FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention-"STABLE PHARMACEUTICAL COMPOSITION OF FESOTERODINE"
2. Applicant(s)
(a) NAME: ALEMBIC PHARMACEUTICALS LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

STABLE PHARMACEUTICAL COMPOSITION OF FESOTERODINE
FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical composition of fesoterodine or pharmaceutically acceptable salts or solvates thereof and the process for preparing the same.
BACKGROUND OF THE INVENTION
Fesoterodine is marketed under the trade name of Toviaz® by Pfizer. It is a urinary antispasmodic, available in a modified release (MR) preparation, approved for the treatment of symptoms that may occur in patients with overactive bladder syndrome (OAB); urinary frequency and urinary urgency incontinence (UUI). Fesoterodine is a pro-drug, which after oral administration, is hydrolysed to 5-hydroxy tolterodine, which is a muscarinic receptor antagonist. Fesoterodine is chemically designated as isobutyric acid 2-((R)-3-diisopropylammonium-1-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fumarate. The empirical formula is C30H41N07 and its molecular weight is 527.66. The structural formula is:

Fesoterodine fumarate is a white to off-white powder. It is freely soluble in aqueous solvents, soluble in some polar protic organic solvents (such as ethanol, methanol, glacial acetic acid, 2-propanol, propylene glycol) and polar non protic solvents. Fesoterodine in base form is available in oily liquid form, which is difficult to develop into a stable solid dosage form and hence the crystalline fesoterodine hydrogen fumarate salt was used for the commercial

development of Toviaz® tablets. Fesoterodine fumarate (Toviaz®) is available in 4 mg and 8 mg strength, having prolonged release profile so as to provide once daily dosage regimen. The formulation is a hydrogel matrix tablet based on hypromellose. Wet granulation process has been employed to develop the commercially available dosage form.
EP1019358B1 assigned to Pharmacia AB and disclose the compound fesoterodine generically. It also discloses the pharmaceutically acceptable acid salts, any optical isomers, racemic mixtures and individual enantiomers of fesoterodine.
EP1077912B1 and US7384980B2 assigned to Schwarz GMBH disclose fesoterodine specifically, whereas any additional pharmaceutically acceptable acid salts, and any optical isomers, racemic mixtures and individual enantiomers are claimed generically. Further this patent discloses a pharmaceutical composition of fesoterodine and its use for antagonizing the muscarinic receptors.
EP1230209B1 and US6858650B1 assigned to Schwarz Pharma AG claims a highly pure, crystalline, stable fesoterodine fumarate. This patent also discloses different intermediates for the preparation of fesoterodine. Further these patents claims use of the disclosed compound for the treatment of disease conditions like urinary incontinence and more specifically urge incontinence.
US7807715B2 and US8088398B2 disclose the pharmaceutical composition of fesoterodine wherein the said composition comprises of stabilizer. According to this patent fesoterodine is susceptible to hydrolyzation and oxidation resulting in the degradation of the compound. Degradation of the compound is surprisingly reduced by incorporation of stabilizer selected from the group consisting of sorbitol, xylitol, polydextrose, isomalt, dextrose, and combinations thereof and at least one further excipient, preferably at least one type of hydroxypropyl methylcellulose. This patent further discloses that in spite of fesoterodine's susceptibility to hydrolyzation it has been found to be more stable when formulated by the process of wet granulation than the dry granulation. However

