Title of Invention	CONTROLLED RELEASE MUCOADHESIVE MATRIX FORMULATION CONTAINING TOLTERODINE AND A PROCESS FOR ITS PREPARATION
Abstract	Controlled release oral pharmaceutical mucoadhesive matrix formulation containing a therapeutically effective amount of tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof dispersed in a rate controlling polymeric matrix comprising (1) a pH independent gelling polymer, such as polyethylene oxide, (2) pH dependent gelling polymer, such as sodium of carboxymethylcellulose (3) Film coating polymer component, such as Eudragit RS100 and other conventional tablet functional excipients. The formulation such as tablets or minitablets in capsules of the present invention relates to a 24 hour controlled release dosage form useful for the treatment of urge incontinence and other symptoms of unstable or overactive urinary bladder. The invention also relates to a process for the preparation of controlled release mucoadhesive matrix formulation containing tolterodine in a tablet or mini tablets in capsule dosage form.

Title of Invention

CONTROLLED RELEASE MUCOADHESIVE MATRIX FORMULATION CONTAINING TOLTERODINE AND A PROCESS FOR ITS PREPARATION

Abstract

Controlled release oral pharmaceutical mucoadhesive matrix formulation containing a therapeutically effective amount of tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof dispersed in a rate controlling polymeric matrix comprising (1) a pH independent gelling polymer, such as polyethylene oxide, (2) pH dependent gelling polymer, such as sodium of carboxymethylcellulose (3) Film coating polymer component, such as Eudragit RS100 and other conventional tablet functional excipients. The formulation such as tablets or minitablets in capsules of the present invention relates to a 24 hour controlled release dosage form useful for the treatment of urge incontinence and other symptoms of unstable or overactive urinary bladder. The invention also relates to a process for the preparation of controlled release mucoadhesive matrix formulation containing tolterodine in a tablet or mini tablets in capsule dosage form.

