Field of the Invention
The present invention relates to controlled release pharmaceutical compositions
comprising tolterodine or pharmaceutically acceptable salts thereof.
Back ground of the Invention
A substantial part (5-10%) of the adult population suffers from urinary incontinence, and
the prevalence, particularly of so-called urge incontinence, increases with age. The
symptoms of an unstable or overactive bladder comprise urge incontinence, urgency
and urinary frequency. It is assumed that unstable or overactive bladder is caused by
uncontrolled contractions of the bundles of smooth muscle fibres forming the muscular
coat of the urinary bladder (the detrusor muscle) during the filling phase of the bladder.
These contractions are mainly controlled by cholinergic muscarinic receptors, and the
pharmacological treatment of unstable or overactive bladder has been based on
muscarinic receptor antagonists.
Tolterodine is well-known antimuscarinic agent specifically developed for treatment of
patients with overactive bladder. It was disclosed in US Patent 5,382,600. Tolterodine is
marketed under the brand name Detrol ®film-coated tablets containing 1 mg or 2 mg of
tolterodine L-tartrate for immediate release in the gastrointestinal tract. Additionally it is
marketed under the brand name Detrol LA ® long acting capsules These capsules
contain either 2 or 4 mg of the active ingredient.
US patent 6,911,217 relates to a controlled release bead comprising: (i) a core unit of a
substantially water-soluble or water-swellable inert material; (ii) a first layer on the core
unit of a substantially water-insoluble polymer; (iii) a second layer covering the first layer
and containing an active ingredient; and (iv) 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. However it is both time and cost intensive
manufacturing technique.
WO 2004/105735 discloses controlled release pharmaceutical composition of tolterodine
that includes one or more coated units. Each coated unit includes a core, a first layer,
and a second layer. The first layer surrounds at least a portion of the core and includes
tolterodine and one or more hydrophilic polymers. The second layer surrounds at least a
2

portion of the first layer and includes one or more polymers that are effective for
controlled release of the tolterodine from the first layer. The above patent application,
involved fewer layering steps.
WO 2005/079748 discloses a pharmaceutical preparation for sustained release of a
pharmaceutically active ingredient(s), which preparation comprises particles having an
inner core (1) and a first coating (2) provided thereon, wherein said coating (2) contains
a mixture of (a) copolymer of ethyl acrylate, methylmethacrylate and
trimethylamminoethyl methacrylate chloride (b) copolymer of ethylacrylate and
methacrylic acid (c) between 1 % and 40% by weight of the pharmaceutically active
ingredient.
WO 2005/016321 discloses a mucoadhesive delivery system for the local or systemic
administration of a pharmaceutical agent. The delivery system of the invention effectively
and facilely enables transport of the pharmaceutical agent through mucosal membranes
and into the vasculature of the mucosa. The delivery system includes an at least partially
water-soluble bioadhesive layer and an at least partially water-soluble backing layer.
Incorporated within either or both of these layers are the pharmaceutical agent and a
mucosal penetration enhancing agent.
WO 2005/048979 discloses a modified release pharmaceutical composition consists of
casing comprising at least two micro tablets, which are coated with rate controlling
agent(s) optionally in combination with auxiliary pharmaceutical excepient(s), wherein
each micro tablet comprises core particles comprising pharmaceutical active ingredient
and rate controlling agent(s), the said core particles optionally coated with rate
controlling agent(s).
Although above mentioned patents and patent applications provide controlled release
dosage forms, but production of dosage forms of these references is lengthy, expensive
process or requires specialized equipments or techniques.
Thus there still exists a need to develop a controlled release pharmaceutical composition
comprising tolterodine or pharmaceutically acceptable salts, wherein the release rate
controlling agent is in the coating.
3

There exists a need to develop a controlled release pharmaceutical composition
comprising tolterodine or pharmaceutically acceptable salts, wherein the release rate
controlling agent is in the coating which offers advantages like simple manufacturing
process, compact dosage form, use of conventional manufacturing equipment, high
throughput, easy scale-up, economic, etc.
Thus the present invention proposes controlled release pharmaceutical compositions of
tolterodine or pharmaceutically acceptable salts thereof comprising immediate release
core and a single coating layer comprising rate controlling agent(s).
Additionally there is a need to provide a controlled release pharmaceutical composition
comprising tolterodine or pharmaceutically acceptable salts thereof, wherein composition
provides a dissolution profile having a reduced dependency from the pH- value and/or
the ionic strength of the dissolving medium of the controlled release composition.
Object of the Invention
Tolterodine for the purpose of the present invention may be selected from tolterodine
base, i. e., (R)-N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl)-3 phenylpropanamine, as
well as the corresponding (S)-enantiomer, the racemate and the active 5-hydroxymethyl
metabolites, prodrug forms and pharmaceutically acceptable salts thereof. The preferred
salt is tolterodine is tartrate.
Therefore, the first object of the present invention provides controlled release
pharmaceutical compositions comprising tolterodine or pharmaceutically acceptable
salts thereof wherein the core comprises tolterodine and auxiliary excipients and a single
coating layer comprising rate controlling agent(s).
Yet another object of the invention provides controlled release pharmaceutical
compositions comprising tolterodine or pharmaceutically acceptable salts thereof
comprising an immediate release core wherein said core comprises tolterodine and
pharmaceutically acceptable salts thereof, water insoluble inert material with one or
more auxiliary pharmaceutical excipients and a single coating layer comprising rate
controlling hydrophobic and/or hydrophilic agents(s).
4

