FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
A STABLE PHARMACEUTICAL COMPOSITION OF FESOTERODINE HYDROCHLORIDE
GENEPHARM INDIA PRIVATE LIMITED
A company incorporated under the laws of India having their office at
Regd. Off.: 1B, Old Post Street, Kolkata-700001
The following specification particularly describes the invention and the manner in
which it is to be performed

A STABLE PHARMACEUTICAL COMPOSITION OF FESOTERODINE HYDROCHLORIDE
The present invention relates to a stable pharmaceutical composition of fesoterodine
hydrochloride and the process for its preparation
Background cf the invention
Fesoterodine is used in the treatment of overactive bladder, urinary incontinence and other dysfunctions of the urinary tract. European Patent number 1077912Bl (assigned to M/s Schwarz Pharma AG and referred to herein as '912 patent) titled novel derivatives of 3, 3-diphenyl- propylamines discloses festoterndine hydrochloride. However. '912 patent does not disclose compositions of fesoterodine hydrochloride. European Patent number 1230209B1 (assigned to M/s Schwarz Pharma AG and referred to herein as '209 patent) discloses stable salts of novel derivatives of 3,3-diphenylpropylamines which
include Fesoterodine hydrogen fumarate.
Though Fesoterodine is known in the art for its potency in treating urinary incontinence, it may exhibit substantia! degradation under stress conditions, like humid environment and increased temperature. Hydrolyzation and oxidation are the probable mechanisms
resulting in degradation. Hence, it is desirable to develop new pharmaceutical
compositions comprising Fesoterodine that are more stable against degradation over an extended period of time even under stress conditions, it has now been surprisingly found that some pharmaceutical exciptents are able to significantly slow down the degradation of Fesoterodine under stress conditions.
United States Patent number 7807715 and United States Patent Publication number 20091117159 (both assigned to M/s UCB Pharma GmbH and referred to herein as '715 patent and '159 publication respectively) disclose a pharmaceutical granulate

comprising fesoterodine or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable stabilizer, such as sorbitol, xylitoi, polydextrose, isomalt, dextrose or combinations thereof. According to these publications, sugar alcohols are very essential to prepare stable compositions of fesoterodine.
Published PCT application 2011117S84A1 (assigned to M/s Cadila Healthcare Limited) discloses fesoterodine compositions free of sugar alcohol
Object of the invention
The object of the present invention is to provide stable pharmaceutical composition comprising fesoterodine hydrochloride.
We have surprisingly found that fesoterodine hydrochloride when admixed with a sugar alcohol selected from mannitol, maltitol and lactitol remains stable when stored at 40°C
and 75% RH for at least three months.
Summary of the invention
A stable pharmaceutical composition comprising fesoterodine hydrochloride, a rate controlling polymer, sugar alcohol and at least one pharmaceutical excipient(s); wherein the sugar alcohol is selected from mannitol, rnaltitoi and lactitol.
More specifically a stable pharmaceutical extended release composition of fesoterodine hydrochloride comprising fesoterodine hydrochloride, a rate controlling polymer, sugar alcohol and at least one pharmaceutical excipient(s); wherein the sugar alcohol is selected from mannitol, maltitol and lactitol and total impurities are less than 1.00%w/w when stored in open vial at 40°C and 75% relative humidity for at least three months.

A process for the preparation of a stable pharmaceutical composition of fesoterodine hydrochloride comprising admixing festoterodine hydrochloride, rate controlling polymer, sugar alcohol and at least one pharmaceutical excipient(s); wherein the sugar alcohol is selected from mannitol, maltitol and lactitol and total impurities are less than 1.00%w/w when stored in open via! at 40°C and 75% relative humidity for at least three months; and optionally compressing.
Description of the invention
The present invention is directed to a stable pharmaceutical composition of fesoterodine hydrochloride. Fesoterodine being an ester is susceptible to hydrolyzation during storage and after administration invivo. On hydrolyzation fesoterodine generates the metabolite (2-[(lR)-3-diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl) phenol along with other degradation products.
According to one embodiment of the present invention a stable pharmaceutical composition of fesoterodine hydrochloride is provided.
The stable pharmaceutical composition of fesoterodine hydrochloride of the present invention will comprise rate controlling, sugar alcohol and at least one pharmaceutical excipient.
The % total impurities in the stable pharmaceutical composition of fesoterodine hydrochloride of the present invention is less than 1.00% w/w when stored in open vial at 40°C/75% RH for at least three months.