Full Text	INTRODUCTION The present invention relates to a controlled release mucoadhesive matrix formulation containing a therapeutically effective amount of tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof The present invention particularly relates to a controlled release mucoadhesive matrix formulation containing tolterodine tartrate in a tablet dosage form. The formulation of the present invention is useful for the treatment of urge incontinence and other symptoms of unstable or overactive urinary bladder. The invention also relates to a process for the preparation of controlled release mucoadhesive matrix formulation containing a therapeutically effective amount of tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof BACKGROUND AND PRIOR ART OF THE INVENTION: A substantial part (5-10%) of the adult population suffers from overactive or unstable urinary bladder, often also referred to as urinary incontinence. The symptoms of an unstable or overactive bladder comprise urge incontinence, urgency and urinary frequency. The prevalence of overactive bladder, particularly of so-called urge incontinence, increases with age. It is assumed that unstable or overactive bladder is caused by uncontrolled contractions of the bundles of smooth muscle fibers 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. The drug of choice has for a long time been oxybutynin. Recently, however, an improved muscarinic receptor antagonist, tolterodine, (R)-N, N-diisopropyl-3- (2-hydroxy-5-me1hylphmyl)-3-phenylpropanamine, has been marketed for the treatment of urge incontience and other symptoms of unstable or overactive urinary bladder. Both tolterodine and its major, active metabolite, the 5-hydroxymetiiyl derivative of tolterodine, which significantly contributes to the therapeutic effect, have considerably less side effects than oxybutynin, especially regarding the propensity to cause dry mouth. The currently marketed administration form of tolterodine is a simple film coated tablet containing 1 mg or 2 mg of tolterodine L-tartrate for immediate release in the gastrointestinal tract, the recommended dosage usually being 2 mg twice a day and also as 4 mg extended release pellets filled in capsules. While, as mentioned, the side effects, such as dry mouth, are much lower than for oxybutynin, they still exist, especially at higher dosages. Tolterodine tartrate is a muscarinic receptor antagonist and it is chemically (+)-N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl)"3"phenylpropylamine L-hydrogen tartrate. The oral administration of tolterodine results in its metabolization in the liver, resulting in the formation of its 5-hydroxymethyl derivative, which is a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite exhibits an anti-muscarinic activity similar to that of the main compound tolterodine, which contributes significantly the therapeutic effect. The most common side effects of tolterodine include dry mouth, dyspepsia, headache, constipation, xerophtiialmia and abnormal vision. The US Patmt No. 5382600 describes preparation of certain novel 3,3-diphenyl propylamines, their use as anticholinergic agents and their pharmaceutical compositions, as plain tablets and capsules for immediate release. The US Patent No, 5559269 also elaborates on similar compounds and generally includes various galenical forms without detailing any compositions. The US Patent Publication No.20030027856 described pharmaceutical compositions in the form of immediate release tablets and transdermal devices comprising tolterodine metabolites. The ingredients for immediate release detailed in this prior art comprise Des- isopropyl-tolterodine, microcrystalline cellulose, lactose, calcium stearate and FD&C blue #1 lake. In this prior art, process details not described. The US Patent publication No.20030124179 describes transdennally administered tolterodine as anti-muscarinic agent for the treatment of overactive bladder. The process described in this prior art is very complex, not economical and release of drug will be subjected to several variables related to product and patirats.- Canadian patent No. 2311755 details a controlled release formulation of tolterodine or its salts for treating unstable or overactive urinary bladder that.administer the drug at a controlled rate for at least 24 hours. It details the production of a controlled release (CR) capsule containing non-pareil beads coated by (i) an ethyl cellulose layer (ii) a tolterodine / HPMC layer, and iii) a sustained release ethyl cellulose / HPMC layer. This process involves a multi-step manufacturing and may not be cost effective besides being time consuming. US Patent No. 6630162 relates to a pharmaceutical formulation containing tolterodine or its derivatives, which exhibit a controlled in vitro release of the active ingredient in phosphate buffer at pH 6.8 of not less than about 80% after 18 hours. After oral administration to a patient it is capable of maintaining a substantially constant serum level of the active moiety or moieties for 24 hours. The process detailed in this prior art comprises sugar spheres coated with Surelease seal coat, drug coat, Surelease / HPMC controlled release coating. The coated spheres were filled in hard gelatin capsules to obtain 2mg and 4mg tolterodine L-tartrate capsules. It was also said that the controlled release beads may be provided as a tablet. As per the processes described in the above said prior art, drug release occurs preferentially by diffusion process through pores created by hydrophilic materials such as HPMC that leads to burst effect of drug release during early hours of drug administration. The above multi-particulate system (a plurality of beads that can be loaded into either a capsule or tablet, each of the "beads" is sorted for a characteristic rate of disintegration) is quite complex, adding significantly to the cost of design and manufacture. Often, a multi-particulate system may even require specialized equipment, further increasing manufacturing costs. Variation in the surface and coating thickness can also translate to incomplete release of the active ingredients one of the shortcomings of this type of technology. A problem frequently encountered with controlled release dosage form is the inability to increase residence time of the dosage form in the stomach and proximal portion of the small intestine. Under fast condition, gastric residence of a dosage form is typically short, which is not more than an hour and it is also common for dosage form to transit rapidly through the small intestine for not more than 3 hours. Rapid GI transit phenomena may consequently diminish the extent of absorption of many drugs. Since many drug compounds are absorbed exclusively in the small intestine or in a limited segment of the intestine, it would therefore be beneficial to develop sustained release dosage form, which remains in the stomach and / or in the proximal portion of the intestine for an extended period of time. Several approaches have been tried to prolong gastrointestinal residence, one of which is the use of oral mucoadhesive formulation. Mucoadhesive polymers have been utilized in many different dosage forms in efforts to achieve systemic delivery of drugs through the different mucosae. The term mucoadhesive is commonly used for materials that bind to the mucin layer of a biological membrane. To serve as mucoadhesive polymers, the polymers should possess some general physiochemical features such as predominantly anionic hydrophilicity with numerous hydrogen bond forming groups, suitable surface property for wetting mucus/mucosal tissue surfaces and sufficient flexibility to penetrate the mucus network or tissue crevices. Mucin molecule behaves as anionic polyelectrolytes at neutral pH. At low pH values, such as found in the stomach, sialic acids are protonated and as resuh, are not charged. Numerous hydroxyl groups of carbohydrates on mucin molecules have the potential to interact with other polymers that can form hydrogen bonds. The interaction between two molecules is composed of attraction and repulsion. For mucoadhesion .to occur, the attractive interaction should be large than nonspecific repulsion. Mucin molecules are negatively charged at neutral pH due to the presence of carboxylate and sulphate groups. A number of charged or neutral polymers have been classified as bio/mucoadhesives, since they are known to bind to mucous via co-valent bonds. Diverse classes of polymers have been investigated for potential use as mucoadhesives. These include synthetic polymers such as poly (acrylic acid) (PAA), hydroxypropyl methylcellulose and poly (methacrylate) derivatives, as well as naturally occurring polymers such as hyaluronic acid and chitosan. Hence there is a need to work on a process, which proves easy and economical for large-scale production and yet at the same time ensures a 24-hour release mechanism by remaining in the stomach or in the proximal portion of the intestine for extended period of time. Accordingly, the main objective of the present invention is to provide an improved oral controlled release matrix dosage formulation in a therapeutic dose, in the tablet form, mini tablets in capsules containing 2 and 4-mg tolterodine tartrate for 24 hour release useful for the treatment of urge incontinence and other symptoms of unstable or overactive urinary bladder. The unit dose may vary according to the age of the patient and the nature and severity of the urge incontinence and other symptoms of unstable or overactive urinary bladder. It generally ranges from 2 to 4 mg, in a single administration, for a daily treatment. Yet another objective of the present invention is to provide a dosage form that reduces fluctuations in blood plasma concentration of Tolterodine so as to have an optimum effective therapeutic window. Still another objective of the present invention is to provide a dosage form enabling the patient to be comparatively free from the side effects such as dry mouth, dyspepsia, headache, constipation, xerophthalmia and abnormal vision. Still another objective of the present invention is to provide a dosage form which releases the drug throughout the gastro-intestinal tract by meeting both temporal and spatial requirements of a once a day medication through its mucoadhesive nature in gastro intestinal tract. Yet another objective of the present invention is to provide control release mucoadhesive matrix tablets, prepared by wet and/or dry granulation processes and direct compressions. Yet another objective of the present invention is to provide controlled release mucoadhesive mini tablets prepared by wet and/or dry granulations processes and direct compression and filled into capsules. Yet another objective of the present invention is to provide a barrier coating for preventing adhesion to oral mucous membrane during administration. Accordingly in the present invention, controlled release mucoadhesive matrix (monolithic) tablets are prepared where the drug is dissolved and/or dispersed in the polymer matrix system. The tablet will bind to the mucin layer of a biological membrane of gastro intestinal tract at the pH range of 1.2 to 6.8 preferentially at pH 4.5 to 6.2. The release of drug from the dosage form is by diffusion through hydrogel (swelling) and controlled erosion of the matrix. More especially, the present invention describes a controlled release mucoadhesive matrix tablet that can be administered by the oral route and that enables sustained and controlled release of the active ingredient, tolterodine tartrate for the treatment of urge incontinence and other symptoms of unstable or overactive urinary bladder, by providing more consistent plasma levels. Accordingly, the present invention provides pharmaceutical formulations containing controlled release mucoadhesive matrix tablet useful for the treatment of urge incontinence and other symptoms of unstable or overactive urinary bladder and which comprises 1. A core matrix tablet comprising a mixture of a therapeutically effective amount of tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof,-polymers, mucoadhesive agents, binders, diluents and-other processing agents that were removed during preparation. 2. A coating on the core with a barrier coating layer comprising a mixture of a polymer, plastisizer and other processing agents that were removed during coating operation. 3. The drug release can be adjusted by changing the amount of one or more of these components of the composition. In the preferred embodiment the mucoadhesive matrix tablets may be prepared by direct compression method. In another preferred embodiment the mucoadhesive matrix tablets may be prepared by wet granulation method. Yet another preferred embodiment mucoadhesive matrix mini tablets may be prepared by direct compression or by wet granulation method and 2 to 10 smaller tablets may be filled into hard gelatin capsules. The core tablet contains a therapeutically effective pharmaceutical ingredient tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof, in the range of about 0.10% to about 80%, preferably about 1% to about 50%, and more preferably about 2% to about 10%, of the total weight of the composition. The pharmaceutical compositions of the present invention may comprise one or more mucoadhesive agents or binders. Polyethylene oxide a pH independent gelling polymer is a preferred mucoadhesive agent used imparts adhesive properties to the powder blend of the tolterodine tartrate formulation. The selected polyethylene oxide is a water soluble, non-ionic homopolymer of ethylene oxide, mucoadhesive tablet binder and thickening agent. The higher molecular weight grades provide delayed drag release via the hydrophilic matrix approach and can be used as tablet binder at various concentrations. The relationship between swelling capacity and molecular weight is a good guide when selecting products for use in immediate or sustained release matrix formulations. The amount of mucoadhesive agent used in the range of about 1% to about 90%, preferably about 5% to about 50 % and more preferably about 6% to about 20%, of the total weight of the composition. According to one preferred embodiment of the composition according to the invention, the polyethylene oxide has a molecular weight, which varies from 50,000 to 8,000, 000 and preferably from 100,000 to 7,000, 000. Optionally other mucoadhesive agents in the core tablet may be selected from thiolated polymers (thiomers), glycoproteins, synthetic polymers such as poly (acrylic acid) (PAA), Hydroxypropyl methylcellulose and poly (methylacrylate) derivatives, naturally occuring polymers such as hyaluronic acid and chitosans, certain carbohydrates, plant lectins, bacterial adhesins, methylcellulose, sodium carboxymethyl cellulose, carbopol and the like. The pharmaceutical composition of the present invention comprises sodium carboxymethylcellulose, a pH dependent gelling polymer as extra granular binder and gelling and mucoadhesive agent in the controlled release matrix tablets. It is a sodium salt of a polycarboxymethyl ether of cellulose with a molecular weight between 90,000 and 7,00,000 and exhibits mucoadhesive property by forming hydrogen bonds with numeroxis carbohydrate hydroxyl groups of mucin molecules. The amount of Sodium CMC used in tile range of about 0.01 % to about 30.00 %, preferably about 0,15 % to about 20 % and more preferably about 0.5% to about 10%, of the total weight of the composition. The pharmaceutical composition of the present invention comprises sodium carboxymethylcellulose viscosity with a range of about 25 to about 2,400 cps, preferably about 80 to about 1,800 cps and more preferably about 600 to about 1,200 cps. Optionally many other polymers such as sodium alginate, hydroxyethyl cellulose, calcium silicate, carbomers, carrageenan, chitosan colloidal silicon dioxide, gelatin, glyceryl monooleate, guar gum, microcrystalline cellulose,- polyethylane alkyl ethers, polyethylene glycol, polyethylene oxide, polymethacrylates, propylene carbonate, sodium ascorbate may be used as gelling agents for the preparation of controlled release mucoadhesive tolterodine tartrate tablets. The pharmaceutical composition of the present invetion comprises polyvinylpyrrolidone (povidone) as binder. Povidone is a synthetic polymer consisting essentially of linear 1-vinyl-2-pyrrolidinone groups, the differing degree of polymerization of which results in polymers of various molecular weighs. The present pharmaceutical compositions comprise one or more binding agents and/or adhesives in the range of about 0.5% to about 35%, preferably about 0.75% to about 25%, and more preferably about 1% to about 20%, of the total weight of the composition. In the present invention povidone has a molecular weight, in the range of about 2,500 to about 3,000,000, preferably about 10,000 to about 1,000,000, and more preferably about 30,000 to about 4,00,000. Optionally one or more suitable binding agents or adhesives such as acacia, tragacanth, sucrose, gelatin, glucose, dextrin, starch, cellulose materials such as, but not limited to, methylcellulose and sodium carboxymethylcellulose, alginic acid and salts of alginic acid, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids, bentonites, polymethacrylates, hyrpomellose, hydroxypropyl cellulose, ethyl cellulose pregelatinized starch may be used. The phannaceutical compositions of the present invention also comprise acetone and isopropyl alcohol in the ratio of 4:6 as processing agents during granulation. Optionally in the present invention one or more solvents such as ethyl alcohol, water and other suitable solvents may be used as processing agents. In the present invention Eudragit RS 100 [poly (ethyl acrylate, methylmethascrylate, trimethylaminoethyl methacrylate chloride: 1:2:0.1)], a low permeable, sustained release retardant polymer, incorporated into matrix tablets as a controlled release binder. Eudragit RS 100 is an insoluble over the entire pH range of gastrointestinal region, but swellable in digestive fluid independently of pH with permeability to water and drug. The amount of polymer employed ranges from 2,00% to 50.00% per tablet, more preferably 5.00 to 15.00% per tablet Optionally Eudragit RLPO [poly (ethylacrylate, methylmethacrylate trimethylammonio ethyl methacrylate chloride) 1:2:0.2], biodegradable polymers such as dl-polylactic acid and polyglycolic acid or their mixture or their copolymers or a mixture thereof, Carbopol 71G, calcium pectinate, pre-gelatinized starch or aqueous or hydro-alcoholic solution of polyvinyl pyrrolidone, hypromellose, hydroxypropyl cellulose, sodium alginate and other salts of alginic acid and the like or a mixture thereof, gastric resistant and intestine soluble enteric polymer such as anionic copolymer Eudragit L100-55(methacrylicacid and ethylacrylate copolymer), Eudragit S 100 and water swellable, pH independent drug permeable polymer such as Eudragit NE SOD, Eudragit NE40D, Eudragit NE SOD or a mixture thereof, may also be incorporated as binding agents. Optionally Eudragit FS 30D may be incorporated in coating composition to retard the release of the drug upto pH to ensure dmg release in the colon. In the present invention microcrystalline cellulose and lactose are used as diluents. The use of extragranular microcrystalline cellulose (that is, microciystalline cellulose added to a wet granulated composition after the drying step) in addition to intragranular microcrystalline cellulose (that is, microcrystalline cellulose added to the composition during or before the wet granulation step) may be used to improve tablet hardness and/or disintegration time. The present pharmaceutical compositions comprise one or more diluents in the range of about 5% to about 99%, preferably about 15% to about 90%, and more preferably about 20% to about 80%, of the total weight of the composition. The diluent or diluents selected preferably exhibit suitable compressibility and pre-compression flow properties. Optionally other diluents such as directly compressible starch, mannitol; sorbitol, dextrose monohydrate, microcrystalline cellulose, dibasic calcium phosphate dihydrate, sucrose-based diluents; confectioners sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate granular, dextrates, dextrin, fructose, kaolin, lactitol, starch, pregelatinized starch, sucrose, Celutab.TM, inositol, hydrolyzed cereal solids such as the Maltrons.TM. and Mor-Rex.TM, amylose; Rexcel.TM, powdered cellulose, calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, and the like may also be incorporated as diluents. Optionally disintegrants such as starch, sodium starch glycolate, croscarmellose sodium, clays (such as Veegum), celluloses (such as purified cellulose, methylcellulose, sodium carboxymethylcellulose and carboxymethylcellulose), alginates, pregelatinized com starches, crospovidone, gums (such as agar, guar, locust bean, KarayaTM, pectin, and tragacanth) may also be incorporated. Disintegrants can be added at any suitable step during the preparation of the pharmaceutical composition, particularly prior to granulation or during the lubrication step prior to compression. The present pharmaceutical compositions comprise one or more disintegrants in the range of about 0.1% to about 30%, preferably about 0.5% to about 10%, and more preferably about 1% to about 6%, of the total weight of the composition. In the present invetion, magnesium stearate, talc and colloidal silicon dioxide are used as lubricants and glidants. The amount of lubricants /glidants ranges from 0.01% to about 10%, preferably about 0.05% to about 8%, and more preferably about 0.8% to about 5%, of the total weight of the composition. ' Optionally other lubricants / glidants such as calcium stearate, calcium silicate, glyceryl behenate, light mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, type I, zinc stearate may be used to obtain desired flow and less friction during compression operation. — -" A- In the present invention Eudragit L 100-55, a methyacrylic acid-ethyl acrylate copolymer (1:1), a gastroresistant enterosoluble material was used as a barrier coating material for controlled release matrix tablets. Eudragit L 100-55 is soluble in intestinal fluid from pH5.5. The present pharmaceutical compositions comprise the coating polymer in the range of about 0.1% to about 25%, preferably about 0.5% to about 15%, and more preferably about 0.75% to about 10%, of the total weight of the composition. In the present invention optionally, Eudragit LlOO, Eudragit L 30 D-55, other polymethacrylates, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, HPMCP, CAP, Polyvinyl Acetate phthalate, hydroxypropylmethylcellulose acetate succinate (HPMCAS) and the like may be used to allow the tablet dosage form to reach the intestinal region where it will be adhered to the mucous membrane and release the drug over a period of 24 hours. In the present invention triethylcitrate was used as a plasticizer for tablet coating, The phannaceutical compositions comprise the plasticizer in the range of about 0.1% to about 30%, preferably about 0.5% to about 20%, and more preferably about 0.75% to about 15%, of the total weight of the composition. Optionally other plasticizers such as glyceryl monostearate, polysorbate 80, acetyltriethyl citrate, acetyltri-n-butyl citrate, dibutyl sebacate, diethyl phthalate, dibutyl phthalate. dioctyl phthalate, triacetin, polyethylene glycol and the like and of fatty alcohol derivatives such as cetyl alcohol, steryl alcohol and the like or mixture of phthalate & fatty alcohol may also be incorporated. In the present invention acetone and isopropyl alcohol in the ratio of 6:4 were used as processing agents during coating. Optionally other solvents such as ethyl alcohol, water and any other suitable solvents may be used as processing agents. Optionally colouring agents in the barrier coating such as titanium dioxide, other suitable colors and mixture thereof may also be incorporated. Optionally tablets may be prepared by direct compression with various acrylic polymers like Eudragit powders such as Eudragit S 100, Eudragit RS PO or their mixture along with flux regulators such as water-soluble and water-insoluble excipients. The granulated mass may contain small amount of sucrose, urea and mannitol to modify drug release characteristics. Water-insoluble materials such as magnesium stearate, talc and kaolin and the Uke may be added to reduce tackiness of the granules and improve flow properties during compression stage. The present invention relates also to the preparation of the matrix tablet. Wet granulation is carried out by mixing the active ingredient, polyethylene oxide 18 NF, sodium carboxymethylcellulose (DVP), and then Lactose anhydrous and microcrystalline cellulose, and then wetting the mixture with a binding solution containing Eudragit RS 100, polyvinyl pyrrolidone in a mixture of acetone and isopropyl alcohol in the ratio of 4 :6. The wet mass is then mixed for a period of time to get uniform granulated mixture, sieved and dried, for example in an oven or a tray dryer to the extent necessary. The dry granules are then reduced in size using particle size reduction equipment such as oscillators or multi mills. The dry granules are then placed in a suitable blender such as a twin - shell blender or double cone blender and the lubricant, anti adherent agent and any additional carrier -materials are added. In a preferred embodiment of this step of the invention, talc, magnesium stearate and colloidal silicon dioxide are added to the granules and the mixture blended for a period of time, preferably a period-of time sufficient to achieve blend uniformity. This blended mixture is then compressed into tablets to the desired weight and hardness using appropriate size tooling where coated tablets are desired, conventional coating techniques known to those of ordinary skill in the art can be employed. The tablets are coated with acrylic polymer, Eudragit L 100-55 The release profile from the controlled release mucoadhesive tablets was studied using pH 6.8 phosphate buffer maintained at 37° C and agitated at 50 rpm and using USP paddle method for 6 hours. The details of the process of the invention are provided in the Example given below which is pro\ided by way of illustration only and therefore should not be construed to limit the scope of the invention. The preparation of controlled release mucoadhesive matrix tablets that can be administered by the oral route is carried out according to the following production process: In the example, the amount of solvent employed in the process evaporates during the processing and in the final tablets is only present in traces within the acceptable regulatory limits. Tolterodine tartrate was mixed geometrically with polyethylene oxide (available from Sumitomo seika chemicals Co. Ltd, supplied by yasham under the commercial product grade PE0-18NF), sodium carboxymethylcellulose (available from Reliance cellulose products LTD, under the commercial product grade DVP), lactose anhydrous and microcrystalline cellulose for one minute with each ingredient. The mixture was sifted through 60# S.S sieve, blended in a double polythene bag for 5 minutes. Binding solution was prepared by dispersing polyvinyl pyrrolidone (K-30) in a mixture of isopropyl alcohol and acetone in the ratio of 6:4 under stirring by using stirrer. Eudragit RS 100, a copolymer of acrylic and methacrylic acid esters with a low content in quatemary ammonium groups (available from degussa) was added slowly under stirring and continued stirring for a period of 30 minutes to get a clear solution. The dry powder mixture was wet granulated with the binding solution and blended for a period of 15 minutes. The wet mass was passed through 18# S.S sieve and the granules were dried in an laboratory oven at 55°C for 45 minutes to reduce the moisture content to between 0.5 and 5.0% and the dried granules were sifted through 20# S.S sieve. if.'