the sorbitol and/or xylitol is hygroscopic in nature and attracts moisture form the environment resulting increase in moisture in the formulation and decrease in hardness of tablet formulation. .Further when the sorbitol is present in the formulation it poses problems during the coating of such formulation resulting rough surfaces and sometimes breaking of tablets.
WO2011050961 discloses pharmaceutical composition containing fesoterodine and/or metabolite and fiber wherein the weight ratio of components fesoterodine and/or metabolite: fiber is in the range of 1:50 to 1:2.
WO2011117884 discloses the stable pharmaceutical composition of fesoterodine without use of sugar alcohol which exhibits the stability at stress conditions.
From the above prior arts there is need in the society to develop a stable pharmaceutical composition of fesoterodine fumarate. Inventors of the present invention have surprisingly found such formulation which provides stable composition of fesoterodine fumarate without any problems as discussed above.
SUMMARY OF THE INVENTION
One of the important components of the commercially available Toviaz® tablet is sorbitol, which act as stabilizer. Sorbitol is a hexavalent sugar alcohol derived from the catalytic reduction of glucose. As sorbitol is hygroscopic in nature, it attracts moisture from the environment. When sorbitol is used in the solid pharmaceutical composition, it always poses the problems of manufacturing and handling during storage. Further when sorbitol is present in the tablet composition in higher amount, coating of such tablet composition needs to be done very critically else it will absorbs the moisture and get dissolved which in turn lead to rough surface on the tablet. Sorbitol being freely soluble in water, its presence in the core portion of the coated tablets compositions poses risks of disintegration during the coating process. Also, the hardness might decrease leading to breakage of tablets during long term storage periods. Hence it is very difficult and cumbersome to prepare pharmaceutical composition in the form of

tablet with presence of sorbitol. Further preparing pharmaceutical composition using sorbitol as one of the excipients in extended or sustained release composition, it is very difficult to control and achieve desired release profile. It may also lead to fluctuation of the release and thereby fluctuation in the plasma concentration of active ingredient which increases the likelihood of toxicity. The present inventors have successfully developed a stable pharmaceutical v composition of fesoterodine which is easy to manufacture and provides a release profile similar to the Toviaz® without the any problems at manufacturing level and storage for longer time.
In one aspect, disclosed is a pharmaceutical composition comprising Fesoterodine or a pharmaceutically acceptable salt or solvate thereof, a stabilizer which is pullulan or derivatives thereof and at least one release controlling agent.
Another aspect of the present invention is to provide a process for the preparation of stable pharmaceutical composition of fesoterodine wherein the process involves direct compression, wet granulation or dry granulation. Further the wet granulation process involves the use of aqueous or non-aqueous solvent, most preferably non-aqueous solvent.
DETAILED DESCRIPTION OF THE INVENTION
As per the present invention the term "fesoterodine" includes pharmaceutically acceptable solvates of 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl) phenyl isobutyrate, particularly hydrates of Fesoterodine. "Fesoterodine" also includes pharmaceutically acceptable salts of 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl) phenyl isobutyrate, particularly the hydrogen fumarate salt, as well as the free base. Preferably the fesoterodine is in the form of hydrogen fumarate salt.
Fesoterodine is an ester which is susceptible to hydrolyzation after administration in vivo as well as during storage under stress conditions to give a main product (2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)

phenol) i.e. 5-hydroxy tolterodine, which is referred to herein as the "active metabolite".
Pharmaceutical composition as used herein refers to physically discrete units suitable as unitary dosages for human beings or other mammals, each unit containing a predetermined quantity of Fesoterodine or its salt calculated to produce the desired therapeutic effect, in addition with suitable pharmaceutical excipients. Most preferred are solid administration forms (such as tablets, coated tablets, granulates and capsules) that only require a once-daily administration to the patient to achieve the desired therapeutic effect. The pharmaceutical composition of the present invention is in the form of extended release. Further, the term "extended release" as used herein refers to the release of an active ingredient from a pharmaceutical composition, in which the active ingredient is released over an extended period of time and is also encompass sustained release, controlled release, modified release, prolonged release, delayed release and the like. The compositions are preferably formulated in a unit dosage form. Each unit dosage form can contain from about 0.5 to about 20 mg, preferably about 1-8 mg, and more preferably about 2, about 4, or about 8 mg of Fesoterodine or a pharmaceutical^ acceptable salt thereof, such as, e.g., the hydrogen fumarate salt.
The stable pharmaceutical composition, like those that described herein, may comprise the active ingredient Fesoterodine or a pharmaceutically acceptable salt or solvate thereof, a stabilizer and at least one release controlling agent, and optionally other pharmaceutically acceptable excipients.
The stable pharmaceutical compositions of the present invention may be prepared by any known processes of manufacturing the pharmaceutical formulation to the person having ordinary skill in the art of pharmaceutical technology such as direct compression, wet granulation, dry granulation, slugging, hot melt extrusion, hot melt granulation, extrusion-spheronization, fluidized bed granulation, spray drying and solvent evaporation.

