microcrystalline cellulose was sifted and mixed with step-5 granules in a blender.
7. Colloidal silicon dioxide and magnesium stearate were sifted and blended with step-6 blend.
8. The step-7 lubricated blend was compressed to form tablets.
9. Dispersed 30% ethyl cellulose dispersion in water and added povidone and triethyl citrate to it, stirred it for about 45 min.
10. The step-8 tablets were film coated with dispersion of step-9.

Example 6

S.No. Ingredients / Qty./tab (mg)
Core: Ingredients
1. Paliperidone 6.000
2. Lactose monohydrate 35.000
3. Povidone 3.000
4. Malic acid 0.600
5. Microcrystalline cellulose 15.000
6. Colloidal silicon dioxide 0.100
7. Magnesium stearate 0.300
8. Purified water q.s.
Weight of Core Tablet (mg) 60.000
Coating Composition: Excipients
9. Eudragit RLPO 7.273
10. Talc 3.636
11. Triethyl citrate 1.091
12 Isopropyl alcohol q.s.
13. Acetone q.s.
Weigltt of Coated Tablet (mg) 72.000
Brief Manufacturing Procedure:
1. Paliperidone, lactose monohydrate, povidone were sifted and dry mixed.
2. Malic acid solution was prepared by dissolving malic acid in purified water.
3. Granulation of step-1 dry mix was done using step-2 binder solution.
4. The granules obtained in step-3 were dried.
5. The step-4 dry granules were sifted.
6. Microcrystalline cellulose was sifted and mixed with step-5 granules in a blender.
7. Colloidal silicon dioxide and magnesium stearate were sifted and blended with step-6 blend.
8. The step-7 lubricated blend was compressed to form tablets.
9. Dispersed eudragit RLPO in isopropyl alcohol and acetone mixture (50:50) stirred for about one hour.
10. Separately dispersed talc and titanium dioxide in isopropyl alcohol and acetone mixture (50:50).

11. Added dispersion of step 10 to dispersion of step 9 with continuous stirring to obtain coating dispersion.
12. Coated the compressed tablets of step 8 using dispersion of step 11.

We Claim:
1. An extended release pharmaceutical composition of paiiperidone comprising
a) a core comprising of therapeutically effective amount of paiiperidone or its pharmaceutically acceptable salts, solvates, enantiomers or mixtures thereof along with pharmaceutical ly acceptable excipients;
b) coating around the said core which comprises of a layer of pharmaceutically acceptable release retardant polymers, optionally paiiperidone, optionally pharmaceutically acceptable excipients.

2. An extended release pharmaceutical composition of claim 1, wherein the coating around core comprises of dry or compression or press coating or film coating.
3. An extended release pharmaceutical composition of claim 2, wherein the dry or compression or press coating comprises a layer of pharmaceutically acceptable release retardant polymers, optionally paiiperidone, optionally pharmaceutically acceptable excipients like binders, gas generating agents, diluents, colorants, pore forming agents, lubricants and glidants.
4. An extended release pharmaceutical composition of claim 2, wherein film coating comprises of a layer of pharmaceutically acceptable release retardant polymers, optionally paiiperidone, optionally pharmaceutically acceptable excipients like pH dependant polymers or pH independent polymers, plasticizers, opacifiers, colorants and antitacking agent.
5. An extended release pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipients of core comprises of diluents, binders, anti-oxidants, acidulants, disintegrants, colorants, glidants and lubricants.
6. An extended release pharmaceutical composition of claim 3 and 5 wherein the diluent comprises of at least one or more of microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, 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, mannitol, magnesium succinate and potassium acid phosphate; more preferably diluent comprises of at least at least one or more of microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, anhydrous lactose, directly compressible lactose, starch 1500, calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, xylitol, dextrose, compressible sugar, dextrin, starch, powdered cellulose, sodium alginate, tragacanth, sodium chloride, potassium chloride and mannitol ; most preferably diluent comprises of at least one or more of microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, anhydrous lactose, directly compressible lactose, compressible sugar, powdered cellulose and mannitol. 7. An extended release pharmaceutical composition of claim 3 and 5, wherein the binder comprises of at least one or more microcrystalline cellulose, 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 and magnesium aluminum silicate; more preferably binder comprises of at least one or more microcrystalline cellulose, povidone, pyrrolidone, co-povidone, acacia gum, guar gum, xanthan gum, gellan gum, gelatin, glucose, sugar, dextrin, sorbitol, maltose, pregelatinised starch, carboxymethyl cellulose sodium, methylcellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, hyroxyethyl cellulose, carbomers, carrageenan, ceratonia, chitosan and poloxamer; most preferable binder comprises of at least one or more of microcrystalline cellulose, povidone, pyrrolidone, co-povidone, acacia gum, guar gum, xanthan gum, sugar, dextrin, pregelatinised starch, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, hyroxyethyl cellulose and carbomers.