- The dried granules were lubricated with colloidal silicon dioxide, talc and magnesium stearate (previously sifted through 60# S.S sieve) by mixing for 2 minutes. The lubricated granules were compressed using 6 mm, round standard concave punches, on a 12 stationary mini press-H MT (Rimek), at a tablet core weight of 100.0 mg. Barrier coating: Eudragit L 100-55 (available from Degussa) was added to a mixture of Isopropyl alcohol and Acetone in the ratio of 4:6 under stirring by using stirrer for a period of 30 minutes. Triethyl citrate was added under stirring and continued stirring for 5 minutes to get a homogeneous solution. The coating solution was applied to the core tablets to give a barrier coating employing a perforated coating paa EXAMPLE 2 Controlled Release mucoadhesive matrix tablets (lOOmg core) containing 2 mg tolterodine tartrate, 7.5% of polyethylene oxide-18 NF and 51.3% of microcrystalline cellulose are prepared according to the procedure given in Example 1. Table 2 shows the formulation details. TABLE 2 Triethyl citrate 0.5 Isopropyl alcohol 25.6 Acetone* 37.8 In the examples, the amount of solvent employed in the process evaporates dxmng the processing and in the final tablets is only present in traces within the acceptable regulatory limits. EXAMPLE 3 Controlled Release mucoadhesive matrix tablets (lOOmg core) containing 2 mg tolterodine tartrate, 8.5% of polyethylene oxide-18 NF and 50.3% of microcrystalline cellulose are prepared according to the procedure given in Example 1. Table 3 shows the formulation details. TABLl Constituents mg/tablet Tolterodine tartrate 2.0 Poly ethylene oxide-18 NF 8.5 Sodium carboxy methyl cellulose (DVP) 3.0 Lactose anhydrous 20.0 Microcrystalline cellulose 50.3 Poly vinyl pyrrolidone K-30 5.0 EudragitRS 100 10.0 Isopropyl alcohol 72 Acetone* 48 Colloidal silicon dioxide 0.1 Purified talc 0.1 Magnesium stearate 1.0 Composition of barrier coating: EudragitL 100-55 3.0 Triethyl citrate 0.5 Isopropyl alcohol* 25.6 Acetone* 37.8 In the examples, the amount of solvent employed in the process evaporates during the processing and in the final tablets is only present in traces within the acceptable regulatory limits. EXAMPLE 4 Controlled Release mucoadhesive matrix tablets (lOOmg core) containing 2 mg tolterodine tartrate, 9.0 % of polyethylene oxide-18 NF and 49.8% of microcrystalline cellulose are prepared according to the procedure given in Example 1. Table 4 shows the formulation details. TABLE 4 Constituents mg/tablet Tolterodine tartrate 2.0 Poly ethylene oxide-18 NF 9.0 Sodium carboxy methyl cellulose (DVP) 3.0 Lactose anhydrous 20.0 Microcrystalhne cellulose 49.8 Poly vinyl pyrrolidone K-30 5.0 EudragitRS 100 10.0 Isopropyl alcohol 72 Acetone* 48 Colloidal silicon dioxide 0.1 Purified talc 0.1 Magnesium stearate 1.0 Composition of barrier coating: Eudragit L 100-55 3.0 Triethyl citrate 0.5 Isopropyl alcohol* 25.6 Acetone* 37.8 In the examples, the amount of solvent employed in the process evaorates during the processing and in the final tablets is only present in traces within the acceptable regulatory limits. EXAMPLE 5 Controlled Release mucoadhesive matrix tablets (lOOmg core) containing 2 mg tolterodine tartrate, 9.5% of polyethylene oxide-18 NF and 49.3% of microcrystalline cellulose are prepared according to the procedure given in Example 1. Table 5 shows the formulation details. TABLE 5 Constituents mg/tablet Tolterodine tartrate 2.0 Poly e%lene oxide-18 NF 9.5 Sodium carboxy methyl cellulose (DVP) 3.0 Lactose anhydrous 20.0 Microcrystalhne cellulose 49.3 Poly vinyl pyrrolidone K-30 5.0 Eudragit RS 100 10.0 Isopropyl alcohol 72 Acetone* 48 Colloidal silicon dioxide 0.1 Purified talc 0,1 Magnesium stearate 1.0 Composition of barrier coating: EudragitL 100-55 3.0 Triethyl citrate 0.5 Isopropyl alcohol* 25.6 Acetone* 37.8 In the examples, the amount of solvent employed in the process evaporates during the processing and in the final tablets is only present in traces within the acceptable regulatory limits. EXAMPLE 6 Controlled Release mucoadhesive matrix tablets (lOOmg core) containing 2 mg tolterodine tartrate, 9.0% of polyethylene oxide-18 NF, 51.8% of microciystalline cellulose and 8.0% eudragit RS 100 are prepared according to the procedure given in Example 1. Table 6 shows Ihe formulation details. TABLE 6 Constituents mg/tablet Tolterodine tartrate 2.0 Poly ethylene oxide-18 NF 9.0 Sodium carboxy methyl cellulose (DVP) 3.0 Lactose anhydrous 20.0 Microcry staliine cellulose 51.8 Poly vinyl pyrrolidone K-30 5.0 Eudragit RS 100 8.0 Isopropyl alcohol 72 Acetone* 48 Colloidal silicon dioxide 0.1 Purified talc 0.1 Magnesium stearate 1.0 Composition of barrier coating: Eudragit L 100-55 3.0 Triethyl citrate 0.5 Isopropyl alcohol* 25.6 Acetone* 37.8 In the examples, ihe amount of solvent employed in the process evaorates during the processing and in the final tablets is only present in traces within the acceptable regulatory limits. EXAMPLE 7 Controlled Release mucoadhesive matrix tablets (lOOmg core) containing 2 mg tolterodine tartrate, 9.0% of polyethylene oxide-18 NF, 51.8% of microcrystailine cellulose, 10.0% eudragit RS 100 and 1.0% sodium carboxy methyl cellulose [DVP] are prepared according to the procedure given in Example 1, Table 7 shows the formulation details. TABLE 7 Constituents mg/tablet Tolterodine tartrate 2.0 Poly ethylene oxide-18 NF 9.0 Sodium carboxy methyl cellulose (DVP) 1.0 Lactose anhydrous 20.0 Microcrystailine cellulose 51.8 Poly vinyl pyrrolidone K-30 5.0 Eudragit RS 100 10.0 Isopropyl alcohol 72 Acetone* 48 Colloidal silicon dioxide 0.1 Purified talc 0.1 Magnesium stearate 1.0 Composition of barrier coating: Eudragit L 100-55 3.0 Triethyl citrate 0.5 Isopropyl alcohol* 25.6 Acetone* 37.8 In the examples, the amount of solvent employed in the process evaporates during the processing and in the final tablets is only present in traces within the acceptable regulatory limits. EXAMPLE 8 Controlled Release mucoadhesive matrix tablets (200mg core) containing 4 mg tolterodine tartrate, 9.0% of polyethylene oxide-18 NF, 51.8% of microcrystailine cellulose, 10.0% eudragit RS 100 and 1.0% sodium carboxymethyl cellulose [DVP] are prepared using 9 mm, round standard concave punch tooling according to the procedure given in Example 1. Table 8 shows the formulation details. TABLE 8 Constituents mg/tablet Tolterodine tartrate 4.0 Poly ethylene oxide-18 NF 18.0 Sodium carboxy methyl cellulose (DVP) 2.0 Lactose anhydrous 40.0 Microcrystalline cellulose 103.6 Poly vinyl pyrrolidone K-30 10.0 EudragitRSlOO 20.0 Isopropyl alcohol 144 Acetone* 96 Colloidal silicon dioxide 0.2 Purified talc 0.2 Magnesium stearate 2,0 Composition of barrier coating: EudragitL 100-55 6.0 Triethyl citrate 10 Isopropyl alcohol* 51.2 Acetone* 75.6 *In the examples, the amount of solvent employed in the process evaporates during the processing and in the fmal tablets is only present in traces within the acceptable regulatory limits. Table 9 (examples 1-5) shows the influence of polyethylene oxide-18 NF on the in vitro release kinetics. The amount of polyethylene oxide-18 NF ranges from 7.0 to 9.5 mg per tablet, thus constituting from 7 to 9.5% of the total weight of the core tablet. The amount of Eudragit RS 100 remains constant and the amount of diluent, microcrystalline cellulose is adjusted to obtain core tablets having a constant weight of 100 mg. The dissolution rate for the resulting tablets is measured using USP Apparatus II (paddles) at 50 r.p.m with 900ml phosphate buffer pH 6.8 at 37°C as the dissolution media. The amount of polyethylene oxide, at a constant weight of Eudragit RS 100 and sodium carboxymethylcellulose influence the release of the active ingredient for a period of time more than 4 hours. Table 10 (examples 6 and 4 show the influence of Eudragit RS 100 on the in vitro release kinetics. The amount of the Eudragit RS 100 ranges from 8 to 10 mg, thus constituting from 8 to 10% of the total weight of the core tablet. The dissolution rate for the resulting tablets is measured using USP Apparatus II (paddles) at 50 r.p.m with 900ml phosphate buffer pH 6.8 at 37°C as the dissolution media. The amount of Eudragit in the matrix strongly influences the release of the active ingredient. Table 11 (examples 4, 7 and 8) shows the influence of sodium carboxymethylcellulose (DVP) on the in vitro release kinetics. The amount of sodium carboxymethylcellulose ranges from 1 to 3mg, thus constituting from 1 to 3% of the total weight of the tablet. The amount of polyethylene oxide and Eudragit RS 100 remains constant and the amount of diluent, microcrystalline cellulose, is adjusted to obtain the core tablets having a constant weight of 100 mg The dissolution rate for the resulting tablets is measured using USP Apparatus II (paddles) at 50 r.p.m with 900ml phosphate buffer pH 6.8 at 37°C as the dissolution media. The amount of sodium carboxymethylcellulose in the controlled release matrix tablets slightly influences the release of the active ingredient. The amount of hardness applied during compression in the controlled release matrix tablets strongly influences the release of the active ingredient and to be maintained in the range of 8 to 15 Kp to obtain specified release profile of the active ingredient. Advantages of the present invention: 1. When administered orally the tablet dosage form completely avoids the dose-dumping phenomenon. 2. The tablets can be produced industrially using already available methods and hence highly adaptable. 3. The composition allows better control of drug release profile. 4. The release of drug can be achieved over a period of 24 hours. 5. In the intestinal tract the release of the drug would be well controlled so as to prevent development of dry mouth, headache and other side effects. What is claimed is: 1. A solid pharmaceutical composition and its process for controlled release oral mucoadhesive matrix tablets and/or mini tablets in capsules comprising a therapeutically effective amount of tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof, to be released at a controlled rate and a sustained release formulation; said controlled release formulation comprising (i) a pH independent gelling polymer, such as polyethylene oxide, (ii) pH dependent gelling polymer, such as sodium carboxymethylcellulose (iii) Film coating polymer component, such as Eudragit RS100 and other conventional tablet functional excipients. 2. A solid pharmaceutical composition as claimed in claim 1 wherein a process comprising the steps consisting of: i) Mixing geometrically in the dry state and for a sufficient time, an active ingredient, polyethylene oxide, sodium carboxymethylcellulose and optionally, one or several additives, ii) Preparing a binding solution with an enteric polymer, such as Eudragit RS 100 and optionally, one or several binders by mixing for a sufficient period of time, iii) Adding solvent followed by mixing for a sufficient period of time, iv) Granulation. v) Sieving the wet mass through suitable Sieve, vi) Drying the granules thus formed for a sufficient period of time, vii) Sieving the dried granules through the suitable Sieve, viii) Optionally adding one or several additives and mixing in the dry state for a sufficient period of time, ix) Optionally barrier coating the said compressed tablet. 3. The composition and process according to claims 2, wherein said granules are compressed with hardness in the range of about 3.5 Kp to about 22 Kp, preferably about 5Kp to 18Kp, and more preferably about 8Kp to 15Kp. 4. The composition and process according to claims 2 to 3, in which the compressing the granules with thickness in the range of about 1.0mm to 5.0mm, and more preferably about 2.0mm to 4.0mm, and more preferably about 2.8mm to 3.5mm. 5. A formulation and process as claimed in claims 1 to 4 wherein the core tablet contains a therapeutically effective pharmaceutical ingredient, tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof, in the range of about 0.10% to about 80%, preferably about 1% to about 50%, and more preferably about 1.5% to about 10%, of the total weight of the composition. 6. A formulation and process as claimed in claims 1 to 5 wherein the pharmaceutical compositions of the present invention comprise a Polyethylene oxide as mucoadhesive agent used in the range of about 1% to about 90%, preferably about 3% to about 50 % and more preferably about 6% to about 20%, of the total weight of the composition. 7. A formulation and process as claimed in claim 1 to 6 wherein the preferred embodiment of the composition according to the invention, the polyethylene oxide has a molecular weight, which varies from 50,000 to 8,000,000 and preferably from 100,000 to 7,000, 000. 8. A formulation and process as claimed in claims 1 to 7 wherein optionally other mucoadhesive agents in the core tablet may be selected from thiolated polymers (thiomers), glycoproteins, synthetic polymers such as poly (acrylic acid) (PAA), Hydroxypropyl methylcellulose and poly (methylacrylate) derivatives, naturally occurring polymers such as hyaluronic acid and chitosans, certain carbohydrates, plant lectins, bacterial adhesins, methylcellulose, sodium carboxymethyl cellulose, carbopol and the like. 9. A formulation and process as claimed in claims 1 to 8 wherein the pharmaceutical compositions of the present invention comprises sodium carboxymethylcellulose, with viscosity at a range of 25 to 2400cps used as extra granular binder, gelling and mucoadhesive agent in the range of about 0.01 % to about 30,00 %, preferably about 0.15 % to about 20 % and more preferably about 0.5% to about 10%, of the total weight of the composition. 10. A formulation and process as claimed in claims 1 to 9 where optionally many other polymers such as sodium alginate, Hydroxyethyl cellulose, calcium silicate, carbomers, carrageenan, chitosan colloidal silicon dioxide, gelatin, glyceryl monooleate, guar gum, microcrystalline cellulose, polyethylene alkyl ethers, polyethylene glycol, polyethylene oxide, polymelhacrylates, propylene carbonate, sodium ascorbate may be used as gelling agents for the preparation of controlled release mucoadhesive tolterodine tartrate tablets. 11. A formulation and process as claimed in claims 1 to 10 wherein the pharmaceutical compositions of the present invention comprises polyvinylpyrrolidone with a molecular weight ranges from 2,500 to 3,000,000 was used as binder in the range of about 0.5% to about 35%, preferably about 0.75% to about 25%, and more preferably about 1% to about 20%, of the total weight of the composition. 12. A formulation and process as claimed in claims 1 to II where one or more suitable binding agents or adhesives such as acacia, tragacanth, sucrose, gelatin, glucose, dextrin, starch, cellulose materials such as, but not limited to, methylcellulose and sodium carboxymethylcellulose, alginic acid and salts of alginic acid, magnesium aluminum silicate, polyethylene glycol, guar gum. polysaccharide acids, bentonites, polymethacrylates, hypromellose, hydroxypropyl cellulose, ethyl cellulose pregelatinized starch may be ysed. 13. A formulation and process as claimed in claims 1 to 12 wherein the pharmaceutical compositions of the present invention acetone and isopropyl alcohol in the ratio of 4: 6 were used as processing agents during granulation. 14. A formulation and process as claimed in claims 1 to 13 wherein the pharmaceutical compositions of the present invention, comprises Eudragit RS 100' [poly (ethyl acrylate, methylmethacrylate, trimethylaminoethyl methacrylate chloride: 1:2:0.1)], as a controlled release binder, ranges from 2.00% to 50.00% per tablet, more preferably 5.00 to 15.00% per tablet 15. A formulation and process as claimed in claim 1 to 14 where optionally Eudragit RL PO [ploy (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2], RS PO, biodegradable polymers such as dl-polylactic acid and polyglycolic add or their mixture or their copolymers or a mixture thereof, Carbopol 71G, calcium pectinate, pre-gelatinized starch or aqueous or hydro-alcoholic solution of polyvinyl pyrrolidone, hypromellose, hydroxypropyl cellulose, sodium alginate and other salts of alginic add and the like or a mixture thereof, gastric resistant and intestine soluble enteric polymer such as anionic copolymer Eudragit L100-55(methacrylicacid and ethylacrylate copolymer), Eudragit S 100 and water swellable, pH independent drug permeable polymer such as Eudragit NE 30D, Eudragit NE 40D, Eudragit NE SOD or a mixture thereof, may also be incorporated as binding agmts. 16. A formulation and process as claimed in claims 1 to 15 where optionally Eudragit FS 30D may be incorporated in coating composition to retard the release of the drug upto pH to enasure dmg release in the colon. 17. A formulation and process as claimed in claims 1 to 16 wherein the phannaceutical compositions of the present invention comprises microcrystalline cellulose and lactose are used as diluents in the range of about 5% to about 99%, preferably about 15% to about 90%, and more preferably about 20% to about 80%, of the total weight of the composition. The diluent or diluents selected preferably exhibit suitable compressibility and pre-compression flow properties. 18. A formulation and process as claimed in claims 1 to 17 where optionally other diluents such as directly compressible starch; mannitol, sorbitol, dextrose monohydrate, microcrystalline cellulose, dibasic calcium phosphate dihydrate, sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate granular, dextrates, dextrin, fructose, kaolin, lactitol, starch, pregelatinized starch, sucrose, Celutab.TM, inositol, hydrolyzed cereal solids such as the Maltrons.TM. and Mor-Rex.TM.; amylose; RexcelTM.; powdered cellulose, calcium carbonate; glycine; bentonite, polyvinylpyrrolidone, and the like may also be incorporated as diluents. 19. A formulation and process as claimed in claims 1 to 18 wherein the pharmaceutical compositions of the present invention optionally disintegrants such as starch, sodium starch glycolate, croscarmellose sodium, clays (such as Veegum), celluloses (such as purified cellulose, methylcellulose, sodium carboxymethylcellulose and carboxymethylcellulose), alginates, pregelatinized com stardies, crospovidone, gums (such as agar, guar, locust bean, Karaya.TM, pectin, and tragcanth) may also be incorporated in the range of about 0.1% to about 30%, preferably about 0.5% to about 10%, and more preferably about 1% to about 6% of the total weight of the composition. 20. A formulation and process as claimed in claims 1 to 19 wherein the present invention comprises, magnesium stearate, talc and colloidal silicon dioxide as lubricants and glidants. The amount of lubricants/glidants ranges from 0.01% to about 10%, preferably about 0.05% to about 8%, and more preferably about 0.08% to about 5%, of the total weight of the composition, 21. A formulation and process as claimed in claims 1 to 20 where optionally other lubricants/glidants such as calcium stearate, calcium silicate, glyceryl behenate, light mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, zinc stearate may be used to obtain desired flow and less friction during compression operation. 22. A formulation and process as claimed in claim 1 to 21 wherein the pharmaceutical compositions of the present invention comprises Eudragit L 100-55, a methyacrylic acid-ethyl acrylate copolymer (1:1), aS barner coating, in the range of about 0.1% to about 25%, preferably about 0.5% to about 15%, and more preferably about 0.75% to about 10%, of the total weight of the composition. 23. A formulation and process as claimed in claims 1 to 22 wherein the pharmaceutical compositions of the present invention comprises optionally Eudragit LIOO. Eudragit L 30 D-55, other polymethacrylates, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, HPMCP, CAP, Polyvinyl Acetate phthalate, hydroxypropylmethylcellulose acetate succinate (HPMCAS) and the like to allow the tablet dosage form to reach the intestinal region where it will be adhered to the mucous membrane and release the drug over a period of 24 hours. 24. A formulation and process as claimed in claims 1 to 23 wherein the pharmaceutical compositions of the present invention comprises triethylcitrate as a plasticizer for tablet coating in the range of about 0.1 % to about 30%, preferably about 0.25% to about 20%, and more preferably about 0.3% to about 15%, of the total weight of the composition. 25. A formulation and process as claimed in claims 1 to 24 where optionally other plasticizers such as glycol monostearate, polysorbate 80, acetyltriethyl citrate, acetyltri-n-butyl citrate, dibutyl sebacate, diethyl phthalate, dibutyl phlhalate, dioctyl phthalate, triacetin, polyethylene glycol and the like and of fatty alcohol derivatives such as cetyl alcohol, steryl alcohol and the like or mixture of r.' phthalate & fatty alcohol may also be incorporated. 26. A formulation and process as claimed in claims 1 to 25 wherein the pharmaceutical compositions comprise acetone and isopropyl alcohol in the ratio of 6:4 as processing agents for dissolving Eudragit L 100-55 during barrier coating. 27. A formulation and process as claimed in claims 1 to 26 wherein optionally one or more solvents such as ethyl alcohol, water or other suitable solvents may be used as processing agents. 28. A formulation and process as claimed in claims 1 to 27 wherein the pharmaceutical compositions of the present invention optionally can comprise in the barrier coating titanium dioxide and other colouring agents and their mixture thereof 29. A formulation and process as claimed in claims 1 to 28 wherein the preferred embodiment comprises mini tablets (2mg or 4mg tolterodine tartrate or its pharmaceutically acceptale salts, prodrugs and metabolites contained in 2 to 10 smaller tablets) prepared by using the same processes detailed in the present invention and may be filled into hard gelatin capsules for 24 hour release. 30. A formulation and process as claimed in claims 1 to 29 wherein the pharmaceutical composition of the present invention, optionally tablets may be prepared by direct compression. 31. A fonnulation and process as claimed in claims 1 to 30 wherein the pharmaceutical composition of the present invention provides a mean, dissolution in phosphate buffer pH 6.8 such that not less than 5% of tolterodine or its pharmaceutically acceptable salts, prodrugs or metabolites released after 1 hour; not less than 15% is released after 2 hours; not less than 30% is released after 6 hours and not less than 60% is released after 12hours and not less than 80% is released after 18 hours.