In one embodiment the stable pharmaceutical composition of the present invention can be prepared by dry or wet granulation of fesoterodine or pharmaceutically acceptable salts or solvates thereof with stabilizer, one or more release controlling agent and optionally, mixing with one or more pharmaceutically acceptable excipients.
In one embodiment the stable pharmaceutical composition of the present invention can be prepared by dry or wet granulation of at least one pharmaceutically acceptable excipient with stabilizer, one or more release controlling agent and then mixing with fesoterodine or pharmaceutically acceptable salts or solvates thereof and optionally mixing with one or more pharmaceutically acceptable excipients.
The active agent, fesoterodine or pharmaceutically acceptable salts thereof is present in the intragranularly or extragranularly. Preferably the fesoterodine or pharmaceutical acceptable salt thereof is present as extra granular component.
Pharmaceutical excipients that may be present in the compositions described herein include stabilizer, release controlling agents, fillers, binder and lubricants. Other excipients can also be included.
Stabilizer
As mentioned in the prior art, the fesoterodine is susceptible to hydrolyzation and oxidation resulting in the degradation of the same. To prevent such degradation by way of hydrolyzation and oxidation the inventors of the present invention have incorporated pullulan as a stabilizer which enhance the stability of the pharmaceutical composition of fesoterodine and at the same time also improve the manufacturing feasibility.
The stabilizer as used herein in the present invention to provide the stable pharmaceutical composition plays very vital role in stabilizing the pharmaceutical composition and at the same time also providing ease of manufacturing,

handling and storage of the pharmaceutical composition without any stability related problems.
The stabilizer used herein is the pullulan or derivatives thereof. The amount of stabilizer present in the pharmaceutical composition ranges from 2 % w/w to 45 % preferably from 5%w/w to 35%w/w.
Pullulan is a polysaccharide polymer consisting of maltotriose units, also known as a-1,4- ;a-1,6-glucan. Three glucose units in maltotriose are connected by an a-1,4 glycosidic bond, whereas consecutive maltotriose units are connected to each other by an a-1,6 glycosidic bond.
Release Controlling Agent
In addition to stabilizer the pharmaceutical composition of the present invention comprises one or more release controlling agents.
The release controlling agent is selected from the group consisting of polymethacrylates, polyvinyl chloride, polyvinyl alcohol, ethyl cellulose, polyethylene oxide, methylcellulose, hydroxypropyl methylcellulose (HMPC), sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium alginate, sodium carboxymethylcellulose, carbomer, xanthan gum, guar gum, locust bean gum and waxes. The amount of release controlling agent present in the pharmaceutical composition ranges from 15 % w/w to 50 % w/w of the composition.
In a preferred embodiment, HPMC which is commercially available under the brand name Methocel® and its various grades that can be used in the present invention can be selected from grades like K100 LV, K100 Premium LV CR, K4M Premium CR, K100M Premium CR, E4M Premium CR and E10M Premium CR or combination thereof.
In one more preferred embodiment, one or more poly ethylene oxide (PEO) of different viscosity is used. Different types of poly ethylene oxide that can be used

in the present invention can be selected from the following grades of POLYOX™ or combination thereof. It is represented below in a tabular format.