8. An extended release pharmaceutical composition of claim 5, wherein anti
oxidant comprises of one or more of substituted phenolic compounds such as
butylated hydroxyanisole, propyl gallate, butylated hydroxytoluene (BHT),
ascorbic acid, ascorbyl palmitate, alpha-tocopherol and biflavonoids; more
preferably antioxidant comprises of at least one or more
substituted phenolic compounds such as butylated hydroxyanisole, propyl gallate, butylated hydroxytoluene (BHT) and ascorbic acid; and most preferable antioxidant comprises of at least one or more of substituted phenolic compounds such as butylated hydroxyanisole, butylated hydroxytoluene (BHT) and ascorbic acid.
9. An extended release pharmaceutical composition of claim 5, wherein acidulants comprises of at least one or more of fumaric acid, citric acid, tartaric acid, malic acid, and anhydrous ascorbic acid; more preferably acidulant comprises of at least one or more of the citric acid, tartaric acid, malic acid, and anhydrous ascorbic acid; most preferable acidulant comprises of at least one or more of the citric acid, tartaric acid and malic acid.
10. An extended release pharmaceutical composition of claim 5, wherein disintegrant comprises of at least one or more of croscarmeilose sodium, crospovidone, sodium starch glycollate, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, microcrystalline cellulose, emcosoy (Soya polysaccharide) and potassium polacrilin; more preferably disintegrant comprises of at least one or more of croscarmeilose sodium, crospovidone, sodium starch glycollate, low-substituted hydroxypropyl cellulose, starch and pregelatinized starch; most preferably disintegrant comprises of at least one or more croscarmeilose sodium, crospovidone, sodium starch glycollate. low substituted hydroxypropyl cellulose and pregelatinized starch.
11. An extended release pharmaceutical composition of claim 3 and 5, wherein glidant comprises of at least one or more of colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, hydrogenated castor oil, sodium lauryl sulfate, precipitated silicon dioxide and starch; more preferably glidant comprises of from at least one or more of colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, precipitated silicon dioxide and starch; most preferably glidant comprises of at least one or more

of colloidal silicon dioxide, talc, magnesium stearate, precipitated silicon dioxide and starch.
12. An extended release pharmaceutical composition of claim 3 and 5, wherein the lubricant comprises of at least one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, magnesium lauryl sulfate, wax, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, palmitic acid, poloxamer, sodium benzoate and sodium lauryl sulfate; more preferably lubricant comprises of at least one or more magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, magnesium lauryl sulfate, glyceryl behenate and glyceryl palmitostearate; most preferred lubricant comprises of at least one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, magnesium lauryl sulfate and glyceryl behenate.
13. An extended release pharmaceutical composition of claim 3 & 4, wherein release retarding polymer comprises one or more of cellulose derivatives like hydroxyl ethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose; polyethylene oxides, carbopols; poly (methacrylicacid, methyl methacrylate) 1:1, poly (ethyl acrylate, methacrylic acid) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2, poly (ethylacrylate, methyl methacrylate, trimethylammonioefhyl methacrylate chloride) 1:2:0.2, poly (ethylacrylate, methyl methacrylate and trimethylammonioethylmethacrylate chloride) 1:2:0.1 and mixture thereof.
14. An extended release pharmaceutical composition of claim 3, wherein gas generating agent of dry or compression or press coating comprises of at least one or more of sodium bicarbonate, sodium carbonate, calcium carbonate, potassium carbonate, potassium bicarbonate, sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate and arginine carbonate; more preferably comprises of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium sesquicarbonate, sodium glycine carbonate and L-lysine carbonate; most preferably comprises of sodium bicarbonate and sodium carbonate.
15. An extended release pharmaceutical composition of claim 3, wherein the pore forming agent of dry or compression or press coating comprises of at least one

or more of sodium chloride, potassium chloride, magnesium sulfate, magnesium chloride, sodium sulfate, fructose, sucrose, sorbitol, xylitol, dextrose, urea, inositol, lactose, mannitol, magnesium succinate, calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, potassium acid phosphate and povidone; more preferably channeling agents comprises of at least one or more of sodium chloride, potassium chloride, fructose, sucrose, sorbitol, xylitol, dextrose, inositol, lactose, mannitol, magnesium succinate, calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, potassium acid phosphate and povidone; most preferably channeling agents comprises of at least one or more of lactose and povidone.
16. An extended release composition of claim 4, wherein the pH dependant
polymer of film coating comprises of one or more of acrylate co-polymers like
dimethyl aminoethyl methylmethacrylate, other neutral methacrylic acid esters,
methacrylic co-polymer like poly (ethyl acrylate, methyl methacrylate) 2:1,
poly (methacrylicacid, methyl methacrylate) 1:1, poly (ethyl acrylate,
methacrylic acid) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2, poly
(methacrylic acid, methyl methacrylate, methacrylic acid) 7:3:1, poly
(ethylacrylate, methyl methacrylate, trirnethylammonioethylmethacrylate
chloride) 1:2:0.2, poly (ethylacrylate, methyl methacrylate and
trimethylammonioethylmethacrylate chloride) 1:2:0.1 and mixture thereof;
pH independent polymer comprises of ethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol povidone poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 and ammonio methacrylate co-polymer, Type A.
17. An extended release pharmaceutical composition of claim 4, wherein
plasticizer in film coating comprises of at least one or more triethyl citrate,
polyethylene glycols, propylene glycol, glycerine, caster oil, acetyltriethyl
citrate, benzyl benzoate, chlorbutanol, dextrin, acetyltributyl citrate, dimethyl
phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, glyceryl
monooleate, glyceryl monostearate, 2-pyrroIidone, sorbitol, stearic acid,
palmitic acid, triacetin, tributyi citrate, triethanolamine, lecithin, surfactants
like polysorbates, sorbitan esters and organic acid esters and mixtures thereof;
more preferably comprises of one or more triethyl citrate, polyethylene

