FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification
[See Sections 10 and rule 13]
Title: Pharmaceutical formulation of Clozapine
Applicant: (a) Name: Astron Research Limited
(b) Nationality: Indian
(c) Address: 10 Floor, Premier House Bodakdev, Opp. Gurudwara Sarkhej - Gandhinagar Highway Ahmedabad 380054
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of the Invention
The present invention relates to a novel pharmaceutical composition for the modified release of Clozapine.
Background and Prior Art
Chemically, Clozapine is 8-Chloro-11 -(4-methyl-1 -piperazinyl)-5H-dibenzo [b,e][l,4] diazepine and have the following structure:

Clozapine was first disclosed in the US patent US3539573 and is classified as an atypical anti-psychotic agent. Clozapine is marketed by Novartis in the US as CLOZARIL® tablets.
US20080026062 discloses a composition of plurality of nano-sized particles of active agent and water-soluble or partially water-soluble polymer matrix wherein particulate pharmaceutical composition is micronized.
US20050079138 discloses pharmaceutical formulation of porous microparticle comprising a pharmaceutical agent blending with at least one excipient, jet milling the powder blend.

US20080026040 discloses plurality of polymeric film layers heat sealed together as a multilayer structure; and controlled amounts of active agent dissolved or dispersed in a liquid vehicle and method of preparation of this by ink-jetting.
EP1931320 discloses microparticles "shell" coated with at least one active ingredient and is of the kind formed by particles of active pharmaceutical each covered by at least two distinct coating film
All above reference patents disclose art relating to either nano-sized, milled or are for multi-layer structure. Nano-sized or milled active ingredients in the composition may lead to higher bioavailability and hence results in dose dumping; whereas multi-layered dosage forms may not result in an effective dosage form for controlling the release of the drug. The subject of the present invention is to develop modified release pharmaceutical composition of Clozapine or its pharmaceutical salt wherein the release of the drug is effectively controlled.
Object of the Invention
An object of the invention is to provide once a day modified release pharmaceutical composition of Clozapine comprising of a minimal of 10 wt% polymer coating.
Another object of the invention is to provide once a day modified release pharmaceutical composition of Clozapine comprising total polymer content not more than 30 wt%.
Another object of the invention is to provide once a day modified release pharmaceutical composition of Clozapine wherein 40 to 60% of the active ingredient is released as immediate release.

Another object of the invention is to provide once a day modified release pharmaceutical composition of Clozapine comprising total polymer content not more than 30 wt% and optionally comprising a coating; wherein 40 to 60% of the active ingredient is released as immediate release.
Another object of the invention is to provide processes for preparing once a day modified release pharmaceutical composition of Clozapine as per the present invention.
Summary of the Invention
Present invention relates to once a day modified release pharmaceutical composition of Clozapine comprising of a minimal of 10 % polymer coating. Further the present invention relates to once a day modified release pharmaceutical composition of Clozapine comprising not more than 30 wt% of total polymer content and optionally comprises of coating; wherein 40 to 60% of the active ingredient is released as immediate release. The invention is to provide processes for preparing once a day modified release pharmaceutical composition of Clozapine as per the present invention.
Detailed Description of the Invention
The present invention discloses modified release of Clozapine wherein 40 to 60% of the active ingredient is released from the composition as immediate release. The said composition according to the present invention comprises total polymer content not more than 30 wt% and further optionally comprises of coating.
The pharmaceutical composition of the present invention comprises a solid oral dosage form in the form of tablet or capsule which comprising of Clozapine, not more than 30 wt% of total polymer content, other pharmaceutically acceptable

excipients and may further optionally comprises of coating; wherein 40 - 60% of the active ingredient is released from the composition as immediate release.
Pharmaceutical composition of the present invention is multi particulate system. The term "multi particulate" in the present invention is defined as granules or pellets or coated granules or coated pellets.
"Clozapine" in the present invention is defined as Clozapine or its pharmaceutically acceptable salts as active ingredient.
The term "modified release" in the present invention is multiple release which includes combination of immediate release with either controlled release or delayed release in a single dosage form. In this multiple release composition immediate release of the active ingredient is 40 to 60% within 60 minutes.
The term "coating" in the present invention is defined as any coating done by pharmaceutically acceptable coating material on the surface of core of the composition.
The term "total polymer content" in the present invention is defined as the amount of polymer in the dosage form.
Clozapine composition according to the present invention comprises of Clozapine 30-60 wt%, diluent 10-80 wt%, polymer content not more than 30 wt%, binder 2-5 wt%, glidant 1-3 wt%, lubricant 2-5 wt% and solvent system.
In the present invention Clozapine may be micronized in which D90 is not more that 150 microns.