Full Text

INTRODUCTION
The present invention relates to a controlled release mucoadhesive matrix formulation containing a therapeutically effective amount of tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof The present invention particularly relates to a controlled release mucoadhesive matrix formulation containing tolterodine tartrate in a tablet dosage form. The formulation of the present invention is useful for the treatment of urge incontinence and other symptoms of unstable or overactive urinary bladder.
The invention also relates to a process for the preparation of controlled release mucoadhesive matrix formulation containing a therapeutically effective amount of tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof
BACKGROUND AND PRIOR ART OF THE INVENTION:
A substantial part (5-10%) of the adult population suffers from overactive or unstable urinary bladder, often also referred to as urinary incontinence. The symptoms of an unstable or overactive bladder comprise urge incontinence, urgency and urinary frequency. The prevalence of overactive bladder, particularly of so-called urge incontinence, increases with age. It is assumed that unstable or overactive bladder is caused by uncontrolled contractions of the bundles of smooth muscle fibers 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. The drug of choice has for a long time been oxybutynin. Recently, however, an improved muscarinic receptor antagonist, tolterodine, (R)-N, N-diisopropyl-3- (2-hydroxy-5-me1hylphmyl)-3-phenylpropanamine, has been marketed for the treatment of urge incontience and other symptoms of unstable or overactive urinary bladder. Both tolterodine and its major, active metabolite, the 5-hydroxymetiiyl derivative of tolterodine, which significantly contributes to the therapeutic effect, have

