FORM 2
THE PATENTS ACT, 1970
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
GASTRO-RETENTIVE COMPOSITIONS OF
DARIFENACIN AND PROCESS FOR
PREPARATION THEREOF
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification describes the nature of the invention and the manner in which it is to by performed:

FIELD OF THE INVENTION
The present invention relates to sustained release pharmaceutical compositions of darifenacin; and process for preparing such compositions. More particularly, it relates to gastro-retentive compositions comprising (i) darifenacin and (ii) a matrix comprising at least one swellable polymer.
BACKGROUND OF THE INVENTION
European Patent No 0388054 A1 assigned to Pfizer Ltd. discloses darifenacin and its pharmaceutically acceptable salts as novel muscarinic receptor antagonists. Chemically, darifenacin is designated as (S)-2-{1-[2-(2, 3-dihydrobenzofuran-5-yl) ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide and is useful in the treatment of diseases associated with altered motility and/or tone of smooth muscle such as urinary incontinence and irritable bowel syndrome. Darifenacin is marketed as its hydrobromide salt by Novartis in the form of extended release tablet under the registered name Enablex®.
The WO 97/09980 patent application assigned to Pfizer Ltd. discloses a pharmaceutical dosage form adapted for administration to the gastrointestinal tract of a patient, characterized in that the dosage form is adapted to deliver at least 10 % by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of the patient. The "lower gastrointestinal tract" is defined therein as the portion of the gastrointestinal tract between the region of the ileo-caecal junction and the rectum inclusive. It describes that a major metabolite of darifenacin (3'-hydroxyl derivative) is 6-fo!d less selective for muscarinic M3 receptors over M1 receptors in comparison with darifenacin, and so the metabolite is more likely than darifenacin to produce unwanted side-effects such as dry mouth, confusion and blurred vision. It discloses that delivering darifenacin and its pharmaceutically acceptable salts to the lower gastrointestinal tract (e.g. in a sustained release formulation) gives rise to a greater ratio of darifenacin to

metabolite in the systemic circulation which increases the bioavailability of darifenacin and minimizes any unwanted side-effects.
There is a need in the art for alternative sustained release compositions of darifenacin wherein the bioavailability of darifenacin is not compromised and which have fewer propensities of side-effects. We have surprisingly found that a sustained release composition may be prepared by providing darifenacin in a gastric retention system, wherein the composition releases more than 90% by weight of the darifenacin to upper part of gastro-intestinal tract of a patient.
SUMMARY OF THE INVENTION
One aspect provides a gastro-retenti've pharmaceutical composition comprising:
(i) darifenacin;
(ii) a matrix comprising at least one swellable polymer; and
(iii) one or more pharmaceutically acceptable excipients; wherein the composition releases more than 90% by weight of the darifenacin to upper part of gastro-intestinal tract of a patient after oral administration.
Another aspect provides a process for preparation of a gastro-retentive pharmaceutical composition, wherein the process comprises:
(i) mixing darifenacin, at least one swellable polymer, and optionally one or
more pharmaceutically acceptable excipients; and
(ii) compressing the mixture of step (i) into a bharmaceutical composition; wherein the composition releases more than 90% by weight of the darifenacin to upper gastro-intestinal tract of a patient of a patient after oral administration.
Yet another aspect provides a process for preparation of a gastro-retentive Pharmaceutical composition, wherein the process comprises:
(i) mixing darifenacin, at least one swellable polymer, and optionally one or
more pharmaceutically acceptable excipients;
(ii) compacting the mixture obtained in step (i) into compacts;
(iii) optionally milling the compacts;

(iv) mixing the product of step (ii) or (iii) with one or more pharmaceutically
acceptable excipients and optionally the swellable polymer; and
(v) compressing the mixture of step (iv) into the pharmaceutical composition;
wherein the opposition releases more than 90% by weight of the darifenacin to
upper gastro-intestinal tract of a patient after oral administration.
Still another aspect provides a process for preparation of a gastro-retentive pharmaceutical composition, wherein the process comprises:
(i) mixing darifenacin, at least one swellable polymer, and optionally one or
more pharmaceutically acceptable excipients;
(ii) granulating the mixture obtained in step (i) with a solvent;
(iii) optionally drying the granules;
(iv) mixing the product of step (ii) or (iii) with one or more pharmaceutically
acceptable excipients and optionally the swellable polymer; and
(v) compressing the mixture of step (iv) into the pharmaceutical composition; wherein the composition releases more than 90% by weight of the darifenacin to upper gastro-iritestinal tract of a patient of a patient after oral administration.
DETAILED DESCRIPTION OF THE INVENTION
The term "darifenacin" as described herein is intended to include darifenacin free base, as well as pharmaceutically acceptable salts, prodrugs, metabolites thereof, or enantiomers thereof. It also includes hydrates, solvates and polymorphs of darifenacin free base or pharmaceutically acceptable salts thereof; or mixtures thereof. The preferred salt of darifenacin is darifenacin hydrobromide. Darifenacin may be present in an amount ranging from about 1 % to about 90 % by weight of the composition.
The term "upper gastro-intestinal tract" as described herein is meant to include stomach and the portion of the tract between the region of the duodenum and ileo-