The composition of the present invention is based on preparation by dry granulation, wet granulation direct compression method or pellet based technology comprising a Clozapine and its pharmaceutically acceptable salt. All the above methods are well defined in the art and are commonly practiced by person skilled in the art,
The uncoated granules are compressed into tablets and then optionally coated or the granules / pellets are optionally coated and then filled into the capsule.
Polymers can be selected from hydrophilic, hydrophobic pH dependent, pH independent, swellable polymers or mixture thereof. Examples of pharmaceutically acceptable polymer used for polymer coating according to the present invention include but are not limited to:
Cellulose ethers such as methylcellulose, ethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose,
hydroxypropylethylcellulose, crosslinked carboxymethylcellulose and its
derivatives, ethylhydroxyethylcellolose, hydroxyethylmethylcellulose,
hydrophobically modified hydroxyethylcellulose, hydrophobically modified ethylhydroxyehtylcellulose, carboxymethylhydroxyethylcellulose, carboxymethyl hydrophobically modified hydroxyethylcellulose and the likes thereof;
- Vinylpyrollidone polymers such as polyvinylpyrollidone, crosslinked polyvinylpyrollidone, or crospovidone, copolymers of vinyl pyrollidone and vinylacetate and the likes thereof;
- Alkylene oxide homopolymers such as polypropylene oxide, preferably ethylene oxide homopolymers and the likes thereof;

- Gums of plant, animals, minieral or synthetic origin and their derivatives their of, eg. Gaur gum, karaya gum, alginates, pectins, dextrans, and the likes thereof;
- An acrylic acid polymers such as cross-linked polymers available under the tradename Carbopol® or homopolymers and co-polymers of acrylate or methacrylate monomers, eg. Eudragit® and the likes thereof.
Diluent can be selected from the group comprising of but not limited to lactose, sucrose, mannitol, sorbitol, microcrystalline cellulose, calcium phosphates, dextrose, gelatin, acacia, sodium phosphates and the likes.
Binder can be selected from the group comprising of but not limited to polyvinylpyrollidone, starch, methyl cellulose, ethyl cellulose, polyethylene glycol, polyvinyl alcohol, hydroxypropyl cellulose and the likes.
Glidants can be selected from the group comprising of but not limited to talc, sodium stearyl fumarate, magnesium stearate, stearic acid, calcium stearate and the likes.
Lubricant can be selected from the group comprising of but not limited to magnesium stearate, stearic acid, talc, calcium stearate, sodium stearyl fumarate and the likes.
Solvents are used as per the quantity required and can be selected from the group comprising of but not limited to isopropyl alcohol, dichloromethane, methanol, purified water, mixture of likes.
Process for preparation of dosage form
The preferred manufacturing process of the solid oral dosage form of the present invention involves Extrusion Spheronization, Drug coating and Functional coating in FBP, Granulation in RMG - Drying -Sizing - Granules coating.

Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
Example
The present invention has been described by way of example only, and it is to be recognized that modifications thereto falling within the scope and spirit of the appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention.
The above said invention can be illustrated by but not limited to following example(s).
Clozapine MR Capsules Example 1

Sr. No. Ingredients Function %w/w
1 Clozapine Active 44.44%
2 MCCPH-101 Diluent 17.77%
3 Lactose monohydrate Diluent 25.0%
4 Hydroxy propyl cellulose (Klucel-LF) Binder 1.67%
5 Purified Water Granulating fluid —
6 Ethyl cellulose Functional polymer 7.77%
7 Hypromellose E5 Pore former 3.33%
8 Isopropyl alcohol Vehicle —
9 Methylene chloride Vehicle ~

Procedure:
1) Clozapine, MCC PH-101, Lactose monohydrate and Hydroxy propyl cellulose (Klucel-LF) were co sifted through 40# and transferred to RMG followed by granulation with purified Water.
2) Wet mass was subjected to Extrusion Spheronization to obtain spheroids.
3) Spheroids were dried using Rapid dryer at 50C inlet temperature.
4) Polymer Solution : Ethyl cellulose and Hypromellose E5 were dissolved in Isopropyl alcohol: Methylene chloride in ratio of 50:50.
5) Functional coating done on spheroids using polymer solution in Fluidized bed processor.
6) Functional coated pellets filled in empty hard gelatin capsule.
Example 2

Sr. No. Ingredients Function %w/w
1 Clozapine Active 50.00 %
2 Lactose monohydrate Diluent 22.00 %
3 Microcrystalline Cellulose Diluent 11.50%
4 HPMC K4M / HPMCK15LV Functional polymer 10.00%
5 PVP K 30 Binder 4.00%
6 P. Water Granulating Fluid —
7 Colloidal Anhydrous Silica Glidant 0.50%
8 Magnesium Stearate Functional polymer 2.0 %
Procedure:
1) Clozapine, Microcrystalline, Lactose monohydrate and HPMC K4M or HPMC K15LV
Were co sifted through 40# and transferred to RMG followed by granulation with PVP in Isopropyl alcohol: P. Water in ratio of 80:20 to 50:50.