considerably less side effects than oxybutynin, especially regarding the propensity to cause dry mouth.
The currently marketed administration form of tolterodine is a simple film coated tablet containing 1 mg or 2 mg of tolterodine L-tartrate for immediate release in the gastrointestinal tract, the recommended dosage usually being 2 mg twice a day and also as 4 mg extended release pellets filled in capsules. While, as mentioned, the side effects, such as dry mouth, are much lower than for oxybutynin, they still exist, especially at higher dosages.
Tolterodine tartrate is a muscarinic receptor antagonist and it is chemically (+)-N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl)"3"phenylpropylamine L-hydrogen tartrate. The oral administration of tolterodine results in its metabolization in the liver, resulting in the formation of its 5-hydroxymethyl derivative, which is a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite exhibits an anti-muscarinic activity similar to that of the main compound tolterodine, which contributes significantly the therapeutic effect.
The most common side effects of tolterodine include dry mouth, dyspepsia, headache, constipation, xerophtiialmia and abnormal vision.
The US Patmt No. 5382600 describes preparation of certain novel 3,3-diphenyl propylamines, their use as anticholinergic agents and their pharmaceutical compositions, as plain tablets and capsules for immediate release.
The US Patent No, 5559269 also elaborates on similar compounds and generally includes various galenical forms without detailing any compositions.
The US Patent Publication No.20030027856 described pharmaceutical compositions in the form of immediate release tablets and transdermal devices comprising tolterodine metabolites. The ingredients for immediate release detailed in this prior art comprise Des-

isopropyl-tolterodine, microcrystalline cellulose, lactose, calcium stearate and FD&C blue #1 lake. In this prior art, process details not described.
The US Patent publication No.20030124179 describes transdennally administered tolterodine as anti-muscarinic agent for the treatment of overactive bladder. The process described in this prior art is very complex, not economical and release of drug will be subjected to several variables related to product and patirats.-
Canadian patent No. 2311755 details a controlled release formulation of tolterodine or its salts for treating unstable or overactive urinary bladder that.administer the drug at a controlled rate for at least 24 hours. It details the production of a controlled release (CR) capsule containing non-pareil beads coated by (i) an ethyl cellulose layer (ii) a tolterodine / HPMC layer, and iii) a sustained release ethyl cellulose / HPMC layer. This process involves a multi-step manufacturing and may not be cost effective besides being time consuming.
US Patent No. 6630162 relates to a pharmaceutical formulation containing tolterodine or its derivatives, which exhibit a controlled in vitro release of the active ingredient in phosphate buffer at pH 6.8 of not less than about 80% after 18 hours. After oral administration to a patient it is capable of maintaining a substantially constant serum level of the active moiety or moieties for 24 hours. The process detailed in this prior art comprises sugar spheres coated with Surelease seal coat, drug coat, Surelease / HPMC controlled release coating. The coated spheres were filled in hard gelatin capsules to obtain 2mg and 4mg tolterodine L-tartrate capsules. It was also said that the controlled release beads may be provided as a tablet.
As per the processes described in the above said prior art, drug release occurs preferentially by diffusion process through pores created by hydrophilic materials such as HPMC that leads to burst effect of drug release during early hours of drug administration.

The above multi-particulate system (a plurality of beads that can be loaded into either a capsule or tablet, each of the "beads" is sorted for a characteristic rate of disintegration) is quite complex, adding significantly to the cost of design and manufacture.
Often, a multi-particulate system may even require specialized equipment, further increasing manufacturing costs. Variation in the surface and coating thickness can also translate to incomplete release of the active ingredients one of the shortcomings of this type of technology.
A problem frequently encountered with controlled release dosage form is the inability to increase residence time of the dosage form in the stomach and proximal portion of the small intestine. Under fast condition, gastric residence of a dosage form is typically short, which is not more than an hour and it is also common for dosage form to transit rapidly through the small intestine for not more than 3 hours. Rapid GI transit phenomena may consequently diminish the extent of absorption of many drugs.
Since many drug compounds are absorbed exclusively in the small intestine or in a limited segment of the intestine, it would therefore be beneficial to develop sustained release dosage form, which remains in the stomach and / or in the proximal portion of the intestine for an extended period of time.
Several approaches have been tried to prolong gastrointestinal residence, one of which is the use of oral mucoadhesive formulation.
Mucoadhesive polymers have been utilized in many different dosage forms in efforts to achieve systemic delivery of drugs through the different mucosae. The term mucoadhesive is commonly used for materials that bind to the mucin layer of a biological membrane. To serve as mucoadhesive polymers, the polymers should possess some general physiochemical features such as predominantly anionic hydrophilicity with numerous hydrogen bond forming groups, suitable surface property for wetting mucus/mucosal tissue surfaces and sufficient flexibility to penetrate the mucus network

or tissue crevices. Mucin molecule behaves as anionic polyelectrolytes at neutral pH. At low pH values, such as found in the stomach, sialic acids are protonated and as resuh, are not charged. Numerous hydroxyl groups of carbohydrates on mucin molecules have the potential to interact with other polymers that can form hydrogen bonds. The interaction between two molecules is composed of attraction and repulsion. For mucoadhesion .to occur, the attractive interaction should be large than nonspecific repulsion. Mucin molecules are negatively charged at neutral pH due to the presence of carboxylate and sulphate groups. A number of charged or neutral polymers have been classified as bio/mucoadhesives, since they are known to bind to mucous via co-valent bonds. Diverse classes of polymers have been investigated for potential use as mucoadhesives. These include synthetic polymers such as poly (acrylic acid) (PAA), hydroxypropyl methylcellulose and poly (methacrylate) derivatives, as well as naturally occurring polymers such as hyaluronic acid and chitosan.
Hence there is a need to work on a process, which proves easy and economical for large-scale production and yet at the same time ensures a 24-hour release mechanism by remaining in the stomach or in the proximal portion of the intestine for extended period of time.
Accordingly, the main objective of the present invention is to provide an improved oral controlled release matrix dosage formulation in a therapeutic dose, in the tablet form, mini tablets in capsules containing 2 and 4-mg tolterodine tartrate for 24 hour release useful for the treatment of urge incontinence and other symptoms of unstable or overactive urinary bladder. The unit dose may vary according to the age of the patient and the nature and severity of the urge incontinence and other symptoms of unstable or overactive urinary bladder. It generally ranges from 2 to 4 mg, in a single administration, for a daily treatment.
Yet another objective of the present invention is to provide a dosage form that reduces fluctuations in blood plasma concentration of Tolterodine so as to have an optimum effective therapeutic window.

Still another objective of the present invention is to provide a dosage form enabling the patient to be comparatively free from the side effects such as dry mouth, dyspepsia, headache, constipation, xerophthalmia and abnormal vision.
Still another objective of the present invention is to provide a dosage form which releases the drug throughout the gastro-intestinal tract by meeting both temporal and spatial requirements of a once a day medication through its mucoadhesive nature in gastro intestinal tract.
Yet another objective of the present invention is to provide control release mucoadhesive matrix tablets, prepared by wet and/or dry granulation processes and direct compressions.
Yet another objective of the present invention is to provide controlled release mucoadhesive mini tablets prepared by wet and/or dry granulations processes and direct compression and filled into capsules.
Yet another objective of the present invention is to provide a barrier coating for preventing adhesion to oral mucous membrane during administration.
Accordingly in the present invention, controlled release mucoadhesive matrix (monolithic) tablets are prepared where the drug is dissolved and/or dispersed in the polymer matrix system. The tablet will bind to the mucin layer of a biological membrane of gastro intestinal tract at the pH range of 1.2 to 6.8 preferentially at pH 4.5 to 6.2. The release of drug from the dosage form is by diffusion through hydrogel (swelling) and controlled erosion of the matrix.
More especially, the present invention describes a controlled release mucoadhesive matrix tablet that can be administered by the oral route and that enables sustained and controlled release of the active ingredient, tolterodine tartrate for the treatment of urge

incontinence and other symptoms of unstable or overactive urinary bladder, by providing more consistent plasma levels.
Accordingly, the present invention provides pharmaceutical formulations containing controlled release mucoadhesive matrix tablet useful for the treatment of urge incontinence and other symptoms of unstable or overactive urinary bladder and which comprises
1. A core matrix tablet comprising a mixture of a therapeutically effective amount of tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof,-polymers, mucoadhesive agents, binders, diluents and-other processing agents that were removed during preparation.
2. A coating on the core with a barrier coating layer comprising a mixture of a polymer, plastisizer and other processing agents that were removed during coating operation.
3. The drug release can be adjusted by changing the amount of one or more of these components of the composition.
In the preferred embodiment the mucoadhesive matrix tablets may be prepared by direct compression method.
In another preferred embodiment the mucoadhesive matrix tablets may be prepared by wet granulation method.
Yet another preferred embodiment mucoadhesive matrix mini tablets may be prepared by direct compression or by wet granulation method and 2 to 10 smaller tablets may be filled into hard gelatin capsules.
The core tablet contains a therapeutically effective pharmaceutical ingredient tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof, in the range of about 0.10% to about 80%, preferably about 1% to about 50%, and more preferably about 2% to about 10%, of the total weight of the composition.