Fesoterodine hydrochloride may be stabilized with sugar alcohol, polyethylene glycol, cyclodextrin, maltodextrin and the like. Sugar alcohols may be selected from mannito!, rnaititol and laciiioi.
The ratio of fesoterodine hydrochloride to sugar alcohol may be selected from 1:25 to 25:1 parts by weight
The rate controlling polymers may be selected from one or more polymers/copolymers
of cellulose or its derivatives such as hydroxypropylmethyl ceiiuiose, hydroxyethyi
cellulose, hydroxypropyl cellulose, hydroxyethyi methyl cellulose, methylcellulose,
carboxymethylcellulose and its salts; polyacrylates, methylacryiates, polyethylene
oxides, polyethylene glycols, gums, chitosan, starch derivatives, polyurethanes,
galactomarmans, polysaccharides, polyalcchols, acrylic acid or its derivatives, ethyl
cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated
vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides,
methylacryiates, polyamides, polycarbonates, polyalkylene, polyalkylene glycols,
polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers,
polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes,
polystyrene, polymers of acrylic and methacrylic esters, polylactides, poly(butyric acid),
poly(valeric acid), poly(lactide-co-glycolides), polyanhydrides, polyorthoesters,
polyffumaric acid), polyfmaleic acid), cellulose acetate, cellulose propionate, cellulose
acetate butyrate, cellulose acetate phthalate, carboxymethylcellulose, cellulose
triacetate, cellulose sulfate sodium salt, polymethylmethacrylate),
poly(ethylmethacrylate), poly(butylmethacrylate), poly(isobutylmethacrylate),
poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(laurylrnethacryl3te), poly(phenylmethacrylate); poly (methylacrylate), poly (isopropylmethacrylate) and the like.

Natural polymers may also be added to the composition such as pectin, zein, casein, gluten, gelatin, serum albumin, collagen, oligosaccharides and polysaccharides such as cellulose, dextrans, geilan, carrageenan, xanthan gum, gum Arabic, alginic acid and the like.
The amount of the rate controlling polymer in the pharmaceutical composition ranges
from about 10 to 80 % w/w of the compositions
The stable pharmaceutical composition of fesoterodine hydrochloride of the present Invention may provide Immediate or sustained or extended or controlled releace of fesoterodine hydrochloride, preferably extended release.
Pharmaceutical composition of fesoterodine hydrochloride of the present invention may be selected from tablets, capsules, pellets, granules, spheroids, beads, minitablets in capsules, pellets in capsule, granules in capsule and powders.
The pharmaceutical composition of fesoterodine hydrochloride of the present invention
may or may not be coated. coating such as film, enteric coating may be used.
.
According to another embodiment of the present invention the stable pharmaceutical composition of fesoterodine hydrochloride is an extended release composition comprising rate controlling polymer, sugar alcohol and at least one pharmaceutical excipient.
The % total impurities in the stable pharmaceutical composition of fesoterodine hydrochloride of the present invention is less than 1.00% w/w when stored in open vial at 40oC/75% RH for at least three months.

