FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION (SECTION 10 and Rule 13)
TITLE OF THE INVENTION "PHARMACEUTICAL FORMULATIONS OF TOLTERODINE"
Emcure Pharmaceuticals Limited,
an Indian company, registered under the Indian Company's Act 1957 and having its
registered office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:

FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising antimuscarnic agents and processes for preparation thereof. Typically, the present invention relates to pharmaceutical compositions of Tolterodine, its pharmaceutically acceptable salt and processes for preparation thereof.
BACKGROUND OF THE INVENTION
Antimuscarnic agents have long been the primary pharmacologic treatment for the chronic and distressing system of overactive bladder. Immediate release oxybutynin was the most widely available agent throughout the world, but its use was limited by a high incidence of antimuscarnic side effects, most notably dry mouth, constipation, blurred vision, and cognitive impairment. Such adverse event frequently resulted in poor patient compliance and discontinuation of treatment. Therefore, research in the field of overactive bladder was focused on identification of effective and better tolerated agents that would improve compliance and persistence.
Tolterodine, (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine, which is a competitive muscarinic receptor antagonist that shows in vivo selectivity for the bladder over the salivary glands compared with oxybutinin was developed by Jonsson et al and is disclosed in U.S. Pat No. 5,382,600. Tolterodine is a tertiary amine with relatively low lipophilicity. After oral administration, tolterodine is rapidly absorbed and the maximum plasma concentration typically occurs within 1-2 h. The immediate release formulations of tolterodine (2 mg) require twice-daily administration. However, the poor tolerability and/or the need for frequent daily dosing with immediate release formulations have led to the development of extended release formulations for once-daily administration. Various methods are already known for the industrial preparation of extended release oral dosage forms comprising an antimuscarinic agent, and in particular Tolterodine or a pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof as an active ingredient due to its useful therapeutical properties.
U.S. Pat No 6,911,217 discloses a formulation containing controlled release beads comprising a core unit of a substantially water soluble or water swellable inert material, a first layer on the

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core of a substantially water insoluble polymer, a second layer over the first that contains an active ingredient and a third layer of polymer on the second layer effective for controlled release of the active ingredient, wherein the first layer is adapted to control water penetration into the core.
U.S. Pat No 8,110,226 also discloses a controlled release drug composition comprising an inert core, a seal layer on said core layer comprising a non-polymeric hydrophobic material, a second layer containing active ingredient and a layer of at least one release-controlling polymer.
U.S. Patent No. 8,642,078 gives extrusion and spheronization method for making pellets containing tolterodine which are subsequently coated with a coating layer comprising ethylcellulose and hydroxypropylmethyl cellulose (HPMC), with a viscosity in the range of 12 to 18 cP to achieve the desired release profile.
WO 2006/21425 discloses a composition comprising a core coated with an outer layer of a hydrophobic sustained release polymer. Said core is either a matrix core made of a matrix core material, tolterodine and a binder or an inert core being provided with a layer of Tolterodine and a binder.
US 2009/0192228 discloses a controlled-release composition, comprising: inert core comprising a water insoluble polymer; with a first layer disposed on the inert core, wherein the first layer comprises tolterodine and a binder; and a second layer disposed on the first layer, wherein the second layer comprises a water insoluble polymer, a plasticizer, and a pore-forming agent.
WO 2009/080061 discloses a sustained release composition comprising Tolterodine as an active ingredient and a wetting agent such as Sodium Docusate to improve the release of the active ingredient.
US 2012/0288532 also disclose a multilayered, multiple unit composition comprising an inert core, a first layer of at least one hydrophilic polymer and at least one hydrophobic polymer which is made in a non-aqueous based solvent system, a second layer comprising active ingredient, a third layer comprising polymers effective for controlling or modifying the release