glycols, propylene glycol, stearic acid, triacetin and mixtures thereof; most preferably plasticizers comprises of at least one or more one or more of triethyl citrate, polyethylene glycols and triacetin. 1 8. An extended release pharmaceutical composition of claim 4, wherein the antitacking agent of film coating comprises of one or more of talc, magnesium stearate, calcium stearate, stearic acid, calcium carbonate, magnesium carbonate, ground limestone, magnesium silicate, aluminum silicate, clay, alumina, titanium oxide, mono-calcium phosphate, di-calcium phosphate, tri-calcium phosphate and combinations thereof; more preferable anti-tacking agent comprises of one or more of talc, magnesium stearate, calcium stearate, stearic acid, calcium carbonate, magnesium carbonate, magnesium silicate, aluminum silicate, alumina, titanium oxide and combinations thereof; most preferred anti-tacking agent comprises of at least one or more talc, magnesium stearate and titanium oxide. 19. An extended release pharmaceutical composition of claim 4, wherein the opacifier of film coating layer comprises of one or more of titanium dioxide, silicates such as talc and aluminium silicate, ethylene glycol palmitostearate, acetates such as zinc acetate, carbonates such as magnesium carbonate, calcium carbonate, stearates such as aluminium stearate and zinc stearate, sulfates such as calcium sulfate, oxides such as magnesium oxide and hydroxides such as aluminiuim hydroxides; more preferred comprises of at least one or more of titanium dioxide, silicates such as talc and aluminium silicate, ethylene glycol carbonates such as magnesium carbonate, calcium carbonate, stearates such as aluminium stearate and zinc stearate; most preferred opacifier used is selected from at least one or more of titanium
dioxide, silicates such as talc and aluminium silicate, stearates such as
aluminium stearate and zinc stearate.
20. An extended release pharmaceutical composition of claim 1 wherein solid dosage form suitable for oral administration comprises of tablets, minitablets, capsules, granules or pellets, preferably tablet dosage form.
21. An extended release pharmaceutical composition of claim 1, wherein the active pharmaceutical ingredient ranges from 0.5 to 30%, diluent ranges from 1 to 90%, acidulant ranges from 1 to 25%, anti-oxidant ranges from 0.01 to 10%, disintegrant ranges from 0.5 to 15%, colorants ranges from 0.01 to 1%,

binder ranges from 1 to 25%, glidant ranges from 0.1 to 5%, lubricant ranges from 0.1 to 5%, release retarding polymer ranges from 10 to 80% of the total coat weight, and coating agents for dry or compression or press coating ranges from 2 to 10 times of core composition and film coating ranges from 1 to 40% of core composition.
22. An extended release pharmaceutical composition of claim ] containing 0.5 to 30% of paliperidone in the core and 0.2 to 5% of paliperidone in the dry or compression or press coated tablet and coating agents ranges from 2 to 10 . times of core composition.
23. An extended release pharmaceutical composition of claim 1 containing 0.5 to 30% of paliperidone in the core and 0.2 to 25% of paliperidone in the film coated tablet and coating agents ranges from 1 to 40%.
24. An extended release pharmaceutical composition of claim 1 wherein the core comprises the paliperidone in crystalline or amorphous form and having a mean particle size in the range of 5 to 40 urn.
25. A process to prepare an extended release pharmaceutical composition of claim 1 which comprises the steps
a. Sifting of active pharmaceutical ingredient and pharmaceutically
acceptable excipients.
b. Dry mixing or granulation of ingredients.
c. Blending and lubrication.
d. Compression of the lubricated blend of step (c) into tablets.
e. Coating of the compressed tablets of step (d).
26. An extended release pharmaceutical composition of claim 1, wherein the dosage form used for the treatment of Schizophrenia and Schizoaffective disorders.
27. An extended release pharmaceutical composition of claim 1, substantially as herein described and illustrated with reference to the accompanying examples.