Fesoterodine hydrochloride may be stabilized with sugar alcohol, polyethylene glycol, cyclodextrin, maltodextrin and the like. Sugar alcohols may be selected from mannitol, maltitol and iactitol.
The ratio of fesoterodine hydrochloride to sugar alcohol may be selected from 1:25 to 25:1 parts by weight.
The rate controlling polymers may be selected from one or more polymers/copolymers of cellulose or its derivatives such as hydroxypropylmethyl cellulose, hydroxyethy! cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, methylcellulose, carboxymethylcellulcse and its salts; polyacrylates, methylacrylates, polyethylene oxides, polyethylene glycols, gums, chitosan, starch derivatives, polyurethanes, galactomannans. polysaccharides, polyalcohols, acrylic acid or its derivatives, ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcoho!, glyceryl behenate, polyanhydrides, methylacrylates, polyamides, polycarbonates, polyalkylene, polyalkylene glycols,
polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes,
polystyrene, polymers of acrylic and methacrylic esters, polylactides, pc!y(butyric acid),
poly(valeric acid), poly(lactide-co-glycolides), polyanhydrides, polyorthoesters,
poiy(fumaric acid), poiyfmaletc acid), cellulose acetate, cellulose propionate, cellulose
acetate butyrate, cellulose acetate phthalate, carboxymethylcellulose, cellulose
triacetate, cellulose sulfate sodium sait, poiy(methyimethacrylate),
poly(ethylmethacrylate), poly(butylmethacrylate), poly(isobutylmethacrylate),
poly(hexyimethacryiate), poiy(isodecyl methacryiate), poiy(iauryimethacryiate), poly(phenylmethacrylate), poly (methylacrylate), poly (isopropylmethacrylate) and the like.

Natural polymers may also be added to the composition such as pectin, zein, casein, gluten, gelatin, serum albumin, collagen, oligosaccharides and polysaccharides such as ceflufose, dextrans, gellan, carrageenan, xanthan gum, gum Arabic, alginic acid and the like.
The amount of the rate controlling polymer in the pharmaceutical composition ranges from about 10 to 80%w/w of the composition.
Pharmaceutical composition of fesoterodine hydrochloride of the present invention may be selected from tablets, capsules, pellets, granules, spheroids, beads, minitablets in capsules, pellets in capsule, granules in capsule and powders.
The pharmaceutical composition of fesoterodine hydrochloride of the present invention may or may not be coated. Coating such as film, enteric coating may be used.
According to yet another embodiment of the present invention is the process for the preparation of stable pharmaceutical composition of fesoterodine hydrochloride is provided. Processes such as direct compression, wet granulation, dry granulation, slugging, roller compaction, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion spheronization, spray drying and the like may be used.
Fesoterodine hydrochloride is admixed with rate controlling polymer, sugar alcohol and at least one pharmaceutically acceptable excipient; wherein sugar alcohol may be selected from mannitol, maltitol and factitol, optionally granulated and optionally compressed.
More specifically, a process for the preparation of a stable pharmaceutical composition of fesoterodine hydrochloride comprising admixing or granulating festoterodine hydrochloride, rate controlling polymer, sugar alcohol and at feast one pharmaceutical

excipient(s); wherein the sugar alcohol is selected from mannitol, maltitol and Jactitol and total impurities are less than 1 %w/w when stored in open vial at 40°C and 75% relative humidity for at least three months; optionally compressing.
The stable pharmaceutical composition of fesoterodine hydrochloride of the present invention may provide immediate or sustained or extended or controlled release of fesoterodine hydrochloride, preferably extended release.
The pharmaceutically acceptable excipient used in the composition and process for preparation of the composition of the present invention must be compatible with fesoterodine hydrochloride.
The pharmaceutical excipients may be selected from diluents, binders, lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, solubilizers, surfactants, glidants, plasticizers, preservatives and sweeteners.
Diluents may be selected from calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystafline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose, isomalt, maltodextrin, maltitol and the like. Diluents may be in the range of 5-98 weight % of the total weight of the composition.
Binders may be selected from acacia, alginic acid, carbomer, carboxymethylcellufose calcium, carbomethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch.