caecal junction (excluding the ileo-caecal junction). Preferably, substantial quantity of the drug is released in stomach.
The "swellable polymer" as described herein may be selected from any hydrophilic polymer which when contacted with water or gastric fluid swells to an extent sufficient to provide gastric retention. Suitable swellable polymers may be selected from various swellable grades of cellulose ethers such as alkyl cellulose, carboxyaikyl cellulose, hydroxy C1-4 alkyl celluloses including methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose sodium, and the like; natural, semi-synthetic, or synthetic di-, oligo- and polysaccharides such as agar, alginates, carrageenan, guar gum, gum arabic, gum tragacanth, karaya gum, locust bean gum, pectin, dextran, gellan gum, xanthan gum, galactomannans, chitin derivates such as chitosan, modified starches like sodium starch glycolate; poiyvinylpyrollidone, copolymers of polyvinylpyrrolidone with polyvinylvinyl acetate (available under the trade-name Kollidon®) or polyvinylalcohol; polyalkylene oxides such as polyethylene oxide and polypropylene oxide, copolymers of ethylene oxide and propylene oxide, various swellable grades of methacrylate co-polymers available under the trade-name Eudragit® RS, RL and NE; carbomers, such as cross-linked polymer of acrylic acid with polyalkenyl ethers or divinyl glycol polymers available under the trade-name Carbopol®, copolymers of methyl vinyl ether and maleic anhydride available under the trade-name Gantrez®, and the like; or mixtures thereof, in one preferred embodiment, the swellable polymer also provides muco-adhesive effect which may assist in extending residence time in the stomach. Suitable swellable polymers which possess muco-adhesive properties include carboxyalkylcelluloses such as carboxymethylcellulose sodium, cross-linked polymer of acrylic acid with polyalkenyl ethers or divinyl glycol polymers (also known as carbomers) available under the trade-name Carbopol®, copolymers of methyl vinyl ether and maleic anhydride available under the trade-name Gantrez®. The swellable polymer may be present in an amount ranging from 1 % to 90 % by weight, more particularly 10 % to 50 % by weight of the composition.

Retention of pharmaceutical compositions in the upper gastrointestinal tract in order for said composition to achieve its beneficial effect poses a difficult problem. Davis et al., Int. J. Pharm. 21, 331-340 (1984) teach that gastrointestinal transit of a pharmaceutical composition depends upon several factors such as size, shape and nature of the system; i.e., whether single unit or multiparticulate; and upon physiological factors, especially upon the presence or absence of food in the stomach. The stomach is known to empty different materials at different rates and to break down digestible materials to about 2 mm or less before they pass through the pylorus into the duodenum. Meals of high calorific value and certain foodstuffs, especially fats, appear to have an inhibitor effect on gastric emptying [Davis et al., Int. J. Pharm. 21, 167-177, (1984)]. Retention of indigestible materials in an empty stomach is further complicated by the ability of the gastrointestinal tract to undergo powerful contractions called the interdigestive myoelectric complex (IMC), also known as interdigestive migrating motor complex, or more simply, "housekeeper wave". This phenomenon tends to sweep indigestible materials from an empty stomach past the pylorus into the duodenum and through the remainder of the small intestine. Thus, the overall dimensions of the compositions are an important aspect of this invention. In the unused condition they must be of a size suitable for oral administration to the mammal to be treated. For example, the largest dimension in the unused condition may vary from about 5.0 mm to about 20.0 mm, more particularly from about 12 mm to about 18 mm. For human use, from a practical standpoint, the largest dimension of the systems in the expanded condition may vary from about 15 mm to 30 mm.
The pharmaceutical compositions as described herein may comprise of one or more pharmaceutically acceptable excipients selected from diluent, binder, swelling modulating agent, glidant or lubricant.
Diluent as described herein may be selected from cellulose derivatives such as powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose;

starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate; saccharides such as lactose, sucrose or dextrose; sugar alcohols such as mannitol, sorbitol or erythritol; and mixtures thereof. Diluent may be present in an amount ranging from 1 % to 80 % by weight of the composition.
Swelling modulating agent as described herein may be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate; and mixtures thereof. Swelling modulating agent may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
Binder as described herein may be selected from hydrophilic polymers such as hydroxypropyl methylcellulose, polyvinylpyrrolidone; hydroxyprapylceHulose, hydroxyethyl cellulose, carbomers, dextrin, gelatin, polymethacrylates, pregelatinized starch, sodium alginate, gums, synthetic resins, and the like. The skilled person may use the swellable polymer as described above in an amount sufficient to produce binding effect. The binder may be present in an amount ranging from 0.1 % to 15 % by weight of the composition.
Lubricant or glidant as described herein may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, sodium stearyl fumarate, magnesium trisilicate; or mixtures thereof. The lubricant or glidant may be present in an amount ranging from 0.1 % to 8 % by weight of the composition.
The pharmaceutical compositions as described herein may be prepared by techniques such as direct compression or granulation. For example, darifenacin may be mixed with a swellable polymer, diluent, swelling modulating agent, glidant, and optionally a binder; the mixture may be lubricated by addition of a lubricant and compressed into tablets. Alternatively, the mixture of darifenacin, swellable polymer, diluent, swelling modulating agent, glidant, and optionally a binder may be

compacted in a roller compacter; the compacts may be milled, lubricated by addition of a lubricant and the mixture compressed into tablets. Alternatively, the mixture of darifenacin, swellable polymer, diluent, swelling modulating agent, glidant, and optionally a binder may be granulated with water or an organic solvent in an apparatus, such as rapid mixer granulator or a fluid bed processor to form granules. The granules may be dried, mixed with one or more excipients such as a diluent or a lubricant, and compressed into tablets. The tablets may optionally be coated.
In one embodiment, a gastro-retentive tablet is prepared by:
(i) mixing darifenacin, at least one swellable polymer, and optionally one or
more pharmaceutically acceptable excipients;
(ii) compressing the mixture obtained in step (i) into a tablet; and
(iii) optionally coating the tablet.
In another embodiment, a gastro-retentive tablet is prepared by :
(i) mixing darifenacin, at least one swellable polymer, and optionally one or
more pharmaceutically acceptable excipients;
(ii) compacting the mixture obtained in step (i) into compacts;
(iii) optionally milling the compacts;
(iv) mixing the product of step (ii) or (iii) with one or more pharmaceutically
acceptable excipients and optionally the swellable polymer;
(v) compressing the mixture obtained in step (iv) into a tablet
(vi) optionally coating the tablet.
In another embodiment, a gastro-retentive tablet is prepared by :
(i) mixing darifenacin, at least one swellable polymer, and optionally one or
more pharmaceutically acceptable excipients;
(ii) granulating the mixture obtained in step (i) with a solvent;
(iii) optionally drying the granules;
(iv) mixing the product of step (ii) or (iii) with one or more pharmaceutically
acceptable excipients and optionally the swellable polymer;
(v) compressing the mixture obtained in step (iv) into a tablet; and

(vi) optionally coating the tablet.
The pharmaceutical compositions as described herein may be illustrated by way of the following examples which are not to be construed as limiting the scope of the invention:
EXAMPLES 1 - 5

1 2 3 4 5
S/N Ingredients Qty / Tab (in mg)
1 Darifenacin hydrobromide 17.86 17.86 17.86 17.86 17.86
2 Carbopol 112.50 135.00 141.75 70.00 118.25
3 Dibasic calcium phosphate 288. 14 288. U 234.14 252.14 304.24
4 Carboxymethylcellulose sodium 22.50 — 47.25 105.00 23.65
5 Talc 4.50 4.50 4.50' - 4.50
6 Magnesium stearate 4.50 4.50 4.50 5.00 4.50
Total 450.00 450.00 450.00 473.00 473.00
PROCEDURE: Darifenacin hydrobromide, carbopol, dibasic calcium phosphate and carboxymethylcellulose sodium (except in Example 2) were sifted and mixed. Talc (except in Example 4) and magnesium stearate were added in the mixture and the mixture was compressed into tablets using appropriate tooling.
EXAMPLES 6 - 9

6 7 8 9
S/N Ingredients Qty/T< ib (in mg)
1 Darifenacin hydrobromide 17.86 17.86 17.86 I 17.86
2 Pofyox 135.00 180.00 120.00 120.00
3 Dibasic calcium phosphate 288.14 390.14 390.14 390.14
4 Carboxymethylcellulose sodium -- -- 60.00
5 Polyvinylpyrrolidone - -- 60.00 ~
6 Talc 4.50 6.00 6.00 6.00
7 Magnesium stearate 4.50 6.00 6.00 6.00
Total 450.00 600.00 600.00 600.00
PROCEDURE: Darifenacin hydrobromide, polyox, dibasic calcium phosphate, polyvinylpyrrolidone (only in Example 8) and carboxymethylceiluiose sodium (only in