of active ingredient, and a fourth layer onto the third layer comprising one or more pharmaceutically acceptable polymers.
US 2011/123610 teaches an extended release pharmaceutical composition comprising mini tablets wherein release of tolterodine is controlled by hydrophobic matrix comprising water insoluble polymer and wax and one or more pharmaceutically acceptable excipients.
US 2011/150937 disclose a drug layer comprising tolterodine tartrate, monosaccharide and/or disaccharide on an inert core; or a drug core comprising tolterodine tartrate, monosaccharide and/or disaccharide; and b) a polymer layer comprising extended release polymer(s).
US 2009/214642 disclose a sustained release pharmaceutical composition comprising a coating comprising at least one water-insoluble permeable polymer and at least one water soluble polymer and homogenous cores containing only tolterodine or a salt thereof and microcrystalline cellulose
However, most of these prior art processes to make a controlled release formulation of tolterodine encounters substantial difficulties in the production of the oral solid formulations of a desirable dissolution profile. Further these processes are very complex, not cost effective and time consuming
Therefore, there exists a need for an alternate, simple and/or improved formulation and process for making a controlled release formulation of tolterodine.
SUMMARY OF THE INVENTION
The present inventors have found that a suitable controlled-release tolterodine composition can be produced with a simpler coating and manufacturing process than the commercially available
controlled-release compositions.
*
The present invention provides for a controlled-release pharmaceutical composition comprising (i) an inert core (ii) atleast one drug layer disposed on the inert core, comprising tolterodine or a pharmaceutically acceptable salt thereof, and suitable pharmaceutical excipients; and (iii) an outer extended-release layer comprising a water insoluble polymer and/or suitable pharmaceutical excipients.

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Thus, in one embodiment, the controlled-release composition comprises (i) an inert core (ii) a first drug layer disposed on the inert core, wherein the first drug layer comprises tolterodine or a pharmaceutically acceptable salt thereof, at least one water insoluble polymer and/or at least one water soluble polymer; (iii) optionally, a second drug layer disposed on the first drug layer, wherein the second drug layer comprises tolterodine and a binder; and (iv) a an outer extended release layer disposed on the second drug layer, wherein the third layer comprises a water insoluble polymer, and a pore-forming agent.
In another embodiment, the first drug layer comprising tolterodine or a pharmaceutically acceptable salt thereof, at least one water insoluble polymer and/or at least one water soluble polymer could be split into two or three layers wherein the first drug layer comprises of the active ingredient and a water soluble polymer and the second layer comprises of water insoluble polymer and water soluble polymer.
In still another embodiment of the present invention, it has been found that the controlled-release composition can be prepared by first layering a hydrophilic and/or a hydrophobic polymer on the inert core, followed by coating with the active ingredient and finally by coating with a water insoluble polymer.
Also disclosed are methods of making the above controlled-release compositions. Further disclosed, are methods of treating overactive bladder or gastrointestinal disorders comprising administering a therapeutically effective amount of the controlled-release compositions described above.
These and other advantages of the compositions disclosed herein, as well as additional inventive features, will be apparent from the description of the invention provided herein.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have found that a suitable controlled-release tolterodine dosage form can be produced from a core-coat technology and by judiciously selecting the excipients and other process parameters. Thus, in one embodiment, a controlled-release composition comprises (i) an inert core (ii) a first drug layer disposed on the inert core, wherein the first drug layer comprises tolterodine or a pharmaceutically acceptable salt thereof, at least one water insoluble

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polymer and/or at least one water soluble polymer; (iii) optionally, a second drug layer disposed on the first layer, wherein the second layer comprises tolterodine and a binder; and (iv) a third layer disposed on the second layer, wherein the third layer comprises a water insoluble polymer, and a pore-forming agent.
In another embodiment of the present invention, it has been found that the controlled-release composition can be prepared by first layering at least one hydrophilic and/or at least one hydrophobic polymer on the inert core, followed by coating with the active ingredient and finally by coating with a water insoluble polymer.
The controlled-release tolterodine composition disclosed herein exhibits suitable dissolution profiles and/or reduced side effects. For example, the controlled-release tolterodine compositions can be administered once daily. The controlled-release tolterodine compositions provide optimal effective plasma levels of tolterodine over an extended period of time.
As used herein, "controlled-release" means a dosage form in which the release of the active agent is controlled or modified over a period of time. "Controlled" includes, for example, sustained, delayed, or pulsed release at a particular time. For example, controlled-release includes release of the active ingredient that is extended for longer than in an immediate release dosage form, i.e., at least over several hours. Controlled-release includes, for example, release over 12 or 24 hours.
As used herein, "pharmaceutically acceptable" means that which is generally safe, non-toxic and, neither biologically nor otherwise undesirable and includes that which are acceptable for veterinary use as well as human pharmaceutical use.
The inert core of the controlled-release composition is made up of water soluble or insoluble material. The cores are preferably of any such material that is conventionally used as cores or any other pharmaceutically acceptable water-soluble, water-insoluble or water-swellable material made into beads or pellets. Preferably, the inert core is made of inert non-pareil sugar spheres, microcrystalline cellulose spheres, glass beads, coarse grade silicon dioxide particles. In one embodiment, the inert core comprises microcrystalline cellulose, for example, CELPHERE®.

