FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - PALIPERIDONE EXTENDED RELEASE ORAL FORMULATIONS
2. Applicant(s)
(a) NAME: CADILA HEALTHCARE LIMITED.
(b) NATIONALITY: INDIAN
(c) ADDRESS: SARKHEJ-BAVLA N.H. No. 8A, MORAIYA, Tal. SANAND, Dist. AHMEDABAD-3 82 210, GUJARAT, INDIA
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention
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Field of the invention:
The present invention relates to extended release formulations of Paliperidone and its pharmaceutically acceptable salts/solvates which are suitable for oral administration. The present invention describes formulations with Paliperidone for once a day administration & processes for preparation thereof.
Paliperidone is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives. Invega® contains a racemic mixture of (+) and (-) paliperidone. The 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-4H- pyrido[l,2-a]pyrimidin-4-one. Its molecular formula is C23H27FN4O3 and its molecular weight is 426.49.
Paliperidone is sparingly soluble in O.IN HCl and methylene chloride; practically insoluble in water, O.IN NaOH, and hexane; and slightly soluble inN,N-dimethylformamide.
Paliperidone is marketed for acute and maintenance treatment of schizophrenia. Paliperidone is marketed in the United States by Janssen, as extended release tablets under the tradename, Invega®. It is available in three strengths, 3 mg, 6mg and 9 mg in the United States. It is also available as Paliperidone prolonged release tablets, 3mg, 6 mg, 9 mg and 12 mg strength in Europe, marketed under the tradename Invega .by Jannsen.
The present invention relates to formulations containing Paliperidone with controlled release action for oral administration and processes of preparation thereof.
Background of the invention:
The compound, 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetr ahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one, is "Paliperidone" disclosed in U.S. Pat. No. 5,158,952 having the following structure:
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Paliperidone is a white to yellow non-hygroscopic powder.
Paliperidone's dissociation constants are pKal = 8.2 (piperidine moiety) and pKa2 = 2.6
(pyrimidine moiety). Its solubility in water is 0.003 g/100 ml, rising to to 2.3 g/100 ml in 0.1
N HC1, whereas in ethanol it is 0.076 g/100 ml. The logP of the substance as a neutral
molecule in a 1-octanol/aqueous buffered solution (pH 11.9) is 2.39, while the logP of the
substance regardless of its form in phosphate solution of pH 7.0 is 1.02.
Paliperidone has one chiral centre and is synthesised as a racemic mixture. Paliperidone is
known in two polymorphs, polymorph I and II, in addition to a hydrate and a solvate. In the
final active substance only polymorph I is present, which is the thermodynamically stable
crystal form.
Paliperidone (9-hydroxy-risperidone) is the major metabolite of risperidone, which is approved for treatment of schizophrenia since 1994. Paliperidone shares the characteristic serotonin (5HT2A) and dopamine (D2) antagonism and receptor binding profile of its parent risperidone. It binds also to al-adrenergic receptors, and, with lower affinity, to Hl-histaminergic and a2-adrenergic receptors, which may explain some of the other effects of paliperidone.
The goals of treatment of schizophrenia are to rapidly eliminate symptoms, reduce the number of relapses, and reduce the severity of the illness. Improving the level of social function and relationships are also important. Antipsychotics are the mainstay of treatment of schizophrenia. Conventional antipsychotics, typified by haloperidol, have a proven track record over the last half-century in the treatment of schizophrenia. While these drugs are highly effective against the positive, psychotic symptoms of schizophrenia, they show little benefit in alleviating negative symptoms or the cognitive
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impairment associated respect to extrapyramidal symptoms. Although a number of products in this class are currently available, treatment challenges and consequently goals for the development of a new second generation antipsychotic continue to exist such as the need for titration, twice daily dosing, slow onset of action necessitating the use of acute intramuscular treatment, and high treatment discontinuation rates due to lack of compliance or other reasons.
Invega®prolonged release tablets are based on the patented OROS®(ORal Osmotic System) Push-Pull™ technology delivery system, designed to deliver the paliperidone active substance in a controlled manner over 24 hours, thereby achieving an effective once-a-day treatment for schizophrenia. The system deploys an osmotic gradient across a semi-permeable membrane for the delivery of the active substance. In addition, paliperidone has been developed as a racemate, since the R- and S-enantiomers have similar pharmacological activity and interconvert in vivo.
