FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification
[ See Sections 10 and rule 13 ]
Title: Muscarinic receptor antagonist composition with improved drug
release property
Applicant: (a) Astron Research Limited
(b) Nationality: Indian
(c) 10th Floor. Premier House Bodakdev, Opp. Gurudwara Sarkhej - Gandhinagar Highway Ahmedabad 380054
The following specification describes the invention:
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Field of the invention
The present invention relates to sustained release formulation of tolterodine or its pharmaceutically acceptable salts for the treatment in urinary incontinency.
Background
As it is known that antimuscarinic agents are specifically developed for the treatment of patients suffering from overactive bladder. These symptoms of overactive bladder comprise urge incontinence, urgency and frequent urination. These symptoms developed because of uncontrolled contraction of muscle fibers of urinary bladder. Such contraction of muscles is controlled by cholinergic muscarinic receptors so the present invention is developed for the treatment of urinary incontinence.
In order to achieve relief in urinary incontinence, the present invention offer controlled release formulation comprising tolterodine or its pharmaceutically acceptable salts and hydrophobic polymers.
Prior art
Tolterodine is Muscarinic receptor antagonist disclosed in US 5382600 as 3,3-Diphenylpropylamines. This is useful in the treatment of urinary incontinency.
US 6911217 relates to formulation containing controlled release beads and method of producing beads comprising (i) inert core (ii) first coat i.e. seal coat of water insoluble polymer for prevention of penetration of water (iii) second coat over seal coat of active ingredient and finally (iv) final coat with the controlled release polymer. In this invention the presence of seal-coat is to control the water penetration and thereby longer in the release rate of active ingredient.
WO2004105735 relates to controlled release composition of tolterodine and process of its preparation, the pharmaceutical composition comprising one or
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more coated units, each coated unit comprising (i) core (ii) a first layer surrounding at least a portion of the core, the first layer comprising tolterodine and one or more hydrophobic polymers and second layer surrounding at least one portion of the first layer and comprising one or more polymers effective for controlled release of the tolterodine from the first layer.
EP 1629834 relates to sustained release composition comprising outer layer of hydrophobic sustained release polymer coated on first layer, and at least one core element, which is selected from inert core provided with first layer comprising tolterodine and a binder the inert core, of drug and binder.
WO2005079748 relates to sustained release of pharmaceutical active ingredient comprises particles having (1) an inner core and (2) first coating wherein first coating contains mixture of (a) between 50% and 95% by weight of a copolymer of ethyl acrylate, methylmethacrylate and trimethylamminoethyl methacrylate chloride in a molar ratio of the three acrylates of 1: 1.8- 2.2: 0.08-0. 12, preferably of 1: 2: 0.1, (b) between 2% and
30% by weight of a copolymer of ethylacrylate and methacrylic acid in a
molar ratio of I: 0.8-1. 2, preferably of 1: 1, (c) between 1% and 40% by
weight of at least one pharmaceutical active ingredient and optionally (d)
physiologically acceptable excipients; and optionally, at least further
coating (3) thereon
Experimental study of the above said prior art shows that presence of seal coat between inert core and coat of active ingredient is of decisive importance as such presence of seal coat does not result in longer release of drug but result into migration of drug into inert core which finally results into reduction in amount of drug to be release after its administration.
Experimental study also shows that the controlled release effect of acrylates in combination can be achieved by use of single hydrophobic drug retardant.
So to provide the effective controlled release composition with advantageous aspects of production cost and production time, inventor has proposed the
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controlled release composition comprises the core of drug and at least one hydrophobic polymer coated with at least one controlled release hydrophobic polymer.
Object of the invention
The main object of the invention is to provide controlled release pharmaceutical composition comprises active core of tolterodine or its pharmaceutical ly acceptable salts for the treatment of the symptoms of unstable or over active bladder.
Another object of the invention is to provide a controlled release formulation comprises core of tolterodine or its pharmaceutically acceptable salt and at least one hydrophobic polymer coated with at least one controlled release polymer with/ without seal coat.
Still another object of the invention is to achieve cost effective with less time consuming preparation of controlled release pharmaceutical composition.
One more object of the invention is to provide a controlled release formulation comprises of tolterodine or its pharmaceutically acceptable salt administered for once a day or twice a day.
Still one more object of the invention is to provide process of preparation of once a day or twice a day controlled release formulation.
Summary of the Invention
According to the present invention, controlled release pharmaceutical composition of tolterodine, in the form of solid dosage form, for treatment of unstable or over active bladder comprises one or more coated pellets/granules wherein each coated pellet comprises:
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(a) core of tolterodine or its pharmaceutically acceptable salts with at least one hydrophobic polymer and optionally pharmaceutically acceptable excipients
(b) optionally seal coat surrounding the core and
(c) outer layer of hydrophobic polymers for controlled release of tolterodine from the core.
Detailed Description of the Invention
The present invention is to provide pharmaceutical composition for the treatment of urinary incontinence arises because of uncontrolled contraction of muscle fibers of urinary bladder, controlled by cholinergic muscarinic receptors.