A first drug layer comprising tolterodine, at least one water insoluble polymer and/or at least one water soluble polymer is disposed on the inert core. As used herein, the term "tolterodine" means tolterodine free base or its pharmaceutically acceptable salts, solvates (including hydrates), polymorphs, all optical isomers, or a combination comprising at least one of the foregoing forms of tolterodine. Tolterodine can be in crystalline or non-crystalline (amorphous) form.
As used herein, a "pharmaceutically acceptable salt" of tolterodine means a derivative of tolterodine, wherein tolterodine is modified by making non-toxic inorganic or organic acid addition salt thereof. A particularly useful salt of tolterodine is tolterodine tartrate, or more specifically, tolterodine L-tartrate.
Tolterodine is disposed onto the inert core in the presence of water soluble and/or water insoluble polymer. In the preferred embodiment, tolterodine, water soluble polymer and water insoluble polymer are mixed together and are deposited on the surfaces of inert core.
Suitable water soluble polymers in the first drug layer include cellulose derivatives, such as, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, and a combination comprising at least one of the foregoing cellulose derivatives. In general, hydroxy propyl methyl cellulose polymers are preferred.
Suitable water insoluble polymers for the first drug layer include, but are not limited to, ethyl cellulose, ethyl acrylate, methyl methacrylate, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, or a combination comprising at least one of the foregoing polymers.
In another embodiment, the first layer comprising tolterodine, at least one water insoluble polymer and/or at least one water soluble polymer are disposed on the inter core as a mixture. In still another preferred embodiment, tolterodine, at least one water insoluble polymer and/or at least one water soluble polymer could be deposited as two or three separate layers wherein the first layer comprises of the active ingredient and a water soluble polymer and the second layer comprises of water insoluble polymer and water soluble polymer. In another

embodiment, to form the first layer comprising tolterodine, the core may be first coated with a water soluble and/or a water insoluble polymer and then with Tolterodine.
The water soluble polymer in the first drug layer may function as a binder or a pore forming agent, whereas the water insoluble polymer may function as release controlling agent.
In one embodiment, the first drug layer comprises tolterodine L-tartrate as active ingredient, hydroxypropyl methyl cellulose as water soluble polymer and ethyl cellulose as water insoluble polymer. The amounts of the tolterodine, the water soluble polymer, and the water insoluble polymer in the first drug layer are about 5 wt % to about 75 wt %, about 8 wt % to about 60 wt %, and 0 wt % to about 85 wt %, respectively, based on the total weight of the first layer.
The amount of the first drug layer is about 0.5 to 30 wt %, or more specifically, about 1 to 20 wt %, or even more specifically, about 1.5 to 10 wt %, based on the total weight of the controlled-release composition.
Following the application of the first drug layer on to the inert core, the resulting inert cores coated with the first layer are optionally, further coated with a second layer comprising tolterodine. The second drug layer contains tolterodine and a binder. Preferably, water soluble polymer is used as binder. More preferably, hydroxy propyl methyl cellulose polymer is used as binder.
In the preferred embodiment, the second drug layer comprises of about 20-90 % of the total therapeutic dose of tolterodine whereas the first layer comprise of about 10-80% of the total therapeutic dose of tolterodine. The amount of the second layer is about 0.5 to 30 wt %, or more specifically, about 1 to 20 wt %, or even more specifically, about 1.5 to 10 wt %, based on the total weight of the controlled-release composition.
The first drug layer and second drug layer may optionally comprise other excipients, for example plasticizer, lubricants. The plasticizer is normally added to increase the flexibility of the binder. The added flexibility allows the binder and drug to adhere more efficiently and uniformly to the inert core. Suitable plasticizers include water-soluble or water-insoluble plasticizers. Exemplary water-soluble plasticizers include triethyl citrate, triacetin,