2) Granules were dried using Rapid dryer at 50C inlet temperature.
3) Granules were sized through 1 mm sieve and blended with 40# sifted Colloidal anhydrous silica and magnesium stearate.
Lubricated blend as such filled in empty hard gelatin capsule or compressed into tablets using sutiable compression machine and filled in to EHG Capsule shell.
Example 3

Sr. No. Ingredients Function %w/w
1 Clozapine Active 41.16%
2 MCCPH-101 Diluent 16.46%
3 Lactose monohydrate Diluent 23.15%
4 Hydroxy propyl cellulose (Klucel-LF) Binder 1.54%
5 Purified water Granulating fluid ~
6 Opadry OY LS 58900 white Seal coat 6.17%
7 Eudragit L30 D-55 Functional polymer 9.83%
8 Polysorbate 80 surfactant 0.20%
9 Tri ethyl citrate Plasticizer 0.98%
10 Glyceryl monostearate Anti adherent 0.49%
11 Purified water Vehicle —
Procedure:
Immediate Release Pellets
1) Clozapine, MCC PH-101, Lactose monohydrate and Hydroxy propyl cellulose (Klucel-LF) were co sifted through 40# and transferred to RMG followed by granulation with P. Water.
2) Wet mass was subjected to Extrusion Spheronization to obtain spheroids.
3) Spheroids were dried using Rapid dryer at 50C inlet temperature.

Modified Release pellets
4) Polymer Solution: In Purified water of 70°C disperse Glyceryl monostearate, Triethyl citrate and Polysorbate 80. Above dispersion mixed to Eudragit 130D500 dispersion using stirrer.
5) Functional coating done on spheroids using polymer solution in Fluidized bed processor.
6) Immediate release pellets and Modified release pellets were mixed in 25:75 or 40:60 or 50: 50 or 60: 40 ratio and filled in empty hard gelatin capsule.
Example 4

Sr. No. Ingredients Function %w/w
1 Non pareil seeds (30-35#) or (20-30#) Inert Core 23.50%
2 Clozapine Active 47.00%
3 PEG-400 Plasticizer 0.94%
4 Hypromellose E5 Binder 9.40%
5 Hydroxy propyl cellulose (Klucel-LF) Binder 4.70%
6 Talc Anti adherent 1.41%
7 Purified Water Vehicle —
8 Ethyl cellulose Functional polymer 9.13%
9 Hypromellose E5 Pore former 3.91%
10 Isopropyl alcohol Vehicle ~
11 Methylene chloride Vehicle —
Procedure:
1) Coating Dispersion :
a) Hypromellose E5, PEG 400 and hydroxy propyl cellulose (Klucel-LF) were dissolved in Purified water followed by dispersion of Talc in same solution.

b) Clozapine was dispersed in P. water.
c) Dispersion (a) mixed to dispersion (b) and stirred for 15 mins.

2) Non Pareil seed of desired fraction transferred to Fluidized bed processor and coated with coating dispersion of Step (1).
3) Drug coated non pareil seeds were dried subjected to functional coating in FBP.
4) Polymer Solution : Ethyl cellulose and Hypromellose E5 were dissolved in Isopropyl alcohol: Methylene chloride in ratio of 50:50.
5) Functional coating done on spheroids using polymer solution in Fluidized bed processor.
6) Functional coated pellets filled in empty hard gelatin capsule.

WE CLAIM:
1. Modified release pharmaceutical composition of Clozapine which provides 40-60% of release of Clozapine by immediate release.
2. Modified release pharmaceutical composition as claimed in claim 1, wherein the composition comprises Clozapine or its pharmaceutically acceptable salt, polymer and pharmaceutical excipients.
3. Modified release pharmaceutical composition as claimed in claim 2, wherein the polymer can be hydrophilic, hydrophobic pH dependent, pH independent, swellable polymers or mixture thereof.
4. Modified release pharmaceutical composition as claimed in the preceding claims, wherein the composition is multi particulate in the form of granules or pellets or coated granules or coated pellets.
5. Modified release pharmaceutical composition as claimed in the preceding claims, wherein the composition can be in the form of tablet or capsule.
6. Modified release pharmaceutical composition as claimed in claim 2, wherein pharmaceutical excipients are selected from a group comprising of diluent, binder, glidant, lubricant and anti-adhering agents.
7. Modified release pharmaceutical composition as claimed in any of the preceding claims, wherein the composition comprises of Clozapine or its pharmaceutically acceptable salt 30-60 wt%, diluent 10-80 wt%, total polymer content not more than 30 wt%, binder 2-5 wt%, glidant 1-3 wt%, lubricant 2-5

wt% and further having optional coating; wherein 40 to 60% of Clozapine is released by immediate release.
8. Modified release pharmaceutical composition of Clozapine, wherein the composition comprises of a core comprising of Clozapine or its pharmaceutically acceptable salt 30-60 wt%, diluent 10-80 wt%, total polymer content not more than 30 wt%, binder 2-5 wt%, glidant 1-3 wt%, lubricant 2-5 wt% and an optional coating surrounding the core; wherein 40 to 60% of Clozapine is released by immediate release.
9. Modified release pharmaceutical composition of Clozapine as herein described with foregoing description and example.