In the pharmaceutical field, significant progress has been made in recent years in the production of increasingly improved systems for the release of active substances, these systems being capable of releasing the active substances according to pharmacokinetics and modes of release designed to allow required therapeutic effects. Controlled drug delivery devices offer clinically significant advantages for various therapeutically active agents by way of increasing patient compliance due to reduced frequency of administration, improve the safety and efficacy of drug substances and reduce undesirable effects in comparison to the corresponding immediate release dosage form. The advantages of controlled release or sustained release or modified release products are well known in the pharmaceutical field.
Many such drug delivery devices are commercially available and are produced by various technologies known in the art. However, some of these technologies require special processes and equipment for production. In addition, some of these systems have limited applications because their ability to produce a desired release profile of a therapeutic agent depends upon several factors, e.g., the physicochemical properties of therapeutic agent, additives in the drug delivery device, physiological factors and the like. The object of a controlled drug delivery device or composition is to limit, control or modify (e.g., slow) the drug release
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characteristics relative to an immediate release system of the same drug. While, many controlled release formulations are already known, certain moderately to poorly soluble or practically insoluble drugs present formulation difficulties and cannot be successfully formulated as a controlled drug delivery device employing these formulation techniques. In addition, due to variability in physicochemical characteristics of the therapeutic agent, variation in their response in the body upon administration and variation in their response on combining with additives, some of the existing technologies are inadequate. The emergence of newer therapeutic agents and understanding of pharmacokinetics and physiological needs make the task of controlled drug delivery more complex.
Invega® utilises the tri-layer core OROS®Push-Pull™technology system developed by Alza. This osmotic delivery system consists of 2 drug layers and a push layer. Drug layer 1 contains a lower drug concentration than drug layer 2, which provides the drug concentration gradient necessary to achieve an ascending release rate pattern. Additionally, the expandable push layer consists of hydrophilic polymers and osmotic excipients and it contributes to the drug delivery. The tablet core is surrounded by a lubricating subcoat, which enhances robustness of the drug release pattern. The semi-permeable membrane acts as a rate controlling membrane and provides to the tablet mechanical durability. Drug release from the tablet is inversely related to the membrane weight applied to the tablets. Two orifices are laser drilled through the membrane and subcoat on the first drug layer side of the elongated core of the tablet to provide exit ports for the drug. The presence of the orifices is vital to meet the specified release profile.
The process for the manufacture of paliperidone ER tablets consists of the following major operating steps: Granulation (Drug Layer 1, Drug Layer 2, Push Layer), Blending (Drug Layer 1, Drug Layer 2, Push Layer), Core Compression, Subcoating, Membrane Coating, Laser Drilling, Drying, Colour Overcoat. Reference : Scientific discussion on Summary of product characteristics, Invega, European Medicinal Agency, EMEA, 2007 Paliperidone is more fully described in U.S. Pat. No. 4,804,663. The paliperidone compound differs from risperidone and related prior art compounds described in U.S. Pat. Nos. 4,352,811 and 4,458,076 by its substitution on the 1-position of the piperidine moiety. U.S. Pat. No. 5,158,952 , discloses, 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one,
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a pharmaceutically acceptable acid addition salt thereof, and an enantiomeric form thereof. It also relates to 3-piperidinyl-l,2-benzisoxazoles having long-acting antipsychotic properties and which are useful in the treatment of warm-blooded animals suffering from psychotic diseases.
US2006/0018965 invention relates to a solid oral dosage form containing one or more pharmaceutically active ingredients solubilised or suspended in a pharmaceutically acceptable solvent or liquid phase and encapsulated in seamless controlled release microcapsules. Accordingly the pharmaceutically acceptable solvent or liquid phase may range from aqueous phase, organic solvent(s), glycols, oils and derivatives of including mono-,di, and triglycerides of short, medium and long chain fatty acids. The microcapsules have a diameter of <1 mm to 8 mm and a drug loading of up to 90%.