POLYOX™
Water-Soluble
Resin NF
Product Approximate
Molecular
Weight Viscosity Range at 25°C, (cP)

5% Solution 2% Solution 1% Solution
WSRN-10 100,000 30-50
WSR N-80 200,000 55-90
WSR N-750 300,000 600-1,200
WSR N-205 600,000 4,500-8,000
WSRN-1105 900,000 8,800-17,600
WSRN-12K 1,000,000 400-800
WSR N-60K 2,000,000 2000-4000
WSR-301 4,000,000 1,650-5,500
WSR Coagulant 5,000,000 5,500-7,500
WSR -303 7,000,000 7,500-10,000
Preferred release controlling agent is selected form the various grades of hydroxypropyl methylcellulose (HMPC) and various grades of polyethylene oxide or combination thereof.
In addition to stabilizer and release controlling agent the pharmaceutical composition of the present invention may include one or more pharmaceutical^ acceptable excipients as described herein.
Fillers
The pharmaceutical compositions described herein can further contain fillers such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, starch (e.g., corn starch or potato starch), pregelatinized starch, fructose, sucrose, dextrose, dextrans, other sugars such as mannitol, maltitol, sorbitol, lactitol and saccharose, siliconized microcrystalline cellulose, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, dicalciumphosphate dihydrate, tricalciumphophate, calcium lactate or mixtures thereof.

Binders
The pharmaceutical compositions described herein can further contain one or more binders such as microcrystalline cellulose, starch (e.g., corn starch or potato starch), pregelatinized starch, silicified microcrystalline cellulose, povidone, cellulose derivatives (e.g., methylcellulose and sodium carboxymethylcellulose), gelatin, glucose, lactose, sucrose, polyethylene glycol, polymethacrylates, hydroxypropylcellulose, hydroxyethylcellulose, pregelatinized starch and sodium alginate.
Lubricants
The compositions and formulations disclosed herein also can comprise lubricants, antiadherent and/or glidants such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, glyceryl behenate, talc, corn starch, silicone dioxide or mixtures thereof. The preferred lubricants are talc, glycerol dibehenate and magnesium stearate and can be used alone or in combinations thereof.
Coatings
Optionally, pharmaceutical compositions described herein, including cores/tablets, can be coated with conventional materials used for film coating or rate controlling polymers for functional coating. Film coating compositions usually contain the following components: polymer(s), plasticizer(s), colorant(s)/opacifier(s), vehicle(s). Minor quantities of flavours, surfactants and waxes also can be used in the film coating solution or suspension. The majority of the polymers used in film coatings are either cellulose derivatives, such as the cellulose ethers, polyvinylpyrrolidone, polyvinyl alcohol or acrylic polymers and copolymers.

The plasticizers that is to be used for the preparation of film coating solution/dispersions can be selected from the group consisting of glycerol, propylene glycol, macrogols, phthalate esters, dibutyl sebacetate, citrate esters, triacetin, castor oil and acetylated monoglycerides.
Film coats may be prepared from ready-to-make preparations which are available on the market. One preferred film-coat material is OPADRY®. Depending on the desired opacity, the preferred amount the coating is about 3-8% w/w of the tablet.
A film coating dispersion or suspension can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water is to be used as solvent.
One more embodiment of the present invention is to provide a method of treating patients suffering from overactive bladder and having symptoms such as urinary frequency and urinary urgency incontinence by administering a pharmaceutical composition of the present invention. In particular, disclosed is a method of treating patients suffering from overactive bladder that may have symptoms such as urinary frequency and urinary urgency incontinence by administering a unit dosage form of the pharmaceutical composition comprising fesoterodine as described herein.
Dissolution of pharmaceutical compositions of the present invention was carried
out as per below parameters:
Media: Phosphate buffer pH 6.8
Volume: 900 ml
Apparatus: Paddle with sinkers
RPM: 75
The following examples are further illustrative of the present invention but should by no means be construed as being limitative of the scope thereof.