The pharmaceutical compositions of the present invention may comprise one or more mucoadhesive agents or binders. Polyethylene oxide a pH independent gelling polymer is a preferred mucoadhesive agent used imparts adhesive properties to the powder blend of the tolterodine tartrate formulation. The selected polyethylene oxide is a water soluble, non-ionic homopolymer of ethylene oxide, mucoadhesive tablet binder and thickening agent.
The higher molecular weight grades provide delayed drag release via the hydrophilic matrix approach and can be used as tablet binder at various concentrations. The relationship between swelling capacity and molecular weight is a good guide when selecting products for use in immediate or sustained release matrix formulations. The amount of mucoadhesive agent used in the range of about 1% to about 90%, preferably about 5% to about 50 % and more preferably about 6% to about 20%, of the total weight of the composition. According to one preferred embodiment of the composition according to the invention, the polyethylene oxide has a molecular weight, which varies from 50,000 to 8,000, 000 and preferably from 100,000 to 7,000, 000.
Optionally other mucoadhesive agents in the core tablet may be selected from thiolated polymers (thiomers), glycoproteins, synthetic polymers such as poly (acrylic acid) (PAA), Hydroxypropyl methylcellulose and poly (methylacrylate) derivatives, naturally occuring polymers such as hyaluronic acid and chitosans, certain carbohydrates, plant lectins, bacterial adhesins, methylcellulose, sodium carboxymethyl cellulose, carbopol and the like.
The pharmaceutical composition of the present invention comprises sodium carboxymethylcellulose, a pH dependent gelling polymer as extra granular binder and gelling and mucoadhesive agent in the controlled release matrix tablets. It is a sodium salt of a polycarboxymethyl ether of cellulose with a molecular weight between 90,000 and 7,00,000 and exhibits mucoadhesive property by forming hydrogen bonds with numeroxis carbohydrate hydroxyl groups of mucin molecules. The amount of Sodium CMC used in

tile range of about 0.01 % to about 30.00 %, preferably about 0,15 % to about 20 % and more preferably about 0.5% to about 10%, of the total weight of the composition.
The pharmaceutical composition of the present invention comprises sodium carboxymethylcellulose viscosity with a range of about 25 to about 2,400 cps, preferably about 80 to about 1,800 cps and more preferably about 600 to about 1,200 cps.
Optionally many other polymers such as sodium alginate, hydroxyethyl cellulose, calcium silicate, carbomers, carrageenan, chitosan colloidal silicon dioxide, gelatin, glyceryl monooleate, guar gum, microcrystalline cellulose,- polyethylane alkyl ethers, polyethylene glycol, polyethylene oxide, polymethacrylates, propylene carbonate, sodium ascorbate may be used as gelling agents for the preparation of controlled release mucoadhesive tolterodine tartrate tablets.
The pharmaceutical composition of the present invetion comprises polyvinylpyrrolidone (povidone) as binder. Povidone is a synthetic polymer consisting essentially of linear 1-vinyl-2-pyrrolidinone groups, the differing degree of polymerization of which results in polymers of various molecular weighs. The present pharmaceutical compositions comprise one or more binding agents and/or adhesives in the range of about 0.5% to about 35%, preferably about 0.75% to about 25%, and more preferably about 1% to about 20%, of the total weight of the composition. In the present invention povidone has a molecular weight, in the range of about 2,500 to about 3,000,000, preferably about 10,000 to about 1,000,000, and more preferably about 30,000 to about 4,00,000.
Optionally one or more suitable binding agents or adhesives such as acacia, tragacanth, sucrose, gelatin, glucose, dextrin, starch, cellulose materials such as, but not limited to, methylcellulose and sodium carboxymethylcellulose, alginic acid and salts of alginic acid, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids, bentonites, polymethacrylates, hyrpomellose, hydroxypropyl cellulose, ethyl cellulose pregelatinized starch may be used.

The phannaceutical compositions of the present invention also comprise acetone and isopropyl alcohol in the ratio of 4:6 as processing agents during granulation.
Optionally in the present invention one or more solvents such as ethyl alcohol, water and other suitable solvents may be used as processing agents.
In the present invention Eudragit RS 100 [poly (ethyl acrylate, methylmethascrylate, trimethylaminoethyl methacrylate chloride: 1:2:0.1)], a low permeable, sustained release retardant polymer, incorporated into matrix tablets as a controlled release binder. Eudragit RS 100 is an insoluble over the entire pH range of gastrointestinal region, but swellable in digestive fluid independently of pH with permeability to water and drug. The amount of polymer employed ranges from 2,00% to 50.00% per tablet, more preferably 5.00 to 15.00% per tablet
Optionally Eudragit RLPO [poly (ethylacrylate, methylmethacrylate trimethylammonio ethyl methacrylate chloride) 1:2:0.2], biodegradable polymers such as dl-polylactic acid and polyglycolic acid or their mixture or their copolymers or a mixture thereof, Carbopol 71G, calcium pectinate, pre-gelatinized starch or aqueous or hydro-alcoholic solution of polyvinyl pyrrolidone, hypromellose, hydroxypropyl cellulose, sodium alginate and other salts of alginic acid and the like or a mixture thereof, gastric resistant and intestine soluble enteric polymer such as anionic copolymer Eudragit L100-55(methacrylicacid and ethylacrylate copolymer), Eudragit S 100 and water swellable, pH independent drug permeable polymer such as Eudragit NE SOD, Eudragit NE40D, Eudragit NE SOD or a mixture thereof, may also be incorporated as binding agents.
Optionally Eudragit FS 30D may be incorporated in coating composition to retard the release of the drug upto pH to ensure dmg release in the colon.
In the present invention microcrystalline cellulose and lactose are used as diluents. The use of extragranular microcrystalline cellulose (that is, microciystalline cellulose added to a wet granulated composition after the drying step) in addition to intragranular

microcrystalline cellulose (that is, microcrystalline cellulose added to the composition during or before the wet granulation step) may be used to improve tablet hardness and/or disintegration time. The present pharmaceutical compositions comprise one or more diluents in the range of about 5% to about 99%, preferably about 15% to about 90%, and more preferably about 20% to about 80%, of the total weight of the composition. The diluent or diluents selected preferably exhibit suitable compressibility and pre-compression flow properties.
Optionally other diluents such as directly compressible starch, mannitol; sorbitol, dextrose monohydrate, microcrystalline cellulose, dibasic calcium phosphate dihydrate, sucrose-based diluents; confectioners sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate granular, dextrates, dextrin, fructose, kaolin, lactitol, starch, pregelatinized starch, sucrose, Celutab.TM, inositol, hydrolyzed cereal solids such as the Maltrons.TM. and Mor-Rex.TM, amylose; Rexcel.TM, powdered cellulose, calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, and the like may also be incorporated as diluents.
Optionally disintegrants such as starch, sodium starch glycolate, croscarmellose sodium, clays (such as Veegum), celluloses (such as purified cellulose, methylcellulose, sodium carboxymethylcellulose and carboxymethylcellulose), alginates, pregelatinized com starches, crospovidone, gums (such as agar, guar, locust bean, KarayaTM, pectin, and tragacanth) may also be incorporated.
Disintegrants can be added at any suitable step during the preparation of the pharmaceutical composition, particularly prior to granulation or during the lubrication step prior to compression. The present pharmaceutical compositions comprise one or more disintegrants in the range of about 0.1% to about 30%, preferably about 0.5% to about 10%, and more preferably about 1% to about 6%, of the total weight of the composition.

In the present invetion, magnesium stearate, talc and colloidal silicon dioxide are used as lubricants and glidants. The amount of lubricants /glidants ranges from 0.01% to about 10%, preferably about 0.05% to about 8%, and more preferably about 0.8% to about 5%, of the total weight of the composition.
' Optionally other lubricants / glidants such as calcium stearate, calcium silicate, glyceryl
behenate, light mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid,
hydrogenated vegetable oil, type I, zinc stearate may be used to obtain desired flow and
less friction during compression operation.
— -" A-
In the present invention Eudragit L 100-55, a methyacrylic acid-ethyl acrylate copolymer (1:1), a gastroresistant enterosoluble material was used as a barrier coating material for controlled release matrix tablets. Eudragit L 100-55 is soluble in intestinal fluid from pH5.5. The present pharmaceutical compositions comprise the coating polymer in the range of about 0.1% to about 25%, preferably about 0.5% to about 15%, and more preferably about 0.75% to about 10%, of the total weight of the composition.
In the present invention optionally, Eudragit LlOO, Eudragit L 30 D-55, other polymethacrylates, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, HPMCP, CAP, Polyvinyl Acetate phthalate, hydroxypropylmethylcellulose acetate succinate (HPMCAS) and the like may be used to allow the tablet dosage form to reach the intestinal region where it will be adhered to the mucous membrane and release the drug over a period of 24 hours.
In the present invention triethylcitrate was used as a plasticizer for tablet coating, The phannaceutical compositions comprise the plasticizer in the range of about 0.1% to about 30%, preferably about 0.5% to about 20%, and more preferably about 0.75% to about 15%, of the total weight of the composition.
Optionally other plasticizers such as glyceryl monostearate, polysorbate 80, acetyltriethyl citrate, acetyltri-n-butyl citrate, dibutyl sebacate, diethyl phthalate, dibutyl phthalate.

dioctyl phthalate, triacetin, polyethylene glycol and the like and of fatty alcohol derivatives such as cetyl alcohol, steryl alcohol and the like or mixture of phthalate & fatty alcohol may also be incorporated.
In the present invention acetone and isopropyl alcohol in the ratio of 6:4 were used as processing agents during coating.
Optionally other solvents such as ethyl alcohol, water and any other suitable solvents may be used as processing agents.
Optionally colouring agents in the barrier coating such as titanium dioxide, other suitable colors and mixture thereof may also be incorporated.
Optionally tablets may be prepared by direct compression with various acrylic polymers like Eudragit powders such as Eudragit S 100, Eudragit RS PO or their mixture along with flux regulators such as water-soluble and water-insoluble excipients. The granulated mass may contain small amount of sucrose, urea and mannitol to modify drug release characteristics.
Water-insoluble materials such as magnesium stearate, talc and kaolin and the Uke may be added to reduce tackiness of the granules and improve flow properties during compression stage.
The present invention relates also to the preparation of the matrix tablet. Wet granulation is carried out by mixing the active ingredient, polyethylene oxide 18 NF, sodium carboxymethylcellulose (DVP), and then Lactose anhydrous and microcrystalline cellulose, and then wetting the mixture with a binding solution containing Eudragit RS 100, polyvinyl pyrrolidone in a mixture of acetone and isopropyl alcohol in the ratio of 4 :6.

The wet mass is then mixed for a period of time to get uniform granulated mixture, sieved and dried, for example in an oven or a tray dryer to the extent necessary. The dry granules are then reduced in size using particle size reduction equipment such as oscillators or multi mills.
The dry granules are then placed in a suitable blender such as a twin - shell blender or double cone blender and the lubricant, anti adherent agent and any additional carrier -materials are added. In a preferred embodiment of this step of the invention, talc, magnesium stearate and colloidal silicon dioxide are added to the granules and the mixture blended for a period of time, preferably a period-of time sufficient to achieve blend uniformity.
This blended mixture is then compressed into tablets to the desired weight and hardness using appropriate size tooling where coated tablets are desired, conventional coating techniques known to those of ordinary skill in the art can be employed.
The tablets are coated with acrylic polymer, Eudragit L 100-55
The release profile from the controlled release mucoadhesive tablets was studied using pH 6.8 phosphate buffer maintained at 37° C and agitated at 50 rpm and using USP paddle method for 6 hours.
The details of the process of the invention are provided in the Example given below which is pro\ided by way of illustration only and therefore should not be construed to limit the scope of the invention. The preparation of controlled release mucoadhesive matrix tablets that can be administered by the oral route is carried out according to the following production process:

*In the example, the amount of solvent employed in the process evaporates during the processing and in the final tablets is only present in traces within the acceptable regulatory limits.
Tolterodine tartrate was mixed geometrically with polyethylene oxide (available from Sumitomo seika chemicals Co. Ltd, supplied by yasham under the commercial product grade PE0-18NF), sodium carboxymethylcellulose (available from Reliance cellulose products LTD, under the commercial product grade DVP), lactose anhydrous and microcrystalline cellulose for one minute with each ingredient. The mixture was sifted through 60# S.S sieve, blended in a double polythene bag for 5 minutes.
Binding solution was prepared by dispersing polyvinyl pyrrolidone (K-30) in a mixture of isopropyl alcohol and acetone in the ratio of 6:4 under stirring by using stirrer. Eudragit RS 100, a copolymer of acrylic and methacrylic acid esters with a low content in

quatemary ammonium groups (available from degussa) was added slowly under stirring and continued stirring for a period of 30 minutes to get a clear solution.
The dry powder mixture was wet granulated with the binding solution and blended for a period of 15 minutes. The wet mass was passed through 18# S.S sieve and the granules were dried in an laboratory oven at 55°C for 45 minutes to reduce the moisture content to
between 0.5 and 5.0% and the dried granules were sifted through 20# S.S sieve.
if.'-
The dried granules were lubricated with colloidal silicon dioxide, talc and magnesium stearate (previously sifted through 60# S.S sieve) by mixing for 2 minutes. The lubricated granules were compressed using 6 mm, round standard concave punches, on a 12 stationary mini press-H MT (Rimek), at a tablet core weight of 100.0 mg.
Barrier coating: Eudragit L 100-55 (available from Degussa) was added to a mixture of Isopropyl alcohol and Acetone in the ratio of 4:6 under stirring by using stirrer for a period of 30 minutes. Triethyl citrate was added under stirring and continued stirring for 5 minutes to get a homogeneous solution.
The coating solution was applied to the core tablets to give a barrier coating employing a perforated coating paa
EXAMPLE 2
Controlled Release mucoadhesive matrix tablets (lOOmg core) containing 2 mg tolterodine tartrate, 7.5% of polyethylene oxide-18 NF and 51.3% of microcrystalline cellulose are prepared according to the procedure given in Example 1. Table 2 shows the formulation details.
TABLE 2