U.S. Pat. No. 5,705,190 describes controlled release compositions for poorly soluble basic drugs comprising a water soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid to facilitate dissolution of the basic drug at a high pH. U.S. Pat. No. 5,536,507 which describes a three component pharmaceutical formulation that utilizes, inter alia, a pH sensitive polymer and optionally an osmotic agent that will swell in the higher pH regions of the lower portion of the small intestine and the large intestine to release drug in those environments. Additional components of the dosage form include a delayed release coating and an enteric coating to provide a dosage form that releases very little, if any, of the drug in the stomach, a relatively minimal amount in the small intestine and reportedly about 85% or more in the large intestine. Such a dosage form provides for a widely varying time-release of drug after administration that may not begin for 1-3 hours until the dosage form has passed from the stomach and an additional 3 hours or more for the dosage form to pass into the large intestine.
US Pat. No. 6,372,254 discloses a single orally administrable tablet that can provide a substantially first order delivery of the active agent, interrupted by a timed, pulsed delivery of an increased amount of the active agent consisting of an immediate release compartment and an extended release compartment.
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WO/2003097018 discloses a porous matrix system exhibiting a biphasic release with active ingredient, a sugar & a gas generating system comprising of atleast one thermostable & atleast one thermolabile component.
WO/2005051322 discloses a controlled-release microparticle composition, which comprises: a tri-component controlled-release microparticle composition [1] a first rapidly releasing microparticle population containing a layer comprised of active ingredient, at least one nitrogen containing polymer and a plasticizer or other pharmaceutically acceptable excipients applied to a cellulose sphere or a cellulose core; and [2] a first controlled release microparticle population comprised of controlled release microparticle contains a layer comprised of active ingredient, at least one nitrogen containing polymer applied to a cellulose sphere or a cellulose core and where each first controlled release granule triggers a release of the active ingredient at a pH of about 5.5; [3] a second controlled release microparticle population comprised of a layer comprised of active ingredient, at least one nitrogen containing polymer and a plasticizer and pharmaceutically acceptable excipients applied to a cellulose sphere or a cellulose core; where each second controlled release granule triggers a release of the active ingredient at a pH of about pH > 6.4; and where each rapidly releasing population, first controlled release population and second controlled release population further are admixed with pharmaceutically acceptable adjuvants, carriers or excipients to form the tri-component controlled-release microparticle- containing dosage form.
It is well known to those skilled in the art that controlled release formulations which are effective in maintaining therapeutic blood levels over extended periods to time result in optimal therapy. They not only reduce the frequency of dosing for enhanced patient convenience and compliance, but they also reduce the severity and frequency of side effects, as they maintain substantially constant blood levels and avoid fluctuations associated with conventional immediate release formulations administered two to three times a day. The advent of controlled release dosage forms has provided a benefit to the pharmaceutical industry. Controlled release formulations have allowed the possibility of reducing dosage regimens for drugs, especially those administered orally to outpatients. The advantages of reduced dosage regimens for the outpatient are convenience and, more
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importantly, better assurance of compliance. For example, the reduction of a dose regimen from four times a day (q.i.d.) to three times a day (t.i.d.) allows the patient to take the prescribed drug during waking hours. A reduction of a dose regimen to twice a day (b.i.d.) allows the patient to take the prescribed drug in the morning and in the evening, which provides greater convenience; e.g., the patient is not required to carry an additional when away from the home. Of course, the most convenient dosage form is a once daily dose regimen
US2004/0092534 relates to a dosage form of Paliperidone extended release system, which utilizes a semipermeable membrane surrounding a three-layer core: the first layer is referred to as a first drug layer and contains low amounts of drug and an osmotic agent such as salt; the middle layer referred to as the second drug layer contains higher amounts of drug, excipients and no salt; and the third layer referred to as the push layer contains osmotic agents and no drug. At least one orifice is drilled through the membrane on the first drug layer end of the capsule-shaped tablet.
Since paliperidone has a long half-life of about one day, it is not a typical candidate for extended delivery. However, side effects such as anxiety, somnolence, dizziness, constipation, extrapyramidal symptoms, may be related to high blood plasma concentration levels restricting the ability to administer a single daily immediate release dose. It is expected that the side effects are likely a result of either rate of rise and/or actual drug blood plasma concentrations exceeding a threshold maximum tolerable concentration (MTC). However, in order to obtain a therapeutic effect, concentrations need to be sustained above a minimum pharmacodynamic concentration (MPC).
The marketed tablets of Paliperidone is a capsule-shaped tablet in appearance, consists of an osmotically active trilayer core surrounded by a subcoat and semipermeable membrane. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There are two precision laser-drilled orifices on the drug-layer dome of the tablet.