Example 9) were sifted and mixed. Talc and magnesium stearate were added in the mixture and the mixture was compressed into tablets using appropriate tooling.
EXAMPLE 10

S/N Ingredients Qty / Tab (in mg)
1 Darifenacin hydrobromide 17.86
2
3 Carbopol 70.95

Polyox 70.95
4 Dibasic calcium phosphate 304.24
5 Talc 4.500
6 Magnesium stearate 4.500
Total 473.00
PROCEDURE: Darifenacin hydrobromide, carbopol, polyox and dibasic calcium phosphate were sifted and mixed. Talc and magnesium stearate were added in the mixture and the mixture was compressed into tablets using appropriate tooling.
EXAMPLES 11 -14

11 12 13 14
S/N Ingredients Qty / Tab (in mg)
1 Darifenacin hydrobromide 17.86 17.86 17.86 17.86
2 Polyox 255.00 255.00 170.00 150.00
3 Dibasic calcium phosphate 543.14 526.14 543.14 588.14
4 Sodium bicarbonate 17.00 34.00 17.00 17.00
5 Polyvinylpyrrolidone - - 85.00 60.00
6 Talc 8.50 8.50 8.50 8.50
7 Maqnesium stearate 8.50 8.50 8.50 8.50
Total 850.00 850.00 850.00 850.00
PROCEDURE: Darifenacin hydrobromide, polyox, dibasic calcium phosphate and polyvinylpyrrolidone (except in Examples 11 and 12) were sifted and mixed. Sodium bicarbonate, talc and magnesium stearate were added in the mixture and the mixture was compressed into tablets using appropriate tooling.

EXAMPLES 15-16

15 16
S/N Ingredients Qty / Tab (in mg)
1 Darifenacin hydrobromide 17.86 17.86
2 Carbopol 127.50 170.00
3 Dibasic calcium phosphate 390.14 296.64
4 Koliidon SR 127.50 255.00
5 Crospovidone 170.00 85.00
6 Sodium bicarbonate - 17.00
7 Talc 8.50 -
8 Magnesium stearate 8.50 8.50
Total 850.00 850.00
PROCEDURE: Darifenacin hydrobromide, carbopol, kollidon-SR and dibasic calcium phosphate were sifted and mixed. Sodium bicarbonate (in example 12), talc (in example 11) and magnesium stearate were added in the mixture and the mixture was compressed into tablets using appropriate tooling.
EXAMPLES 17-18

17 18
S/N Ingredients Qty/Ta t> (in mg)
1 Darifenacin hydrobromide 17.86 17.86
2 Polyox 170.00 255.00
3 Dibasic calcium phosphate 296.64 211.64
4 Koliidon SR 255.00 255.00
5 Crospovidone 85.00 85.00
6 Sodium bicarbonate 17.00 17.00
7 Magnesium stearate 8.50 8.50
Total 850.00 850.00
PROCEDURE: Darifenacin hydrobromide, polyox, kolfidon-SR and dibasic calcium phosphate were sifted and mixed. Sodium bicarbonate and magnesium stearate were added in the mixture and the mixture was compressed into tablets using appropriate tooling.

EXAMPLES 19-21

19 20 21
Ingredients Qty / Tab (in % by weight)
Darifenacin 1-90% 1-90% 1-90%
Dibasic calcium phosphate 1-50% 1-80 % 1-80%
Gantrez® 1-80% 1-35% 1-15%
Carboxymethylcellulose sodium - 1-40% -
Sodium alginate - - 1-40 %
Magnesium stearate 0.1-2% 0.1-2% 0.1-2 %
PROCEDURE: Darifenacin, dibasic calcium phosphate, gantrez®, ca rboxymethyl cellulose sodium (in Example 20) and sodium alginate (in Example 21) are mixed, magnesium stearate is added to the mixture and the mixture is compressed into a tablet using appropriate tooling.
EXAMPLES 22-23

22 23
Ingredients Qty / Tab (in % by weight)
Darifenacin 1-90% 1-90 %
Dibasic calcium phosphate 1-50% 1-50%
Xanthan gum 1-80% 1-60%
Sodium alginate - 1-40 %
Magnesium stearate 0.1-2 % 0.1-2%
PROCEDURE: Darifenacin, dibasic calcium phosphate, xanthan gum and sodium alginate (in Example 23) are mixed, magnesium stearate is added to the mixture and the mixture is compressed into a tablet using appropriate tooling.