EXAMPLES
Example 1: Fesoterodine Fumarate Tablets 8 mg

Ingredients % w/w
Fesoterodine Fumarate 2.35
Microcrystalline cellulose (AVICEL PH 112) 34.82
Polyethylene oxide (Polyox WSR-301) 26.47
Aerosil 200 3.76
Pullulan 7.88
Glycerol dibehenate 9.41
Talc 9.41
Film Coating
Opadry II Blue85G50517 5.90
Purified Water q.s
Total 100.00
Procedure:
1. Fesoterodine Fumarate, Microcrystalline cellulose and Aerosil 200 were sifted through 30# screen, Polyox WSR -301 and Pullulan were sifted through 20# screen and Glycerol dibehenate and talc were sifted through 60# screen.
2. Fesotrodine Fumarate was mixed with Microcrystalline Cellulose geometrically and passed through 30# screen.
3. Presifted Polyox WSR -301 and Pullulan were mixed with the blend of step-2 for 15 minutes.
4. Blend of step-3 was mixed with presifted Aerosil 200 for 10 min and result ant blend were further mixed with presifted glycerol dibehenate for 5 min and resultant blend with further mixed with presifted talc for 5 minutes.
5. Lubricated blend of step-4 were compressed using suitable oval shaped punches.
6. Film Coating:
a). Opadry II Blue 85G50517 were dispersed in purified water and stirred for
45 minutes, b). Coating was performed on the compressed tablets of step-5.

Dissolution data:

Time (Hr) % Drug dissolved

Example 1 Toviaz®
1 20 19
2 32 32
4 52 51
6 66 64
' 8 77 73
12 90 84
16 97 90
20 98 91
Stability data of Example 1

Tablets of Example 1 stored in HDPE bottles TOVIAZ® Tablets stored in HDPE bottles
Impurity Initial 1 week at 60°C 2 week at 60°C Initial 1 week at 60°C 2 week at 60°C
Di hydroxy 0.163 0.802 1.638 0.336 1.197 3.031
Fumaric acid ester 0.027 0.049 0.049 0.025 0.054 0.112
Aldehyde ND 0.000 0.000 0.071 0.224 0.070
Benzylated hydroxy 0.025 0.071 0.088 0.000 0.014 0.000
Tolterodine ester ND 0.007 0.004 0.000 0.000 0.028
Diester 0.048 0.232 0.458 0.272 0.984 1.657
Maximum Unknown 0.028 0.216 0.773 0.218 0.200 2.058
Total impurity 0.327 1.584 3.455 1.403 3.062 9.241
Example 2: Fesoterodine Fumarate Tablets 8 mg

Ingredients % w/w
Microcrystalline cellulose (AVICEL PH 112) 5.82
Lactose monohydrate 8.77
Pullulan 23.58
Hypromellose (Methocel K4M ) 7.08
Hypromellose (Methocel K100M) 35.38
Hydroxypropyl cellulose (Klucel LF) 2.95
Isopropyl alcohol q-s
Fesoterodine Fumarate 2.36
Microcrystalline cellulose (AVICEL PH 112) 2.95
Talc 2.50
Glycerol dibehenate 2.95
Film Coating
Opadry II Blue 85G50517 i 5.66

Purified Water q.s
Total 100.00
Procedure:
1. Fesoterodine Fumarate was sifted through 40# screen, Lactose
monohydrate, microcrystalline cellulose, Methocel K4M Premium CR and
Methocel K100M Premium CR were sifted through 30# screen, Pullulan were
sifted through 20# screen and Glycerol dibehenate and talc were sifted
through 60# screen.
2. Binder solution was prepared by dissolving Klucel LF in isopropyl alcohol.
3. Lactose monohydrate, microcrystalline cellulose, Methocel K4M Premium CR and Methocel K100M Premium CR were loaded in rapid mixer granulator and granulated with binder solution prepared in step-2.
4. Granules of step-3 were dried and sifted through 30# screen.
5. Dried and sifted granules of step-4 were blended with fesoterodine fumarate,
microcrystalline cellulose and talc for 15 minutes.
6. Granules of step-5 were lubricated with glycerol dibehenate for 5 minutes.
7. Lubricated blend of step-6 were compressed using suitable oval shaped
punches.
8. Film Coating:
a). Opadry II Blue 85G50517 were dispersed in purified water and stirred for
45 minutes, b). Coating was performed on the compressed tablets of step-7.
Dissolution data:

Time (Hr) % Drug d issolved

Example 2 Toviaz®
1 15 19
2 26 32
4 42 51
6 55 64
8 65 73
12 80 84
16 89 90
20 94 91