As it is a tri-layer tablet with laser-drilled orifices, in addition to using a lengthy process of preparation of three types of granules, it also utilizes a laser drilling technology to achieve a controlled release of active ingredient through the orifice.
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Thus, it is highly desirable to have extended release formulation of Paliperidone which will be intended to be administered once-a-day and can be produced using a simple technology, which does not involve multiple granulation stages. The present invention discloses extended release formulations of Paliperidone without use of costly equipments or technologies such as sophisticated compression machines designed to produce multi-layered tablets and laser drilling machine to create orifices on the dosage form. Thus the present invention relates to controlled release dosage forms of Paliperidone, which are less tedious to prepare and having the major advantage of reduced cost of manufacturing as compared to that of the current marketed forms.
Object of the invention:
The principal object of the invention is to provide extended release oral formulations of Paliperidone and its pharmaceutically acceptable salts/solvates. Another object of the invention is to provide processes for manufacturing extended release formulations of Paliperidone and its pharmaceutically acceptable salts/solvates.
Detailed description of the invention :
Paliperidone is sparingly soluble in 0.1 N HC1 and methylene chloride; practically insoluble in water, 0.1N NaOH, and hexane; and slightly soluble in N,N-dimethylformamide.
The present invention relates to formulations of Paliperidone and/or its pharmaceutically acceptable salts/solvates and processes thereof which are suitable for oral administration.
First aspect of the present invention relates to preparation of granules of Paliperidone or pharmaceutically acceptable salt of Paliperidone, a rate controlling agent and optionally use of excipients selected from the class of filler, channeling agents, binder, disintegrant, lubricant and other process aids, the release of the drug being controlled by use of a suitable rate controlling agent. Granules formed may be either compressed to tablets or filled in capsules to form an extended release system.
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Rate controlling agent may a hydrophilic or hydrophobic or lipophilic. The hydrophilic rate controlling agent may be selected from the class consisting of polymers selected from celluloses, hydroxy propyl methylcellulose, hydroxy propylcellulose, hydroxy ethylcellulose, xanthan gum, alginic acid, alginates, gums.
Hydrophobic rate controlling agents may be selected from class of excipients selected from ethyl cellulose, polymethyacrylates, acyrlates, cellulose acetate, cellulose acetate propionate, cellulose ethyl butyrate. Lipophilic rate controlling excipients may be selected from waxes, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, glyceryl monostearate, hydrogenated castor oil, glyceryl behenate, low melting substances. Rate controlling agent can be used alone or as mixtures of polymers.
The rate controlling agent may be used in concentration from 5% w/w to 60% w/w of the dosage form. More preferably the rate controlling agent may be used in concentration from 10%w/w to 40%w/w of the dosage form.
The most preferable hydrophilic polymers may be selected from group hydroxy propyl methylcellulose, hydroxy propyl cellulose, alginates, gums, celluloses, hydroxy ethylcellulose, xanthan gum, starches & polysaccharides. Most preferable hydrophilic polymer is hydroxy propyl methylcellulose. Hydroxy propyl methylcellulose described herein typically include, for example, that manufactured and sold by Dow Chemicals, under the trademark "Methocel®". Low melting substances may include cetyl alcohol, stearyl alcohol, cetostearyl alcohol, beeswax, carnauba wax, gelatin, white wax, paraffin wax , glyceryl monostearate, poloxamers, polyethylene glycols.
Channeling agents may include excipients capable of regulating the release from the
controlled release system like sodium chloride, lactose, mannitol, dextrose, dicalcium
phosphate.
Channeling agents in the present invention are class of excipients which compete with other
excipients and being more soluble than the drug used in the system dissolve faster than other
excipients in the dosage form and thereby creating channels for the drug to diffuse out.
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The diluents may be selected from commonly used pharmaceutical diluents such as dicalcium phosphate, microcrystalline cellulose, powdered microcrystalline cellulose, pregelatinised starch, lactose, mannitol, dextrose, sugars and other such pharmaceutically acceptable substances that can be used as diluents known to a person skilled in the art.
Suitable binders may selected povidone, hypromellose, gelatin, gum acasia, xanthan gum, carboxy methylcellulose, polyvinyl alcohol, starch, pregelatinised starch sodium carboxymethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose and any suitable binder known to a person skilled in the art.