EXAMPLE 24

Ingredients Amount (in % by weight)
Darifenacin 1-90 %
Dibasic calcium phosphate 1-80%
Sodium alginate 1-20%
Hydroxypropyl methylcellulose 1-50%
Magnesium stearate 0.1-2 %
PROCEDURE: Darifenacin, dibasic calcium phosphate, sodium alginate and hydroxypropyl methylcellulose are mixed, magnesium stearate is added to the mixture and the mixture is compressed into a tablet using appropriate tooling.
EXAMPLE 25

Ingredients Amount (in % by weight)
Darifenacin 1-90%
Dibasic calcium phosphate 1-80%
Eudragit® 1-40 %
Ethylcellulose 1-30%
Magnesium stearate 0.1-2%
PROCEDURE: Darifenacin, dibasic calcium phosphate, eudragit® and ethylcellulose are mixed, magnesium stearate is added to the mixture and the mixture is compressed into a tablet using appropriate tooling.

EXAMPLE 26

Ingredients Amount (in % by weight)
Darifenacin 1-90 %
Dibasic calcium phosphate 1-50%
Hydroxypropyl methylcellulose 1-50%
Glyceryl behenate 1-20%
Magnesium stearate 0.1-2%
PROCEDURE: Darifenacin, dibasic calcium phosphate, hydroxypropyl methylcellulose and glyceryl behenate are mixed, magnesium stearate is added to the mixture antj the mixture is compressed into a tablet using appropriate tooling.

We Claim:
1) A gastro-retentive pharmaceutical composition comprising:
(i) darifenacin;
(ii) a matrix comprising at least one swellable polymer; and
(iii) one or more pharmaceutically acceptable excipients; wherein the composition releases more than 90% by weight of the darifenacin to upper part of gastro-intestinal tract of a patient after oral administration.
2) The composition according to claim 1, wherein darifenacin is present in an amount ranging from 1 to 90 % by weight of the composition.
3) The composition according to claim 1, wherein swellable polymer is present in an amount ranging from 1 to 90 % by weight of the composition.
4) The composition according to claim 1, wherein swellable polymer is selected from a group consisting of hydroxypropyl methylcellulose, carboxymethylcellulose sodium, xanthan gum, sodium alginate, polyvinylpyrollidone, copolymers of polyvinylpyrrolidone and polyvinylvinyl acetate, polyethylene oxide, methacrylate co-polymers, copolymers of methyl vinyl ether and maleic anhydride, carbomer; and mixtures thereof.
5) The composition according to claim 1, wherein the largest dimension of the composition is in the range of about 5 mm to about 20 mm.
6) The composition according to claim 1. wherein the pharmaceutically acceptable excipient is selected from a group consisting of diluent, swelling modulating agent, binder, glidant, lubricant, anti-adherent, and mixtures thereof.

7) A process for preparation of a gastro-retentive pharmaceutical composition,
wherein the process comprises:
(i) mixing darifenacin, at least one swellable polymer, and optionally one or
more pharmaceutically acceptable excipients; and
(ii) compressing the mixture of step (i) into a pharmaceutical composition; wherein the composition releases more than 90% by weight of the darifenacin to upper gastro-intestinal tract of a patient of a patient after oral administration.
8) A process for preparation of a gastro-retentive pharmaceutical composition,
wherein the process comprises:
(i) mixing darifenacin, at least one swellable polymer, and optionally one or
more pharmaceutically acceptable excipients;
(ii) compacting the mixture obtained in step (i) jnt0 compacts;
(iii) optionally milling the compacts;
(iv) mixing the product of step (ii) or (iii) with one or more pharmaceutically
acceptable excipients and optionally the swellable polymer; and
(v) compressing the mixture of step (iv) into the pharmaceutical composition; wherein the composition releases more than 90% by weight of the darifenacin to upper gastro-intestinal tract of a patient after oral administration.
9) A process for preparation of a gastro-retentive pharmaceutical composition,
wherein the process comprises:
(i) mixing darifenacin, at least one swellable polymer, and optionally one or
more pharmaceutically acceptable excipients;
(ii) granulating the mixture obtained in step (i) with a solvent;
(iii) optionally drying the granules;
(iv) mixing the product of step (ii) or (iii) with one or more pharmaceutically
acceptable excipients and optionally the swellable polymer; and
(v) compressing the mixture of step (iv) into the pharmaceutical composition; wherein the composition releases more than 90% by weight of the darifenacin to upper gastro-intestinal tract of a patient of a patient after oral administration.

10) A sustained release pharmaceutical composition as substantially described and exemplified herein.