polyethylene glycol, propylene glycol, sorbitol, glycerin, and combinations comprising at least one of the foregoing plasticizers. Exemplary water-insoluble plasticizers include dibutyl sebacate, diethyl phthalate, dibutyl phthalate, tributyl citrate, acetyl tributyl citrate, castor oil, mineral oil, glyceryl monostearate, and a combination comprising at least one of the foregoing plasticizers.
Following the application of the first and optional second drug layer, the resulting drug layered spheres are further coated with the third layer comprising water insoluble polymer. The third layer comprises a water insoluble polymer, a pore-forming agent and optionally a plasticizer.
It has been found that by using a combination of a water insoluble polymer, a plasticizer, and a pore-forming agent in the third layer, desirable controlled-release profile of tolterodine is obtained. The selection of the water insoluble polymer, the pore-forming agent, the plasticizer, and the thickness of the third layer provide a particularly desirable dissolution profile of tolterodine at neutral and/or acidic pH-ranges.
Suitable pore-forming agents include pH-independent and pH-dependent agents. Exemplary pH-independent pore-forming agents include polyvinyl pyrrolidone, polyvinyl alcohol, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose, polyethylene glycol, and a combination comprising at least one of the foregoing pH-independent pore-forming agents. In one embodiment, the pore-forming agent is hydroxypropylmethyl cellulose.
Exemplary pH-dependent pore forming agents include acrylic acid or methacrylic acid/methacrylate based polymers, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, shellac, cellulose acetate trimellitate, cellulose acetate phthalate, and a combination comprising at least one of the foregoing pH-dependent pore-forming agents.
Suitable plasticizers for the third layer include, but are not limited to, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, tributyl citrate, acetyl tributyl citrate, castor oil, mineral oil, glyceryl monostearate, and a combination comprising at least one of the foregoing plasticizers.
In one embodiment, the third layer comprises ethyl cellulose polymer and hydroxypropylmethyl cellulose as a pore-forming agent.

The amounts of the water insoluble polymer, the plasticizer, and the pore-forming agent in the third layer are about 60 wt % to about 95 wt %, about 0 wt % to 10 wt %, and about 7 wt % to 25 wt %, respectively, based on the total weight of the third layer.
The amount of the third layer is about 5 to 40 wt %, or more specifically, about 7 to 25 wt %, or even more specifically, about 8 to 20 wt %, based on the total weight of the controlled-release composition.
The first drug layer, optional second drug layer and the third layer are applied onto the inert core by using techniques known in the art, for example, a fluidized bed or a coating pan. Fluidized bed coaters, for example, bottom, tangential, or top-spray coaters, are suitable for spraying.
In an exemplary process, a first layer coating mixture comprising tolterodine, a water soluble polymer and a water insoluble polymer and optionally with other excipients, and a solvent (solution) or dispersing agent (suspension) is prepared for coating the inert core. Suitable solvents and dispersing agents include water, methanol, ethanol, isopropyl alcohol, acetone, alcohol USP (95% ethanol, 5% water), denatured alcohol with methanol as a denaturant, for example, SDA-3A alcohol, and a combination comprising at least one of the foregoing solvents or dispersing agents. In one embodiment, the solvent is a mixture of a methanol and water.
In one embodiment, the first drug layer coating mixture is deposited onto the inert cores using a fludized bed process. The temperature, pressure, spraying rate, and other parameteres are adjusted to minimize agglomeration of the cores and/or to allow for efficient coating of the first layer on the inert core.
The second drug layer comprising tolterodine is applied to the inert cores coated with the first layer, typically, using fluidized bed process as described above. Suitable solvents or dispersing agents are the same as those described above for preparing the first layer coating mixture.
The third layer of controlled-release coating is applied to the inert cores coated with the second layer using fluidized bed process as described above. Suitable solvents or dispersing agents are the same as those described above for preparing the first layer coating mixture.