An appropriate lubricant, flow-aid known to a person skilled in the art may be selected to suit the manufacturing process.
In one embodiment of the first aspect of invention, granules may be prepared by mixing Paliperidone or a pharmaceutically acceptable salt/solvate of Paliperidone, a rate controlling agent or mixture of two or more rate controlling agents and other excipients selected from the group consisting of diluents, binders, disintegrants and channeling agent. The blend may be granulated with water or with use of organic solvent or a hydroalcoholic solution. Wet granules may be suitably dried in a tray drier or in a fluidised bed drier. Granules may be made without using a solvent by slugging or roll compaction. Granules made either by wet granulation or dry granulation may to sized using a suitable mill with sieve aperture 0.7 - 1.2 mm. Sized granules may be mixed with disintegrants, flow-aid, lubricant and optionally a channeling agent. The granules may be compressed to tablets or filled in capsules. The compressed tablets may be coated with a rate controlling polymer.
In another embodiment of the first aspect of invention, two types of granules may be prepared. One type of granules may contain 5%-40% of drug to contribute to immediate release fraction of the total system. This immediate release fraction may be prepared with Paliperidone or any pharmaceutically acceptable salt/solvate of Paliperidone & ingredients optionally selected from the class of diluent, disintegrant, binder, flow-aid & lubricant. Granules may be prepared by conventional methods like wet granulation, dry granulation or
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simple blending of drug with the excipients. The second type of granules may be prepared using 10% - 90% of drug with controlled release pattern and the release may be controlled with the use of suitable rate controlling agent and may include excipients optionally selected from the class of diluent, binder, disintegrant, flow-aid, channeling agent and a lubricant. The second type of granules may be prepared by conventional wet granulation or dry granulation. The two types of granules may be mixed and filled in capsules. The two types of granules may also be mixed and compressed into a tablet or may compressed as a bilayer tablet with one layer comprising of immediate release granules & the other layer comprising of granules with controlled release of the drug.
Second aspect of the present invention relates to preparing two types of granules of Paliperidone or pharmaceutically acceptable salt of Paliperidone. One set of granules may be prepared with 20% - 80% of drug with a rate controlling polymer and optionally use of a channeling agent. The release of the drug being controlled by use rate controlling agent and/or a chanelling agent. Rate controlling agent can be used alone or as mixtures of polymers. Other excipients may include use of suitable binders, disintegrants, diluents, flow aid, lubricants. Granules may be prepared either by wet granulation or by dry granulation. The second set of granules may be prepared with 5%w/w - 60% w/w of drug with a low melting substance. Low melting substances may include cetyl alcohol, stearyl alcohol, cetostearyl alcohol, beeswax, carnauba wax, gelatin, white wax, paraffin wax , glyceryl monostearate, poloxamers, polyethylene glycols.The second set of granules may be prepared by melting the low melting substance at a temperature above its melting range in a suitable heat generating mixer. The drug may be dispersed in the molten low melting substance. Optionally a diluent, sugar, binder, disintegrant may be added to the molten mass. The molten mass may be cooled while mixing to form granules. Optionally the drug and the low melting substance may be first mixed and then heated to a temperature above the melting range of the low melting substance, in a heat generating mixer The granules may be sized using a suitable mill with screen size of 0.5-1.2 mm. Sized granules may be mixed with disintegrants, flow-aid and a lubricant. The two types of granules may be mixed and filled in capsules. The two types of granules may also be mixed and compressed into a tablet or may
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be compressed as a bilayer tablet with one layer comprising of granules formed with low melting substance & the other layer comprising of granules with rate controlling polymer.
Third aspect of the present invention relates to preparing blend of Paliperidone with 5% to 60% of rate controlling polymer and other excipients selected from the group of suitable binders, channeling agents, disintegrants, diluents, flow aid, lubricants. The blend is compressed into tablets. The tablets are coated with one or more rate controlling agent. The tablets may be optionally further coated with enteric coating or aesthetic overcoat.
Rate controlling polymer is preferably selected from hydroxypropylmethylcellulose, gums, hydroxypropylcellulose, hydroxyethyl cellulose, gums, cellulosic derivatives, starches, polysaccharides, and alginates. Rate controlling agent can be used alone or as mixtures of polymers.
Channeling agents may include excipients capable of regulating the release from the controlled release system like sodium chloride, lactose, mannitol, dextrose, dicalcium phosphate.