sucrose, tragacanth, low-substituted hydroxypropyl cellulose, glucose, sorbitol. Binders may be in the range of 1-40 weight % of the total weight of the composition.
Suitable fillers are preferably selected from atleast one of starch derivatives, such as corn starch, potato starch, maize starch maize or rice starch. Polysaccharides such as dextrins, maltodextrins, dextrates, microcrystalline cellulose, powdered cellulose, mixture of microcrystalline cellulose and guar gum, coprocessed blends of microcrystalline cellulose; and polyhydric alcohols, such as xylitol, sorbitol and the like.
Disintegrants may be selected from alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropyl cellulose, methylcellulose, poiacrilin potassium , poloxamer, povidone, sodium glycine carbonate, sodium laulyl sulfate, sodium starch glycolate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and the like. Disintegrants may be in the range of 5 - 25 weight % of the total weight of the composition.
Glidants may be selected from calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide and the like. Glidants may be in the range of 0.01-2 weight % of the total weight of the composition.
Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, glyceryl behenate and the like. Lubricants may be in the range of 0.1-2 weight % of the total weight of the composition.
Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; aspartame and the like.

Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green appie flavour, spearmint flavor, peppermint flavor and the like.
Solubilizers may be selected from complex forming agents such as cyclodextrins, ion exchange resins, crown ethers and the like.
Surfactants may be selected from polyoxyethylene alcohol ethers, polysorbates, polyoxypropylene polyoxyethylene copolymers such as poioxamers and the like.
The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope of the invention.

EXAMPLES
Example 1
Accelerated 1 month Open vial study at 40°C and 75% relative humidity

Total impurities% API (HCI salt) APl+Mannitol (1:9w/w)
Zero time 0.13 0.09
1M OV 0.49 0.23
Example 2

Fesoterodine HCI Fesoterodine HCI + Mannitot Fesoterodine HCI +Mannitol+HPMC
Total Impurities {%)
Zero time 0.13 0.09 0.13
lM OV 40° C and75% relative humidity 0.49 n to 0.16
Example 3

BP(043)11-R2 (mg/tab)
Fesoterodine HCI 6.83
HPMCK100 50.00
HPMCK15 50.00
PVP 20.00
Pearlitol 30.00
MicrocelaclOO 149.17
Talc 7,00
MgSt 7.00
Tablet weight: 320.0

BP(043)11-R2
Total Impurities
Zero time 0.14
1M closed vial 40°C and 75% relative humidity 0.23

Example 4
Prestabilfty study results (Open vial)
Two different compositions of Fesoterodine XR, lot BP(043)47B & BP(043)49B, are prepared using direct compression manufacturing process and kept for 1 month in open vials at accelerated stability conditions (40°C, 75% Relative humidity).

BP(043)47B BP(043)49B
Composition
(mg per tablet) (mg per tablet)
Fesoterodine HCI 6.80
(equivalent to 8mg
Fesoterodine
Fumarate) 6.80
(equivalent to Smg
Fesoterodine
Fumarate)
HPMCK100 160.00 100.00
HPMCK15 - 50.00
Mannitol 30.00 30.00
Starch - 50.00
MCC 68.70 16.70
Lactose 25.50 49.90
Talc - 7.00
Comprito!888 9.00 9.60
Opadry (PVA based) 10.00 10.00

The XR tablets are tested for in vitro dissolution profile (USP apparatus II, pH= 6.8, 900mL, 50 rpm) in zero time and in 1 month open vial at accelerated conditions and the results are shown below:

BP{043)47B BP(043)49B
Dissolution profile zero time
Time fh) (%) (%)
1 16.3 14.9
2 25.6 24.1
4 40.4 38.4
6 52.9 49.9
8 62.9 61.1
12 78.2 76.4
16 88.3 87.5
20 94.9 93.6
Dissolution profile 1M Accelerated sta biltty conditions
Time (h)
1 16.8 18.8
2 28.1 29.8
4 42.4 45.0
6 54.9 58.4
8 65.0 69.4
12 80.7 85.2
16 91.5 97.7
20 99.5 103.3
Similarity factor (f2) for Accelerated stability con zero time and 1M Open Vial ditions
BP(043)47B 77.3
BP(043)49B 54 .8
Results indicate a controlled release profile of fesoterodine hydrochloride, releasing approximately 55% of fesoterodine hydrochloride in 6hrs; and the profile remained stable after tablet storage in open via! at accelerated conditions for 1 month.