The controlled-release compositions described above are in the form of coated particles, granules, pellets, or spheres. These particles, pellets, granules, or spheres are ultimately processed in the form of tablets, capsules, or other dosage forms suitable for oral administration. In one embodiment, the controlled-release compositions, for example, coated particles, granules, pellets or spheres, are filled into hard gelatin capsule shells to provide a desired quantity of tolterodine in an oral dosage form.
The controlled-release tolterodine compositions described above exhibit desirable dissolution profiles. In one embodiment, the compositions exhibit a dissolution profile such that after 1 hour, about 5 to 25 %, or more specifically, about 10-20%, of the tolterodine is released; after 3 hours, about 40 to 70 %, or more specifically, about 45-60% of the tolterodine is released; after 5 hours, about 70 to 90 %, or more specifically, about 75-85% of the tolterodine is released and after 7 hours, not less than 80 % of the tolterodine is released, wherein the dissolution is performed with 900 ml of pH 6.8 phosphate buffer at 37 °C. in USP Type 1 Apparatus, at a paddle speed of 100 rpm.
Also disclosed herein are methods of preparing controlled-release compositions of tolterodine. In one embodiment, the method comprises a) providing an inert core of a water soluble or insoluble polymer; b) applying a first drug layer comprising tolterodine, at least one water soluble polymer and/or at least one water insoluble polymer onto the inert core; c) applying a optional second drug layer comprising tolterodine onto the inert core coated with first layer and d) applying a extended release layer of a water insoluble polymer, onto the previous layer.
The following examples further illustrate the invention but should not be construed as in any way limiting its scope. In particular, the processing conditions are merely exemplary and can be readily varied by one of ordinary skill in the art.
Example -1: Preparation of Controlled release formulation of Tolterodine tartrate:
A controlled release formulation containing the ingredients summarised in Table -1 was prepared by coating first drug layer on the MCC spheres in Fluidized bed dryer. Subsequently second layer was applied on the first drug layer, which was further coated with the third outer extended release layer containing release controlling polymer. Finally the coated spheres were filled in the hard gelatin capsule.

Table -1: Controlled release formulation of Tolterodine tartrate
Sr.No Ingredients %wt
01 MCC Spheres
Firstlai ler
01 Tolterodine Tartrate 5-25
02 Hydroxypropylmethylcellulose 8-60
03 Ethyl cellulose 15-85
04 Purified water qs
Total weight 100 %
Second layer
01 Tolterodine Tartrate 50-75
02 Hydroxypropylmethylcellulose 25-50
03 Methanol qs
04 Purified water qs
Total weight 100%
Third layer
01 Ethyl cellulose 60-95
02 Hydroxypropylmethylcellulose 5-40
03 Purified water qs
04 Total weight 100%
Example - II: Preparation of Controlled release formulation of Tolterodine tartrate:
A controlled release formulation containing the ingredients summarised in Table -2 was prepared. In this example, the first layer of Example -1, i.e. a layer containing tolterodine, water soluble polymer and water insoluble polymer was applied as mentioned in Table -2. Finally the coated spheres were filled in the hard gelatin capsule.
Table -2: Controlled release formulation of Tolterodine tartrate

Sr.No Ingredients %wt
01 MCC Spheres
First Iaj ^er (Part - A)
01 Tolterodine Tartrate 5-25
02 Hydroxypropylmethylcellulose 8-50
03 Methanol Qs
04 Purified water qs
First laj er (Part - B)
05 Ethyl cellulose 15-85
06 Hydroxypropylmethylcellulose 5-15
07 Purified water qs
Total weight 100%
Second layer

01
Tolterodine Tartrate 50-75
02 Hydroxypropylmethylcellulose 25-50
03 Methanol qs
04 Purified water qs
Total weight 100 %
Third layer
01. Ethyl cellulose 60-95
02 Hydroxypropylmethylcellulose 5-40
03 Purified water QS
04 Total weight 100%
Example - III: Preparation of Controlled release formulation of Tolterodine tartrate:
A controlled release formulation containing the ingredients summarised in Table -3 was prepared. In this example, the inert microcrystalline cellulose polymer beads were coated with a hydrophilic polymer, followed by hydrophobic polymer. Then the drug layer was deposited on the seal coated polymer, which were then coated with extended release polymer. Finally the coated spheres were filled in the hard gelatin capsule.
Table -3: Controlled release formulation of Tolterodine tartrate
Sr.No Ingredients %wt
First layer (Part -A)
01 MCC spheres 95-99
02 Hydroxypropylmethylcellulose (HPMC) 1-5
03 Purified water Qs
Total weight 100%
First la yer (Part- B)
01 Seal Coated Spheres-1 95-98
02 Surelease (Ethylcellulose) Dispersion 1.5-3
03 Hydroxypropylmethylcellulose (HPMC) 1-2.5
04 Purified water QS
Total weight 100 %
First la yer (Part - C)
01 Seal Coated Spheres- II 94-98
02 Tolterodine Tartrate 1.5-4
03 Hydroxypropylmethylcellulose (HPMC) 1-3
04 Purified water QS
Total weight 100%
Second layer
01 Active Layered Spheres 85-95
02 Surelease (Ethylcellulose) Dispersion 5-15
03 Hydroxypropylmethylcellulose (HPMC) 1-2