The tablets prepared by any of the aspects described herein may be optionally coated with an enteric coating or an aesthetic coating.
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The novel formulations and processes thereof provide Paliperidone extended release oral formulations described herein are illustrative of the invention and should not be read as limiting the scope of the present invention.
Example 1

Ingredient mg/tab
Paliperidone 9.0
Microcrystalline cellulose 109.0
Hydroxypropyl methylcellulose 100,000 cps 80.0
Magnesium stearate 2.0
Total 200.0
Process :
Step 1 : Paliperidone, microcrystalline cellulose, hydroxypropylmethylcellulose were
mixed in a diffusion blender.
Step 2 : Magnesium stearate was added to Step 1 and blended..
Step 3 : Step 2 was compressed into tablets using with a hardness of about 8- 10 Kp
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Example 2

Ingredient mg/tab
Paliperidone 9.0
Microcrystalline cellulose 109.0
Hydroxypropyl methylcellulose 100,000 cps 80.0
Magnesium stearate 2.0

Coating composition % w/w
Ethyl cellulose 94
Hydroxypropyl methylcellulose 6cps 5
Polyethylene glycol 3050 1
IPA q.s.
Methylene chloride q.s.
Process :
Step 1 : Paliperidone, microcrystalline cellulose, hydroxypropylmethylcellulose were
mixed in a diffusion blender.
Step 2 : Magnesium stearate was added to Step 1 and blended..
Step 3 : Step 2 was compressed into tablets using with a hardness of about 8-10 Kp
Step 4 : Coating solution preparation: Hydroxypropyl methylcellulose was added in
mixture of IPA and methylene chloride, followed by addition of PEG and ethyl cellulose.
Step 3 tablets were coated with ethyl cellulose solution with different coating percentages
in the range of 2-8 % weight gain using a perforated coating pan.
Example 2A : Step 4 tablets with 2% w/w coating.
Example 2B :. Step 4 tablets with 4% w/w coating
Example 2C : Step 4 tablets with 6% w/w coating
Example 2D : Step 4 tablets with 8% w/w coating
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Dissolution profile of the tablets manufactured in example 2 A, 2B, 2C , 2D and the marketed formulation, Invega®, Paliperidone 9 mg extended release tablets was carried out in 500 mL 0.0825 N HC1 with 0.2% w/w of NaCl, pH 1.0, at 50 rpm, USP apparatus Type II, the results of which are given below:
Figure 1: Dissolution profile of Examples 2A, 2B, 2C, 2D and Invega®, Paliperidone extended release dosage forms and in 500 mL 0.0825 N HC1 with 0.2% w/w of NaCl pH 1.0, at 50 rpm, USP apparatus Type II.

Dissolution of Paliperidone Extended Release Tablets in 0.0825N HC1 with 0.2% NaCl, pH 1.2,50 RPM, USP II apparatusi fin ^
1UU■oI 80 -£« 60 -c o? 40 -0)Q.1 20 -




u 0 2 4 6 8 10 12 14 16 18 20 22 24
—B- Invega 0 0 4 9 16 26 37 49 60 74 87 94 103
-*-Ex. 2A 0.00 0.00 5.30 13.9 23.7 33.6 43.4 51.9 60.1 67.8 72.3 76.6 81.5
-•-Ex. 2B 0.00 0.00 4.70 12.9 22.6 32.8 43.0 50.7 60.2 67.3 72.3 77.5 82.3
-X-Ex. 2C 0.00 0.00 0.00 5.10 11.9 17.9 26.9 36.2 45.1 57.3 65.7 72.2 79.0
—1—Ex. 2D 0 0 1.8 5.3 11.2 18.2 26.8 34.2 44.3 53.8 62.1 72.3
It is observed that dissolution of example 2A, 2B, 2C and 2D show controlled release profile upto around 24 hrs. Hence matrix tablets of the present invention with rate controlling agent, involving simple processes known in the art are capable of providing controlled release of Paliperidone at-least upto 16 hrs and more preferably upto 24 hrs. The extended release tablets
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of the present invention do not require sophisticated compression machines designed to produce multi-layered tablets and laser drilling machine to create orifices on the dosage form.
Dated 04th day of Mar 2008
Signature:
RAKHIROHRA
Principal Scientist -IPR
CADILA HEALTHCARE LIMITED
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