Yet another object of the present invention provides controlled release pharmaceutical
compositions of tolterodine or pharmaceutically acceptable salts thereof wherein
additionally a composition contains dissolution enhancing agents comprising organic
acids.
Detail description of the Invention
The dosage forms of the invention typically contain 1 to 20 mg tolterodine as base. The
dosage forms of the invention optionally may comprise salts of tolterodine, preferably
tolterodine tartrate.
The term "immediate release core" herein refers to core comprising tolterodine or
pharmaceutically acceptable salts thereof devoid of any release-controlling agent(s).
The term "controlled release compositions" herein refers to any composition or dosage
form which comprises an active drug and which is formulated to provide a longer
duration of pharmacological response after administration of the dosage form than is
ordinarily experienced after administration of a corresponding immediate release
composition comprising the same drug in the same amount. Controlled release
compositions include, inter alia, those compositions described elsewhere as "extended
release", "delayed release", "sustained release", "prolonged release", "programmed
release", "time release" and/or "rate controlled" compositions or dosage forms.
The hydrophilic release controlling agents are selected from but are not limited to
hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl
cellulose (HEC) polyethylene oxide, polyvinyl alcohol, polyvinylpyrrolidone, xanthan
gum, guar gum, chitosan and its derivatives, carbomer, carrageenan, carboxymethyl
cellulose, sodium alginate, polyglycolized glycerides, polyethylenglycol, or mixture
thereof.
The hydrophobic release controlling agents are selected from but are not limited to
polyvinyl acetate dispersion, ethyl cellulose, cellulose acetate, cellulose propionate
(lower, medium or higher molecular weight), cellulose acetate propionate, cellulose
acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl
methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl
methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl
5

methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl
acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), waxes such as beeswax,
carnauba wax, paraffin wax, microcrystalline wax, and. ozokerite; fatty alcohols such as
cetostearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol, and fatty acid
esters such as glyceryl monostearate; glycerol monooleate, acetylated monoglycerides,
tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, and
hydrogenated vegetable oils.
The term "controlled release pharmaceutical compositions" includes a pharmaceutical
composition that encompasses one or more individual coated units. The coated units
may be a capsule or tablet or may be in form of granules, pellets, minitablets or beads.
The compositions of the present invention can also include other materials such as
dissolution enhancing agents, binders, diluents, anti-adherents, glidants and lubricants.
Dissolution enhancing agents include pharmaceutically acceptable organic acids.
Examples include but not limited to ascorbic acid, succinic acid, malonic acid, oxalic
acid, tartaric acid, fumaric acid, adipic acid, glucono delta-lactone and malic acid.
Diluents may be, for example, any pharmaceutically acceptable, non-toxic diluent.
Particular examples include lactose, dextrose, sucrose, maltose, microcrystalline
cellulose, starch, calcium hydrogen phosphate, mannitol and the like.
Binders may be, for example, starch, sugars, gums, low molecular weight hydroxypropyl
methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or the like.
Lubricants may be, for example, talc, magnesium stearate, calcium stearate, stearic
acid, sodium stearyl fumarate, sodium benzoate or the like.
Antiadherents and Glidants may be, for example, colloidal silicon dioxide, talc or the like.
Solid oral dosage forms of the present invention may be prepared by any conventional
techniques for example dry granulation, direct compression, wet granulation, and
extrusion-spheronization. Wet granulation and extrusion-spheronization are the
preferred techniques.
In the wet granulation method, tolterodine or pharmaceutically acceptable salt thereof
and other auxiliary pharmaceutical ingredients are granulated with a granulating fluid
(e.g., isopropyl alcohol, ethyl alcohol, and water) in a planetary mixer, high shear mixer,
or fluidized bed granulator. The binder and organic acid solution is prepared in suitable
vehicles, both can be mixed. Only binder or mixed solution of binder and organic acid
6