Stability data of Example 2

8t Tig Tablets of Exam stored in HDPE bott pie 2 es TOVIAZ® Tablets 8 mg stored in HDPE bottles
Impurity Initial 1 week
at
60°C 2 week
at 60°C 3 Month 40°C/75
%RH Initial 1 week
at 60°C 2 week
at 60°C 3 Month
40°C/75
%RH
Di hydroxy 0.197 0.355 0.770 0.654 0.336 1.197 3.031 2,573
Fumaric acid ester 0.037 0.044 0.004 0.062 0.025 0.054 0.112 0.018
Aldehyde 0.039 0.034 0.049 0.052 0.071 0.224 0.070 0.152
Benzylated hydroxy 0.000 ND 0.000 0.000 0.000 0.014 0.000 0.000
Tolterodine ester 0.000 ND 0.000 0.000 0.000 0.000 0.028 0.000
Diester 0.060 0.094 0.335 0.337 0.272 0.984 1.657 1.149
Maximum Unknown 0.047 0.043 0.092 0.058 0.218 0.200 2.058 0.402
Total impurity 0.467 0.717 1.411 1.275 1.403 3.062 9.241 5.237
Bio Study of Example 2:
Fasting study : Open label, balanced, randomized, two-treatment, two-
sequence, two-period, single-dose, crossover oral bioequivalence study of
fesoterodine fumarate extended-release tablets 8 mg of example 2 and Toviaz®
extended-release Tablets 8 mg, Distributed by Pfizer Labs, USA in healthy,
adult, human male subjects under fasting conditions. .„
Fed study : Open label, balanced, randomized, two-treatment, two-sequence, two-period, single-dose, crossover oral bioequivalence study of fesoterodine fumarate extended-release tablets 8 mg of example 2 and Toviaz® extended-release Tablets 8 mg, Distributed by Pfizer Labs, USA in healthy, adult, human male subjects underfed conditions. Results:

Fasting Condition Fed Condition
Parameter 8 mg Tablets of Example 2
(T) TOVIAZ®
Tablets 8 mg
(R) 8 mg Tablets of Example 2
(T) TOVIAZ® Tablets 8 mg
(R)
Cmax (pg/ml) 5660.7300 6057.0017 7092.8930 7145.1828
AUCo-t (pg.hr/ml) 83163.7947 80032.9510 97430.6565 100093.6454
T/R Ratio (%) 93.46 103.91 100.74 102.73

CLAIMS
We claim;
1. A Pharmaceutical composition comprising fesoterodine or a pharmaceutical^ acceptable salt or solvate thereof, a stabilizer which is pullulan or derivatives thereof and at least one release controlling agent.
2. The pharmaceutical composition according to claim 1, wherein the release controlling agent is selected from the group consisting of polymethacrylates, polyvinyl chloride, polyvinyl alcohol, ethyl cellulose, polyethylene oxide, methylcellulose, hydroxypropyl methylcellulose (HMPC), sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium alginate, sodium carboxymethylcellulose, carbomer, xanthan gum, guar gum, locust bean gum and waxes.
3. The pharmaceutical composition according to claim 1, wherein the release ^_ controlling agent is selected from hydroxypropyl methylcellulose (HMPC) and polyethylene oxide or combination thereof.
4. The pharmaceutical composition according to claim 1, wherein the release controlling agent is present from 15 % w/wto 50 % w/wof the composition.
5. The pharmaceutical composition according to claim 1, wherein the pullulan is present from 2 % w/w to 45 %.

6. The pharmaceutical composition according to claim 1, wherein the fesoterodine or pharmaceutically acceptable salts thereof is present as intragranular component or extragranular component.
7. The pharmaceutical composition according to claim 1, wherein the composition is prepared by process selected from direct compression, wet granulation, dry granulation, hot melt extrusion, hot melt granulation, extrusion-spheronization, fluidized bed granulation, spray drying and solvent evaporation.

8. The pharmaceutical composition according to claim 1, wherein the composition is prepared by process selected from direct compression, wet granulation or dry granulation.