Triethyl citrate 0.5
Isopropyl alcohol* 25.6
Acetone* 37.8
*In the examples, the amount of solvent employed in the process evaporates dxmng the processing and in the final tablets is only present in traces within the acceptable regulatory limits.
EXAMPLE 3
Controlled Release mucoadhesive matrix tablets (lOOmg core) containing 2 mg tolterodine tartrate, 8.5% of polyethylene oxide-18 NF and 50.3% of microcrystalline cellulose are prepared according to the procedure given in Example 1. Table 3 shows the formulation details.
TABLl
Constituents mg/tablet
Tolterodine tartrate 2.0
Poly ethylene oxide-18 NF 8.5
Sodium carboxy methyl cellulose (DVP) 3.0
Lactose anhydrous 20.0
Microcrystalline cellulose 50.3
Poly vinyl pyrrolidone K-30 5.0
EudragitRS 100 10.0
Isopropyl alcohol* 72
Acetone* 48
Colloidal silicon dioxide 0.1
Purified talc 0.1
Magnesium stearate 1.0
Composition of barrier coating:
EudragitL 100-55 3.0
Triethyl citrate 0.5
Isopropyl alcohol* 25.6
Acetone* 37.8
*In the examples, the amount of solvent employed in the process evaporates during the processing and in the final tablets is only present in traces within the acceptable regulatory limits.
EXAMPLE 4
Controlled Release mucoadhesive matrix tablets (lOOmg core) containing 2 mg tolterodine tartrate, 9.0 % of polyethylene oxide-18 NF and 49.8% of microcrystalline cellulose are prepared according to the procedure given in Example 1. Table 4 shows the formulation details.

TABLE 4
Constituents mg/tablet
Tolterodine tartrate 2.0
Poly ethylene oxide-18 NF 9.0
Sodium carboxy methyl cellulose (DVP) 3.0
Lactose anhydrous 20.0
Microcrystalhne cellulose 49.8
Poly vinyl pyrrolidone K-30 5.0
EudragitRS 100 10.0
Isopropyl alcohol* 72
Acetone* 48
Colloidal silicon dioxide 0.1
Purified talc 0.1
Magnesium stearate 1.0
Composition of barrier coating:
Eudragit L 100-55 3.0
Triethyl citrate 0.5
Isopropyl alcohol* 25.6
Acetone* 37.8
*In the examples, the amount of solvent employed in the process evaorates during the processing and in the final tablets is only present in traces within the acceptable regulatory limits.
EXAMPLE 5
Controlled Release mucoadhesive matrix tablets (lOOmg core) containing 2 mg
tolterodine tartrate, 9.5% of polyethylene oxide-18 NF and 49.3% of microcrystalline
cellulose are prepared according to the procedure given in Example 1. Table 5 shows the
formulation details.
TABLE 5
Constituents mg/tablet
Tolterodine tartrate 2.0
Poly e%lene oxide-18 NF 9.5
Sodium carboxy methyl cellulose (DVP) 3.0
Lactose anhydrous 20.0
Microcrystalhne cellulose 49.3
Poly vinyl pyrrolidone K-30 5.0
Eudragit RS 100 10.0
Isopropyl alcohol* 72
Acetone* 48

Colloidal silicon dioxide 0.1
Purified talc 0,1
Magnesium stearate 1.0
Composition of barrier coating:
EudragitL 100-55 3.0
Triethyl citrate 0.5
Isopropyl alcohol* 25.6
Acetone* 37.8
*In the examples, the amount of solvent employed in the process evaporates during the processing and in the final tablets is only present in traces within the acceptable regulatory limits.
EXAMPLE 6
Controlled Release mucoadhesive matrix tablets (lOOmg core) containing 2 mg tolterodine tartrate, 9.0% of polyethylene oxide-18 NF, 51.8% of microciystalline cellulose and 8.0% eudragit RS 100 are prepared according to the procedure given in Example 1. Table 6 shows Ihe formulation details.
TABLE 6
Constituents mg/tablet
Tolterodine tartrate 2.0
Poly ethylene oxide-18 NF 9.0
Sodium carboxy methyl cellulose (DVP) 3.0
Lactose anhydrous 20.0
Microcry staliine cellulose 51.8
Poly vinyl pyrrolidone K-30 5.0
Eudragit RS 100 8.0
Isopropyl alcohol* 72
Acetone* 48
Colloidal silicon dioxide 0.1
Purified talc 0.1
Magnesium stearate 1.0
Composition of barrier coating:
Eudragit L 100-55 3.0
Triethyl citrate 0.5
Isopropyl alcohol* 25.6
Acetone* 37.8
*In the examples, ihe amount of solvent employed in the process evaorates during the processing and in the final tablets is only present in traces within the acceptable regulatory limits.

EXAMPLE 7
Controlled Release mucoadhesive matrix tablets (lOOmg core) containing 2 mg tolterodine tartrate, 9.0% of polyethylene oxide-18 NF, 51.8% of microcrystailine cellulose, 10.0% eudragit RS 100 and 1.0% sodium carboxy methyl cellulose [DVP] are prepared according to the procedure given in Example 1, Table 7 shows the formulation details.
TABLE 7
Constituents mg/tablet
Tolterodine tartrate 2.0
Poly ethylene oxide-18 NF 9.0
Sodium carboxy methyl cellulose (DVP) 1.0
Lactose anhydrous 20.0
Microcrystailine cellulose 51.8
Poly vinyl pyrrolidone K-30 5.0
Eudragit RS 100 10.0
Isopropyl alcohol* 72
Acetone* 48
Colloidal silicon dioxide 0.1
Purified talc 0.1
Magnesium stearate 1.0
Composition of barrier coating:
Eudragit L 100-55 3.0
Triethyl citrate 0.5
Isopropyl alcohol* 25.6
Acetone* 37.8
*In the examples, the amount of solvent employed in the process evaporates during the processing and in the final tablets is only present in traces within the acceptable regulatory limits.
EXAMPLE 8
Controlled Release mucoadhesive matrix tablets (200mg core) containing 4 mg tolterodine tartrate, 9.0% of polyethylene oxide-18 NF, 51.8% of microcrystailine cellulose, 10.0% eudragit RS 100 and 1.0% sodium carboxymethyl cellulose [DVP] are prepared using 9 mm, round standard concave punch tooling according to the procedure given in Example 1. Table 8 shows the formulation details.
TABLE 8

Constituents mg/tablet
Tolterodine tartrate 4.0
Poly ethylene oxide-18 NF 18.0
Sodium carboxy methyl cellulose (DVP) 2.0
Lactose anhydrous 40.0
Microcrystalline cellulose 103.6
Poly vinyl pyrrolidone K-30 10.0
EudragitRSlOO 20.0
Isopropyl alcohol* 144
Acetone* 96
Colloidal silicon dioxide 0.2
Purified talc 0.2
Magnesium stearate 2,0
Composition of barrier coating:
EudragitL 100-55 6.0
Triethyl citrate 10
Isopropyl alcohol* 51.2
Acetone* 75.6
*In the examples, the amount of solvent employed in the process evaporates during the processing and in the fmal tablets is only present in traces within the acceptable regulatory limits.
Table 9 (examples 1-5) shows the influence of polyethylene oxide-18 NF on the in vitro release kinetics. The amount of polyethylene oxide-18 NF ranges from 7.0 to 9.5 mg per tablet, thus constituting from 7 to 9.5% of the total weight of the core tablet. The amount of Eudragit RS 100 remains constant and the amount of diluent, microcrystalline cellulose is adjusted to obtain core tablets having a constant weight of 100 mg.
The dissolution rate for the resulting tablets is measured using USP Apparatus II (paddles) at 50 r.p.m with 900ml phosphate buffer pH 6.8 at 37°C as the dissolution media.
The amount of polyethylene oxide, at a constant weight of Eudragit RS 100 and sodium carboxymethylcellulose influence the release of the active ingredient for a period of time more than 4 hours.

Table 10 (examples 6 and 4 show the influence of Eudragit RS 100 on the in vitro release kinetics. The amount of the Eudragit RS 100 ranges from 8 to 10 mg, thus constituting from 8 to 10% of the total weight of the core tablet.
The dissolution rate for the resulting tablets is measured using USP Apparatus II (paddles) at 50 r.p.m with 900ml phosphate buffer pH 6.8 at 37°C as the dissolution media.

The amount of Eudragit in the matrix strongly influences the release of the active ingredient.
Table 11 (examples 4, 7 and 8) shows the influence of sodium carboxymethylcellulose (DVP) on the in vitro release kinetics. The amount of sodium carboxymethylcellulose ranges from 1 to 3mg, thus constituting from 1 to 3% of the total weight of the tablet. The amount of polyethylene oxide and Eudragit RS 100 remains constant and the amount of diluent, microcrystalline cellulose, is adjusted to obtain the core tablets having a constant weight of 100 mg
The dissolution rate for the resulting tablets is measured using USP Apparatus II (paddles) at 50 r.p.m with 900ml phosphate buffer pH 6.8 at 37°C as the dissolution media.

The amount of sodium carboxymethylcellulose in the controlled release matrix tablets slightly influences the release of the active ingredient.
The amount of hardness applied during compression in the controlled release matrix tablets strongly influences the release of the active ingredient and to be maintained in the range of 8 to 15 Kp to obtain specified release profile of the active ingredient.
Advantages of the present invention:
1. When administered orally the tablet dosage form completely avoids the dose-dumping phenomenon.
2. The tablets can be produced industrially using already available methods and hence highly adaptable.
3. The composition allows better control of drug release profile.
4. The release of drug can be achieved over a period of 24 hours.
5. In the intestinal tract the release of the drug would be well controlled so as to prevent development of dry mouth, headache and other side effects.

What is claimed is:
1. A solid pharmaceutical composition and its process for controlled release oral mucoadhesive matrix tablets and/or mini tablets in capsules comprising a therapeutically effective amount of tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof, to be released at a controlled rate and a sustained release formulation; said controlled release formulation comprising (i) a pH independent gelling polymer, such as polyethylene oxide, (ii) pH dependent gelling polymer, such as sodium carboxymethylcellulose (iii) Film coating polymer component, such as Eudragit RS100 and other conventional tablet functional excipients.
2. A solid pharmaceutical composition as claimed in claim 1 wherein a process comprising the steps consisting of:
i) Mixing geometrically in the dry state and for a sufficient time, an active
ingredient, polyethylene oxide, sodium carboxymethylcellulose and optionally,
one or several additives, ii) Preparing a binding solution with an enteric polymer, such as Eudragit RS 100
and optionally, one or several binders by mixing for a sufficient period of time, iii) Adding solvent followed by mixing for a sufficient period of time, iv) Granulation.
v) Sieving the wet mass through suitable Sieve, vi) Drying the granules thus formed for a sufficient period of time, vii) Sieving the dried granules through the suitable Sieve, viii) Optionally adding one or several additives and mixing in the dry state for a
sufficient period of time, ix) Optionally barrier coating the said compressed tablet.