can be used to granulate the powder mass. The wet granules are dried in an oven or
fluidized bed dryer, and then sieved through a suitable screen to obtain free flowing
granules. The resulting granules are blended with a suitable lubricant and glidant. These
granules are compressed into solid dosage from of suitable size. These are further
coated with the one or more hydrophobic and/or hydrophilic controlling agent(s) effective
for the controlled release of tolterotidine or pharmaceutical acceptable salts thereof.
In extrusion-spheronization method, tolterodine and pharmaceutically acceptable salts is
geometrically mixed with water insoluble inert material. The binder and organic acid
solution is prepared in suitable vehicles, both can be mixed. Only binder or mixed
solution of binder and organic acid is used to granulate the blend of active material with
water insoluble inert material. Then wet mass is extrudated using suitable extruder and
spheronized using spheronizer. Pellets or spheroids thus obtained are dried and coated
with release controlling hydrophilic and/or hydrophobic controlling agent(s). The so-
formed multiple units may be filled into hard shell capsules or compressed into a tablet.
The following examples illustrate various aspects of the present invention. These
examples should not be construed as limiting the scope of the invention.
Example: 1

Sr.
No. Ingredient Mg/Capsule
CORE
1. Tolterodine Tartarate 4.00
2. Microcrystalline Cellulose 133.20
3. HPMC 2.80
4. Purified Water Q.S.
Total: 140.00
CONTROLLED RELEASE COATING
1. Ethyl Cellulose 9.80
2. HPMC 4.20
3. Triethyl Citrate Q.S.
4. Talc 4.60
5. Isopropyl Alcohol Q.S.
6. Dichloromethane Q.S.
7

Brief Manufacturing Procedure:
1. Mix Tolterodine Tartarate geometrically with Microcrystalline Cellulose (sifted
through 40 mesh) and load in RMG.
2. Prepare HPMC solution in suitable quantity of water.
3. Granulate the powder mass of step 1 with binder solution of step 2.
4. Extrudate the wet mass through 1 mm sieve using extruder and spheronized
using spheronizer.
5. Dry the pellets at temperature of 60°C in FBD. Sized to suitable fraction.
6. Prepare the controlled release solution in the organic solvents.
7. Coat pellets with sustained release coating in FBP to get the desired build up.
Example 2:

Sr.
No. Ingredient Mg/Capsule
CORE
1. Tolterodine Tartarate 4.00
2. Microcrystalline Cellulose 128.70
3 Tartaric acid 4.5
4 HPMC 2.80
5 Purified Water Q.S.
Total: 140.00
CONTROLLED RELEASE COATING
1. Ethyl Cellulose 9.80
2. HPMC 4.20
3. Triethyl Citrate Q.S.
4. Talc 4.60
5. Isopropyl Alcohol Q.S.
6. Dichloromethane Q.S.
Brief Manufacturing Procedure:
1 Mix Tolterodine Tartarate geometrically with Microcrystalline Cellulose (sifted
through 40 mesh) and load in RMG.
2 Prepare HPMC solution in suitable quantity of water.
3 Tartaric acid was dissolved in suitable quantity of water.
4 Mix Solution of step 2 and 3
5 Granulate the powder mass of step 1 with solution of step 4
6 Extrudate the wet mass through 1 mm sieve using extruder and spheronized
using spheronizer.
7 Dry the pellets at temperature of 60°C in FBD. Sized to suitable fraction.
8

8 Prepare the controlled release solution in the organic solvents.
9 Coat pellets with sustained release coating in FBP to get the desired build up.
Example 3:

Sr.
No. Ingredient Mg/Capsule
CORE
1. Tolterodine 4.00
2. Microcrystalline Cellulose 133.20
3. HPMC 2.80
4. Purified Water Q.S.
Total: 140.00
CONTROLLED RELEASE COATING
1. Ethyl cellulose 168.00
2. HPMC 3.80
3. Triacetin QS
4. Water QS
1 Mix Tolterodine geometrically with Microcrystalline Cellulose and HPMC (sifted
through 40 mesh) and load in RMG.
2 Granulate the powder mass of step 1 with purified water.
3 Dry the granules of step 2 in a suitable dryer
4 Lubricate the granules and compressed into solid dosage form
5 Prepare the controlled release solution in the suitable solvents.
6 Coat solid dosage form with controlled release coating to get desired the build
up.
Dated this 29th day of October 2007

9
A controlled release pharmaceutical composition containing a core comprising tolterodine or pharmaceutically acceptable salts and auxiliary excipients and a single coating layer comprising rate controlling agents(s). A controlled release pharmaceutical composition comprising tolterodine or pharmaceutically acceptable salts thereof wherein the core comprises tolterodine or pharmaceutically acceptable salts thereof and auxiliary excipients and a single coating layer comprising rate controlling agents(s) wherein said composition further comprises dissolution enhancing agent(s).