The tablets are also checked for their degradation products under the same stability conditions and the table below summarizes the % Diol i.e. R(+)-2-(3-diisopropylamino-l-phenylpropyl)-4-hydroxymethylphenol and % of Total impurities formed during storage.

Prestability Results
BP(043)47B BP(043)49B
Zero time
%diol 0.03 O.Oi
% total impurities 0.17 0.15
IM Open Vial Accelerated stability conditions
% diol 0.14 0.35
% total impurities 0.24 0.51
Results indicate that fesoterodine hydrochloride remained stable in the proposed formulations during storage in the tested conditions (Open vial, Accelerated stability conditions).

We claim
1. A stable pharmaceutical composition comprising fesoterodine hydrochloride, a rate controlling polymer, sugar alcohol and at least one pharmaceutical excipient(s); wherein the sugar alcohol is selected from mannitol, maltito! and lactitol.
2. A stable pharmaceutical composition as claimed in 1 wherein total impurities are less than 1.00 %w/w when stored in open vial at 40°C and 75% relative humidity for at least three months.
3. A stable pharmaceutical composition as claimed in 1 wherein the ratio of fesoterodine hydrochloride to sugar alcohol is about 1:25 to 25:1 parts by weight.
4. A stable pharmaceutical composition as claimed in 1 wherein the composition is an extended release composition.
5. A stable pharmaceutical composition as claimed in 1 wherein the rate controlling polymer is selected from one or more polymers/copolymers of cellulose or its derivatives such as hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, methylcellulose, carboxymethylcellulose and its salts; polyacrylates, methylacrylates, polyethylene oxides, polyethylene glycols, gums, chitosan, starch derivatives, polyurethan'es, galactomannans, polysaccharides, polyalcohols, acrylic acid or its derivatives, ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, methylacrylates, polyamides,

polycarbonates, polyalkylene, pofyaikylene glycols, polyaikylene oxides,
polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl
halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes,
polystyrene, polymers of acrylic and methacrylic esters, polylactides, poly(butyric
acid), poly(valeric acid), poly(lactide-co-glycolides), polyanhydrides,
polyorthoesters, poly(fumaric acid), poly(maleic acid), cellulose acetate, cellulose
propionate, cellulose acetate butyrate, cellulose acetate phthalate,
carboxymethylcellulose, cellulose triacetate, cellulose sulfate sodium salt,
poly(methylmethacrylate), poly(ethylmethacrylate), poly(butylmethacrylate),
poly(isobutylmethacrylate), poly(hexylmethacrylate), poly(isodecyl
methacrylate), poly(laurylmethacrylate), poly(phenylmethacrylate), poly (methylacrylate) and poly (isopropylmethacrylate).
6. A stable pharmaceutical composition as claimed in 1 wherein the pharmaceutical excipient(s) is selected from diluents, binders, lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, solubilizers, surfactants, glidants, plasticizers; preservatives and sweeteners.
7. A stable pharmaceutical composition as claimed in 1 wherein the composition is selected from tablets, capsules, pellets, granules, spheroids, beads, minitablets in capsules, pellets in capsule, granules in capsule and powders.
8. A stable pharmaceutical extended release composition comprising fesoterodine hydrochloride, a rate controlling polymer, sugar alcohol and at least one pharmaceutical excipient(s); wherein the sugar alcohol is selected from mannitol, maititol and lactitol and total impurities are less than 1.00%w/w when stored in open vial at 40°C and 75% relative humidity for at least three months.

9. A process for the preparation of a stable pharmaceutical composition of fesoterodine hydrochloride comprising admixing or granulating festoterodine hydrochloride, rate controlling polymer, sugar alcohol and at least one pharmaceutical excipient(s); wherein the sugar alcohol is selected from mannitol, maltitol and lactitol; and optionally compressing.
10. A process for the preparation of a stable pharmaceutical composition of fesoterodine hydrochloride as claimed in claim 9 wherein the composition is an extended release composition.