04 Purified water QS
Total weight 100%
Example - IV: Preparation of Controlled release formulation of Tolterodine tartrate:
A controlled release formulation containing the ingredients summarised in Table -4 was prepared by coating first drug layer on the MCC spheres in Fluidized bed dryer. Subsequently second extended release layer containing release controlling polymer was applied on the first drug layer. Finally the coated spheres were filled in the hard gelatin capsule.
Table -4: Controlled release formulation of Tolterodine tartrate

Sr.No Ingredients %wt
1 MCC spheres
First layer (Active Layered Spheres -I)
2 Tolterodine Tartrate 50-75
3 Hydroxypropylmethylcellulose (HPMC) 25-40
4 IPA (Isopropyl Alcohol) q.s
5 Purified water q.s
Total weight 100%
Second Layer (Extended Release Layering)
1 Active Layered Spheres 80-90
2 Ethyl Cellulose 7 cps ( Ethocel 7 cps) 5-15
3 Hydroxypropylmethylcellulose (HPMC 5 cps) 2-10
4 Polyethylene Glycol (PEG 400) 1-3
5 Purified water q.s.
6 IPA (Isopropyl Alcohol)
Total weight 100%

We claim:
1. A controlled-release composition, comprising: (i) an inert core; (ii) a first drug layer disposed
on the inert core, wherein the first drug layer comprises tolterodine or a pharmaceutically acceptable salt thereof (iii) an outer extended release layer comprising atleast one water insoluble polymer.
2. The controlled-release composition of claim 1, wherein the first drug layer disposed on the
inert core comprises tolterodine or a pharmaceutically acceptable salt thereof, at least one water soluble polymer and/or at least one water insoluble polymer.
3. The controlled-release composition of claim 2, wherein the tolterodine or a pharmaceutically
acceptable salt thereof, at least one water soluble polymer and/or a water insoluble polymer are disposed on the inert core as a mixture.
4. The controlled-release composition of claim 2, wherein the tolterodine or a pharmaceutically
acceptable salt thereof, at least one water soluble polymer and/or a water insoluble polymer are disposed on the inert core as two layers, wherein the first layer comprises tolterodine and at least one water soluble polymer and the second layer comprises of at least one water insoluble polymer and/ or at least one water soluble polymer.
5. The controlled-release composition of claim 2, wherein the tolterodine or a pharmaceutically
acceptable salt thereof, at least one water soluble polymer and/or a water insoluble polymer are disposed on the inert core as two layers, wherein the first layer comprises at least one water soluble and/or at least one water insoluble polymer and the second layer comprises of tolterodine and at least one water soluble polymer
6. The controlled-release composition of claim 2, wherein the water soluble polymer in the first
drug layer is hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose,

carboxymethylhydroxyethyl cellulose, or a combination comprising at least one of the foregoing polymers.
7. The controlled-release composition of claim 2, wherein the water insoluble polymer in the first
drug layer is ethyl cellulose, ethyl acrylate, methyl methacrylate, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, or a combination comprising at least one of the foregoing polymers.
8. The controlled-release composition of claim 1, wherein the water insoluble polymer in the
extended release layer is ethyl cellulose, ethyl acrylate, methyl methacrylate, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, or a combination comprising at least one of the foregoing polymers.
9. The controlled-release composition of claim 1, wherein an additional layer comprising
tolterodine or a pharmaceutically acceptable salt thereof and a binder is applied before the extended release layer comprising water insoluble polymer.
10. A method of producing a controlled-release composition of claim 1, wherein the method
comprises: a) providing an inert core; b) applying a first layer comprising tolterodine or a pharmaceutically acceptable salt thereof, at least one water soluble polymer and/or at least one a water insoluble polymer onto the inert core; c) optionally, applying a second layer comprising tolterodine or a pharmaceutically acceptable salt thereof and c) applying a third extended release layer comprising a water insoluble polymer, a pore-forming agent and a plasticizer onto the second layer;