The present invention provides controlled release composition comprises
(i) core of toleterodine or its pharmaceutically acceptable salts, at least one
hydrophobic polymer and optionally pharmaceutically acceptable excipient
(ii) optional seal coat over the core and
(iii) outer layer of at least one hydrophobic polymer
Core of this pharmaceutical composition include tolterodine or its pharmaceutically acceptable salt, pharmaceutical acceptable drug retardant, diluents and other pharmaceutically acceptable excipient
The tolterodine or its pharmaceutically acceptable salts present in the core of this pharmaceutically composition is in amounts ranging from 1 to 5 % w/w, more preferably 1.5 to 3 %w/w, most preferably 1.8% w/w.
Drug retardant in the core, ranges from 1 to 30 % w/w, used for controlled release of the active ingredients is hydrophobic polymers selected from the group comprising but not limited to ethyl acrylate, methyl methacrylate, ethylcellulose, polyvinyl acetate, polyvinyl pyrrolidone, trimethyl amminoethyl methacrylate chloride or mixtures thereof
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Diluents in the core, ranges from 30 to 90% w/w, is selected from the group comprising but not limited to cellulose derivative like microcrystalline cellulose, ethyl cellulose or lactose monohydrate and like or mixtures thereof.
The optional seal coat of the composition comprises film forming agent, glidant and opacifier.
The film forming agent in the seal coat of composition, ranges from 2 to 10 % w/w are selected from the group comprising but not limited to sodium alginate, hydroxy propyl methyl cellulose, natural gum or their derivatives, sodium carboxy methyl cellulose or mixtures thereof
The glidant in the seal coat of composition, ranges from 1 to 5 % w/w are selected from but not limited to talc.
The opacifier in the seal coat of composition, ranges from 0.1 to 5 % w/w are selected from but not limited to titanium dioxide.
The outer layer of the composition comprises at least one drug retardant polymer, plasticizer, and anti sticking agent.
The drug retardant polymers in the outer layer of the composition are hydrophobic polymers, ranges from I to 30% w/w, selected from the group comprising but not limited to ethyl acrylate, methyl methacrylate, ethylcellulose, polyvinyl acetate, polyvinyl pyrrolidone, trimethyl amminoethyl methacrylate chloride or mixtures thereof.
Plasticizer in the outer layer of the composition, ranges from 0.5 to 5% w/w, can be chosen from the group comprising but not limited to triethyl citrate, acetylated triethyl citrate, methyl citrate, propylene glycol, polyethylene glycol, triacetin etc.
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Antisticking agent in the outer layer of the composition, ranges from 1 to 10% w/w, can be chosen from the group comprising but not limited to talc, silicone dioxide or combination thereof.
The process for preparing the formulation of the present invention could be by fluidized bed coating technology, which comprises following steps:
Process:
Preparation of Core:
Core can be pellets or granules. Granules are prepared by wet or dry granulation method.
Mix the pharmaceutical^ active ingredient with other inactive ingredients and bind the mixed materials by using solvent. Extrude and then spheronize the wet mass. Dry and separate the pellet from fines by sifting process.
Preparation of seal coat (Optional)
Prepare the seal coating solution. Load the pellets/granules in fluid bed processor and coat them by using seal coating solution. Dry and separate the seal coated pellets/granules from any fines & agglomerates by sifting process.
Preparation of functional coat:
Prepare the functional coating solution. Load the pellets/granules in fluid bed processor and coat them using functional coating solution. Dry and separate the functional coated pellets/granules.
Blending
Blend the functional coated pellets/granules with anti agglomeration agent.
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The said controlled release composition can be present in the form of particles, such as pellets/granules, which are either filled in the capsules or compressed into tablets.
The said controlled release composition shows in vitro dissolution profile for tolterodine is preferably not more than 25 % in 1 hour, 40 to 70 % in 3 hours and not less than about 75% in 7 hours.
The composition can be administered with well-controlled release of tolterodine and thereby maintained the serum level of its active moiety or moieties in-patient for 24 hours.
The ingredients of the composition in formulation range as below:

Sr.No. Ingredient % w/w
Core Composition
1 Pharmaceutical Active Ingredient 1 to 5 %
2 Diluents 30 to 90%
3 Drug Retardant 1 to 30%
4 Solvent Q.S.
Seal Coat (Optional)
5 Film Former 2 to 10%
6 Glidant 1 to 5%
7 Opacifier 0.1 to 5%
8 Solvent Q.S.
Functional Coat
9 Drug Retardant 1 to 30%
10 Plasticizer 0.5 to 5%
11 Anti sticking Agent 1 to 10%
12 Solvent Q.S.
Blending (Optional)
13 Anti Agglomeration Agent 0.1 to 1%
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Throughout this specification and the appended claims it is to be understood that the words "comprise" and include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
Dated this 23rd day of November 2006.

-----------------------------
Ketana Laljibhai Babaria
For & on behalf of an applicant
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