3. The composition and process according to claims 2, wherein said granules are compressed with hardness in the range of about 3.5 Kp to about 22 Kp, preferably about 5Kp to 18Kp, and more preferably about 8Kp to 15Kp.
4. The composition and process according to claims 2 to 3, in which the compressing the granules with thickness in the range of about 1.0mm to 5.0mm, and more preferably about 2.0mm to 4.0mm, and more preferably about 2.8mm to 3.5mm.
5. A formulation and process as claimed in claims 1 to 4 wherein the core tablet contains a therapeutically effective pharmaceutical ingredient, tolterodine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof, in the range of about 0.10% to about 80%, preferably about 1% to about 50%, and more preferably about 1.5% to about 10%, of the total weight of the composition.
6. A formulation and process as claimed in claims 1 to 5 wherein the pharmaceutical compositions of the present invention comprise a Polyethylene oxide as mucoadhesive agent used in the range of about 1% to about 90%, preferably about 3% to about 50 % and more preferably about 6% to about 20%, of the total weight of the composition.
7. A formulation and process as claimed in claim 1 to 6 wherein the preferred embodiment of the composition according to the invention, the polyethylene oxide has a molecular weight, which varies from 50,000 to 8,000,000 and preferably from 100,000 to 7,000, 000.
8. A formulation and process as claimed in claims 1 to 7 wherein optionally other mucoadhesive agents in the core tablet may be selected from thiolated polymers (thiomers), glycoproteins, synthetic polymers such as poly (acrylic acid) (PAA), Hydroxypropyl methylcellulose and poly (methylacrylate) derivatives, naturally occurring polymers such as hyaluronic acid and chitosans, certain carbohydrates,

plant lectins, bacterial adhesins, methylcellulose, sodium carboxymethyl cellulose, carbopol and the like.
9. A formulation and process as claimed in claims 1 to 8 wherein the pharmaceutical compositions of the present invention comprises sodium carboxymethylcellulose, with viscosity at a range of 25 to 2400cps used as extra granular binder, gelling and mucoadhesive agent in the range of about 0.01 % to about 30,00 %, preferably about 0.15 % to about 20 % and more preferably about 0.5% to about 10%, of the total weight of the composition.
10. A formulation and process as claimed in claims 1 to 9 where optionally many other polymers such as sodium alginate, Hydroxyethyl cellulose, calcium silicate, carbomers, carrageenan, chitosan colloidal silicon dioxide, gelatin, glyceryl monooleate, guar gum, microcrystalline cellulose, polyethylene alkyl ethers, polyethylene glycol, polyethylene oxide, polymelhacrylates, propylene carbonate, sodium ascorbate may be used as gelling agents for the preparation of controlled release mucoadhesive tolterodine tartrate tablets.
11. A formulation and process as claimed in claims 1 to 10 wherein the pharmaceutical compositions of the present invention comprises polyvinylpyrrolidone with a molecular weight ranges from 2,500 to 3,000,000 was used as binder in the range of about 0.5% to about 35%, preferably about 0.75% to about 25%, and more preferably about 1% to about 20%, of the total weight of the composition.
12. A formulation and process as claimed in claims 1 to II where one or more suitable binding agents or adhesives such as acacia, tragacanth, sucrose, gelatin, glucose, dextrin, starch, cellulose materials such as, but not limited to, methylcellulose and sodium carboxymethylcellulose, alginic acid and salts of alginic acid, magnesium aluminum silicate, polyethylene glycol, guar gum.

polysaccharide acids, bentonites, polymethacrylates, hypromellose, hydroxypropyl cellulose, ethyl cellulose pregelatinized starch may be ysed.
13. A formulation and process as claimed in claims 1 to 12 wherein the pharmaceutical compositions of the present invention acetone and isopropyl alcohol in the ratio of 4: 6 were used as processing agents during granulation.
14. A formulation and process as claimed in claims 1 to 13 wherein the pharmaceutical compositions of the present invention, comprises Eudragit RS 100' [poly (ethyl acrylate, methylmethacrylate, trimethylaminoethyl methacrylate chloride: 1:2:0.1)], as a controlled release binder, ranges from 2.00% to 50.00% per tablet, more preferably 5.00 to 15.00% per tablet
15. A formulation and process as claimed in claim 1 to 14 where optionally Eudragit RL PO [ploy (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2], RS PO, biodegradable polymers such as dl-polylactic acid and polyglycolic add or their mixture or their copolymers or a mixture thereof, Carbopol 71G, calcium pectinate, pre-gelatinized starch or aqueous or hydro-alcoholic solution of polyvinyl pyrrolidone, hypromellose, hydroxypropyl cellulose, sodium alginate and other salts of alginic add and the like or a mixture thereof, gastric resistant and intestine soluble enteric polymer such as anionic copolymer Eudragit L100-55(methacrylicacid and ethylacrylate copolymer), Eudragit S 100 and water swellable, pH independent drug permeable polymer such as Eudragit NE 30D, Eudragit NE 40D, Eudragit NE SOD or a mixture thereof, may also be incorporated as binding agmts.
16. A formulation and process as claimed in claims 1 to 15 where optionally Eudragit FS 30D may be incorporated in coating composition to retard the release of the drug upto pH to enasure dmg release in the colon.

17. A formulation and process as claimed in claims 1 to 16 wherein the phannaceutical compositions of the present invention comprises microcrystalline cellulose and lactose are used as diluents in the range of about 5% to about 99%, preferably about 15% to about 90%, and more preferably about 20% to about 80%, of the total weight of the composition. The diluent or diluents selected preferably exhibit suitable compressibility and pre-compression flow properties.
18. A formulation and process as claimed in claims 1 to 17 where optionally other diluents such as directly compressible starch; mannitol, sorbitol, dextrose monohydrate, microcrystalline cellulose, dibasic calcium phosphate dihydrate, sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate granular, dextrates, dextrin, fructose, kaolin, lactitol, starch, pregelatinized starch, sucrose, Celutab.TM, inositol, hydrolyzed cereal solids such as the Maltrons.TM. and Mor-Rex.TM.; amylose; RexcelTM.; powdered cellulose, calcium carbonate; glycine; bentonite, polyvinylpyrrolidone, and the like may also be incorporated as diluents.
19. A formulation and process as claimed in claims 1 to 18 wherein the pharmaceutical compositions of the present invention optionally disintegrants such as starch, sodium starch glycolate, croscarmellose sodium, clays (such as Veegum), celluloses (such as purified cellulose, methylcellulose, sodium carboxymethylcellulose and carboxymethylcellulose), alginates, pregelatinized com stardies, crospovidone, gums (such as agar, guar, locust bean, Karaya.TM, pectin, and tragcanth) may also be incorporated in the range of about 0.1% to about 30%, preferably about 0.5% to about 10%, and more preferably about 1% to about 6% of the total weight of the composition.
20. A formulation and process as claimed in claims 1 to 19 wherein the present invention comprises, magnesium stearate, talc and colloidal silicon dioxide as lubricants and glidants. The amount of lubricants/glidants ranges from 0.01% to

about 10%, preferably about 0.05% to about 8%, and more preferably about 0.08% to about 5%, of the total weight of the composition,
21. A formulation and process as claimed in claims 1 to 20 where optionally other lubricants/glidants such as calcium stearate, calcium silicate, glyceryl behenate, light mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, zinc stearate may be used to obtain desired flow and less friction during compression operation.
22. A formulation and process as claimed in claim 1 to 21 wherein the pharmaceutical compositions of the present invention comprises Eudragit L 100-55, a methyacrylic acid-ethyl acrylate copolymer (1:1), aS barner coating, in the range of about 0.1% to about 25%, preferably about 0.5% to about 15%, and more preferably about 0.75% to about 10%, of the total weight of the composition.
23. A formulation and process as claimed in claims 1 to 22 wherein the pharmaceutical compositions of the present invention comprises optionally Eudragit LIOO. Eudragit L 30 D-55, other polymethacrylates, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, HPMCP, CAP, Polyvinyl Acetate phthalate, hydroxypropylmethylcellulose acetate succinate (HPMCAS) and the like to allow the tablet dosage form to reach the intestinal region where it will be adhered to the mucous membrane and release the drug over a period of 24 hours.
24. A formulation and process as claimed in claims 1 to 23 wherein the pharmaceutical compositions of the present invention comprises triethylcitrate as a plasticizer for tablet coating in the range of about 0.1 % to about 30%, preferably about 0.25% to about 20%, and more preferably about 0.3% to about 15%, of the total weight of the composition.

25. A formulation and process as claimed in claims 1 to 24 where optionally other
plasticizers such as glycol monostearate, polysorbate 80, acetyltriethyl citrate,
acetyltri-n-butyl citrate, dibutyl sebacate, diethyl phthalate, dibutyl phlhalate,
dioctyl phthalate, triacetin, polyethylene glycol and the like and of fatty alcohol
derivatives such as cetyl alcohol, steryl alcohol and the like or mixture of
r.'
phthalate & fatty alcohol may also be incorporated.
26. A formulation and process as claimed in claims 1 to 25 wherein the pharmaceutical compositions comprise acetone and isopropyl alcohol in the ratio of 6:4 as processing agents for dissolving Eudragit L 100-55 during barrier coating.
27. A formulation and process as claimed in claims 1 to 26 wherein optionally one or more solvents such as ethyl alcohol, water or other suitable solvents may be used as processing agents.
28. A formulation and process as claimed in claims 1 to 27 wherein the pharmaceutical compositions of the present invention optionally can comprise in the barrier coating titanium dioxide and other colouring agents and their mixture thereof
29. A formulation and process as claimed in claims 1 to 28 wherein the preferred embodiment comprises mini tablets (2mg or 4mg tolterodine tartrate or its pharmaceutically acceptale salts, prodrugs and metabolites contained in 2 to 10 smaller tablets) prepared by using the same processes detailed in the present invention and may be filled into hard gelatin capsules for 24 hour release.
30. A formulation and process as claimed in claims 1 to 29 wherein the pharmaceutical composition of the present invention, optionally tablets may be prepared by direct compression.

31. A fonnulation and process as claimed in claims 1 to 30 wherein the pharmaceutical composition of the present invention provides a mean, dissolution in phosphate buffer pH 6.8 such that not less than 5% of tolterodine or its pharmaceutically acceptable salts, prodrugs or metabolites released after 1 hour; not less than 15% is released after 2 hours; not less than 30% is released after 6 hours and not less than 60% is released after 12hours and not less than 80% is released after 18 hours.

Documents:

393-che-2004-abstract.pdf

393-che-2004-claims filed.pdf

393-che-2004-claims granted.pdf

393-che-2004-correspondnece-others.pdf

393-che-2004-correspondnece-po.pdf

393-che-2004-description(complete)filed.pdf

393-che-2004-description(complete)granted.pdf

393-che-2004-description(provisional).pdf

393-che-2004-form 1.pdf

393-che-2004-form 3.pdf

393-che-2004-form 5.pdf

393-che-2004-other documents.pdf

393-che-2004-pct.pdf

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Patent Number

227178

Indian Patent Application Number

393/CHE/2004

PG Journal Number

07/2009

Publication Date

13-Feb-2009

Grant Date

05-Jan-2009

Date of Filing

28-Apr-2004

Name of Patentee

NATCO PHARMA LIMITED

Applicant Address

NATCO HOUSE, ROAD NO. 2, BANJARA HILLS, HYDERABAD - 500 033,

Inventors:

#	Inventor's Name	Inventor's Address
1	RONGALA APPALASWAMY NAIDU	NATCO PHARMA LIMITED,NATCO HOUSE, ROAD NO. 2, BANJARA HILLS, HYDERABAD - 500 033,
2	PARVATANENI DURGA MAHESWARI	NATCO PHARMA LIMITED,NATCO HOUSE, ROAD NO. 2, BANJARA HILLS, HYDERABAD - 500 033,
3	PODILE KHADGAPATHI	NATCO PHARMA LIMITED,NATCO HOUSE, ROAD NO. 2, BANJARA HILLS, HYDERABAD - 500 033,
4	VENKAIAH CHOWDARY NANNAPANENI	NATCO PHARMA LIMITED,NATCO HOUSE, ROAD NO. 2, BANJARA HILLS, HYDERABAD - 500 033,

PCT International Classification Number

A61K 9/50

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA