CA2758657A1

CA2758657A1 - Controlled release formulations of tolterodine and process of manufacturing

Info

Publication number: CA2758657A1
Application number: CA2758657A
Authority: CA
Inventors: Vinayak Pathak; Prashant Manohar Mandaogade; Naresh Talwar
Original assignee: Pharmascience Inc
Current assignee: Pharmascience Inc
Priority date: 2011-11-18
Filing date: 2011-11-18
Publication date: 2013-05-18
Also published as: CA2795893A1

Abstract

The present invention is directed to a controlled-release composition containing an active ingredient and processes for manufacturing same. The active ingredient is preferably tolterodine, or a pharmaceutically acceptable salt thereof. The composition comprises an inert core; a first layer comprising a hydrophilic film coating polymer and at least one excipient; a second layer disposed comprising an active ingredient and at least one excipient; a third layer comprising a pH-independent control release polymer and at least one excipient; and a fourth layer comprising an enteric polymer and at least one excipient, wherein administration of the composition to a patient allows for relatively constant bioavailability of the active pharmaceutical ingredient, regardless of the fasted or fed state of said patient.

Description

CONTROLLED RELEASE FORMULATIONS OF TOLTERODINE
AND PROCESS OF MANUFACTURING

FIELD OF THE INVENTION
The present invention relates to the field of pharmaceuticals, and specifically to pharmaceutical formulations comprising a controlled release multiple unit pharmaceutical composition and a process of manufacturing a controlled release composition. In particular, the multiple unit pharmaceutical compositions comprise tolterodine, or a pharmaceutically acceptable salt thereof, as an active ingredient.
BACKGROUND OF THE INVENTION
Tolterodine, (R)-N,N-diisopropy1-3-(2-hydroxy-5-methylpheny1)-3-phenylpropanamine, is an antimuscarinic drug that is used to treat urinary incontinence.

4101CH 3 .= H 3 C CH 3 CH3 Tolterodine, and its pharmaceutically acceptable salts, is administered as a tablet and an extended-release capsule to relieve urinary difficulties, including frequent urination and inability to control urination. It works by preventing bladder contraction. Tolterodine is presently being sold in a number of different countries under the brand name Detrol or Detrositol .
In order to maximize patient compliance, it is desirable to reduce the frequency of dosing to obtain effective therapy, while at the same time providing an oral dosage form which is palatable to the patient.
One method of accomplishing this goal is the use of controlled release formulations. The intention of controlled release formulations is to provide an extended duration of the pharmacological response after administration of the dosage form; generally providing a constant concentration of 4171721 v2 the active substance in body fluids for a certain period of time. The extended release dosage form may be in the form of a single unit or a multiple unit formulation. Single unit controlled release dosage forms of drugs have known disadvantages. For example, dosage forms may either pass undisintegrated through the gastrointestinal tract thus not releasing the active ingredient or release the entire drug load in a burst (referred to as dose dumping). These dosage forms are also heavily dependent upon gastric emptying rates and transit times, as well as intra and inter-individual variations. Multiple unit dosage forms may take the shape of a variety of forms, including a multiplicity of individual units contained within a rapidly dissolving capsule or compressed into a tablet. Soon after ingestion of the formulations, individual units are directly available in the gastrointestinal tract.

Extended-release capsules of tolterodine are usually taken once a day to maintain a therapeutic serum level of tolterodine and to minimize the effects of missed doses of the drug caused by lack of patient compliance.

Several advantages of multiple unit dosage forms have previously been disclosed. It is, for example, possible to obtain reproducible results in regards to the emptying of the units from the stomach into the small intestine when the particles are less than 1-2 mm.
Dispersion over a large area in drugs with the decreased plasma concentrations defined by the decreased peak plasma concentration (CmAx) and/or area under the curve (AUC) due to increase of the gastric pH and consequently impaired in vivo dissolution are for example poorly-water soluble weakly basic drugs.

Decreased or increased as used above relates to values compared to the ones obtained by administering the drugs to patients having normal stomach and gastrointestinal pH. Elevated gastric pH might also change the pharmacokinetic properties of the coated formulations, because the pH in the stomach changed as a result of the use of food to the values that are characteristic for the small intestine, thus the release of the drug may begin already in the stomach, resulting in shorter TMAX (time to reach maximum concentration) and increased CMAX.

The high probability of impaired gastric pH associated with diseases and conditions selected form different groups, particularly urinary diseases, thus requires that drugs used for the manufacturing of the medicament for treatment of above diseases and/or conditions are formulated into a pharmaceutical composition exhibiting predictable pH dependant dissolution characteristics.

4171721 v2 There exist many types of oral dosage formulations which are directed to the controlled release of a pharmaceutically active ingredient, including many types of multi-layered controlled release beads. Indeed, these beads generally consist of an inert core, a first layer of polymer (i.e. a "seal-coat") applied onto the inert core, a layer containing the pharmaceutically active ingredient (i.e. a drug-containing layer), and an outer layer for controlling the release rate of the drug contained from the drug-containing layer.
For example, Canadian Patent No. 2,350,061 (issued May 17, 2005) discloses a formulation of tolterodine which is composed of three-layered coated multiparticulates. The beads comprising (i) a core unit of a substantially water-soluble or water-swellable inert material, (ii) a first layer on the core unit of a substantially water-insoluble polymer, (iii) a second layer covering the first layer and containing an active ingredient, and (iv) a third layer of polymer on the second layer effective for controlled release of the active ingredient, wherein the first layer is adapted to control water penetration into the core. A method of producing the controlled release bead is also disclosed.
PCT Publication No. W02004/105735 (published December 9, 2004) discloses a controlled release pharmaceutical composition of tolterodine that includes one or more coated units. Each unit has a core, a first layer and a second layer. The first layer surrounds the core and includes tolterodine and one or more hydrophilic polymers. The second layer includes one or more polymers effective for controlled release of the tolterodine from the first layer.
PCT Publication No. W02004/012700 (published February 12, 2004) discloses a dosage form comprising of a high dose, high solubility active ingredient as modified release and a low dose active ingredient as immediate release where the weight ratio of immediate release active ingredient and modified release active ingredient is from 1:10 to 1:15000 and the weight of modified release active ingredient per unit is from 500 mg to 1500 mg; a process for preparing the dosage form.
PCT Publication No. W02007/011131 (published January 25, 2007) discloses a novel pharmaceutical composition which is capable of improving the stability over time of a drug pellet during storage and distribution of the pellet having controlled release properties. More specifically, the present invention provides a novel pharmaceutical composition which is capable of preventing moisture-induced changes in a drug release rate during storage and distribution of a drug pellet, 4171721 v2 via coating of a controlled-release pellet, particularly sustained-release pellet, comprising tolterodine, a tolterodine compound or a pharmaceutically acceptable salt thereof as a drug, with a dimethylaminoethyl methacrylate/ methyl methacrylate copolymer (Eudragit E) or polyvinylacetal diethylaminoacetate ("AEA") which is insoluble at a pH of 5.5 or higher.

PCT Publication No. W02009/003724 (published January 8, 2009) discloses a controlled release bead comprising: a microcrystalline cellulose core unit; a water soluble coat surrounding said core comprising a vinyl pyrrolidone polymer; a drug layer comprising tolterodine or a pharmaceutically acceptable salt and a pharmaceutical acceptable binder; and a controlled release layer comprising a pH independent polymer, preferably a polyacrylate, and a process for preparing these beads, to a pharmaceutical dosage form, and to their use.

Canadian Patent Application No. 2,693,166 (published January 29, 2009) discloses a drug composition comprising a coated bead that is used in the manufacture of immediate release and/ or controlled release drug compositions. In a specific embodiment, the bead includes an inert core of a water-soluble or water-swellable material, which has been coated with a seal layer formed from a non-polymeric hydrophobic material. The immediate and/or controlled release beads may be used to form tablets or capsules. A method of making the beads by sequential deposition of multiple layers on the inert cores is also described.

Similarly, Canadian Patent Application No. 2,693,163 (published January 29, 2009) discloses a pharmaceutical composition containing tolterodine L-tartrate stabilized against degradation with an acid. Acid-stabilized tolterodine L-tartrate may be used to make various types of immediate release and controlled release dosage forms.

The Applicant's international application, PCT Publication No. W02009/121178 (Canadian Patent Application No. 2,718,753), also relates to a controlled-release bead containing a pharmaceutically active ingredient. The controlled-release bead comprises a core made of a substantially water-insoluble inert material. A first layer is disposed over the core, with the first layer comprising a substantially water-soluble polymer. A second layer disposed over the first layer, the second layer containing the pharmaceutically active ingredient and a polymer. Finally, a third layer is disposed over the second layer, with the third layer comprising a controlling release polymeric system. The application also discloses dosage forms, such as tablets and capsules, comprising the controlled-release beads, and methods of manufacturing the controlled-release beads.

4171721 v2 . .

Some more references for pharmaceutical composition contains coated beads of Tolterodine are known to exist in prior art as: PCT Publication No. W02011/013082 (published February 3, 2011);
Canadian Patent Application No. 2,637,444 (published July 26, 2007) (W02007/082770); Canadian Patent No. 2,311,755 (issued March 23, 2010) (W02000012069); Canadian Patent Application No.
2,647,765 (published October 11, 2007) (W02007113207); PCT Publication No.

(published November 1, 2007); PCT Publication No. W02009/140557 (published November 19, 2009); and PCT Publication No. W02003/053428 (published July 3, 2003).

Several advantages have been disclosed in the prior art regarding multiple unit dosage forms of the extended release formulation of tolterodine, or a pharmaceutically acceptable salt. However, given the different mechanism of action, as well as effect of food intake on the pharmacokinetics, of the known extended release formulations, there is a need for improved formulations of tolterodine (or a pharmaceutically acceptable salt thereof) comprising a controlled release multiple unit pharmaceutical composition.

SUMMARY OF THE INVENTION

One aspect of the present invention is to address existing disadvantages by developing a unique controlled release tolterodine formulation which can be used for the treatment of urinary incontinence due to overactive bladder.

A further aspect of the present invention is to provide tolterodine controlled release beads and formulations which provide substantially uniform bioavailability, regardless of the fasted or fed state of the patient being treated (i.e. the food effect).

Another aspect of the present invention is to provide a tolterodine controlled release composition that is bioequivalent to DETROL LA and different compositions of tolterodine extended release capsules.

A further aspect of the present invention provides a process for making this product with more conventional manufacturing process by preparing multiple unit controlled release tolterodine formulation, which is simple, therapeutically effective and less expensive.

An aspect of the present invention provides a controlled-release composition for oral administration, comprising:

4171721 v2 (i) an inert core;
(ii) a first layer disposed over the inert core, the first layer comprises a hydrophilic film coating polymer and at least one pharmaceutically acceptable excipient;
(iii ) a second layer disposed over the first layer, the second layer comprises an active pharmaceutical ingredient and at least one pharmaceutically acceptable excipient;
(iv) a third layer, disposed over the second layer, the third layer comprises a pH-independent control release polymer and at least one pharmaceutically acceptable excipient;
and (v) a fourth layer disposed over the third layer, the fourth layer comprises an enteric polymer and at least one pharmaceutically acceptable excipient, wherein said composition diminishes the food effect when administered to a patient that has eaten, i.e. administration of the composition to a human patient allows for relatively constant bioavailability of the active pharmaceutical ingredient, regardless of the fasted or fed state of said patient.

Preferably, the active pharmaceutical ingredient is selected from the group consisting of:
tolterodine, the 5-hydroxymethyl metabolite of tolterodine, the (S)-enantiomer of tolterodine, the 5-hydroxymethyl metabolite of the (S)-enantiomer of tolterodine, the racemate of tolterodine, its prodrug forms and pharmacologically acceptable salts thereof. Even more preferably, the pharmaceutically active ingredient is tolterodine or a pharmacologically acceptable salt thereof.
And more preferably, the active ingredient is tolterodine tartrate.

In another aspect of the present invention, the controlled-release composition has an in vitro dissolution profile of the said composition provides from about 80% to about 90 % of the active ingredient released after 11 hours, as measured by USP Type 1 Apparatus (rotating basket), with 900 ml of pH 6.8 phosphate buffer, at 37 C, at a basket speed of 100 rpm.

In a further aspect, the controlled-release composition is suitable for use in the treatment of a disorder selected from the group consisting of: overactive urinary bladder, including urinary incontinence, nocturia and gastrointestinal disorders.
In a preferred embodiment, the administration of the controlled-release compositions of the present invention to a patient provides maximum plasma concentrations (Cmax) T/R ratio from about 50%

4171721 v2 to about 135% and AUCt T/R ratio from about 60 % to about 125% (with 90 %
confidence interval) in bioequivalence studies comparing the composition to a reference product, in particular, DETROL LA , and said composition diminishes the food effect when administered to a patient that has eaten.
Further aspect of the present invention there is provided a controlled-release composition for oral administration, wherein the pharmaceutically active ingredient exhibits an in vitro dissolution profile such that:
= from about 1% to about 20% of the pharmaceutically active ingredient is released after 1 hour;
= from about 20% to about 50% of the pharmaceutically active ingredient is released after 3 hours;
= from about 50% to about 80% of the pharmaceutically active ingredient is released after 7 hours, and = from about 80% to about 90 % of the pharmaceutically active ingredient is released after 11 hours, as measured by USP Type 1 Apparatus (rotating basket), with 900 ml of pH 6.8 phosphate buffer at 37 C, at a basket speed of 100 rpm.
In a further aspect of the present invention, a bioequivalence study of the controlled-release composition exhibits a value of maximum plasma concentrations (Cmax) T/R ratio from about 250%
when there is no enteric coat to about 50% achieved when said composition comprises about 6% of enteric coat.
Another aspect of the present invention provides that in bioequivalence study conducted against DETROL LA , the controlled-release composition exhibits a value of a maximum plasma concentration (Cmax) T/R ratio from about 250% when there is no enteric coat to about 135%
achieved when said composition comprises about 4.2% of enteric coat.
Preferably, the controlled-release composition provides that administration of a 4 mg dose of the said pharmaceutical composition to human patient results in a tolterodine Cmax ranging from about 1200 pg/ ml to about 5000 pg/ml. More preferably, a tolterodine Cm ax ranging from about 1200 pg/ ml to about 2600 pg/ml.

4171721 v2 Another aspect of the present invention provides the controlled-release composition in which the AUCt T/R ratio of unbound pharmaceutically active ingredient exhibits a value as follows: from about 140% when there is no enteric coat to about 60 % when said composition comprises about 6%
w/w of enteric coat over the third layer.
Another aspect of the present invention provides the controlled-release composition in which the AUCt T/R ratio of unbound pharmaceutically active ingredient exhibits a value from about 140%
when there is no enteric coat to about 125% when said composition comprises about 4% w/w of enteric coat over the third layer.
Preferably, the tolterodine area under the curve from time 0 to the last measured time (AUCt) after administration of a 4 mg dose of the pharmaceutical composition to a human patient ranges from about 15000 pg hr/ml to about 32000 pg .hr/ml. More preferably, the tolterodine area under the curve from time 0 to the last measured time (AUCt) after administration of a 4 mg dose of the pharmaceutical composition ranges from about 15000 pg hr/ ml to about 24000 pg hr/ml.
Also preferably, the tolterodine area under the curve from time 0 to time infinity (AUCO-inf) after administration of a 4 mg dose of the pharmaceutical composition to a human patient ranges about 15000 pg fir/m1 to about 32000 pg hr/ml. More preferably, the tolterodine area under the curve from time 0 to time infinity (AUCO-inf) after administration of a 4 mg dose of the pharmaceutical composition ranges about 15000 pg fir/m1 to about 24000 pg fir/ml.
Preferably, the Tmax ranges from about 4 to about 8 hours after administration of 4 mg dose of the pharmaceutical composition to a human patient.
Preferably, the water insoluble inert core of the present pharmaceutical composition is microcrystalline cellulose.
Preferably, the hydrophilic film coating polymer in the first layer of the said pharmaceutical composition is hydroxypropyl cellulose. Also preferably, the amount of the hydrophilic film coating polymer in the first layer ranges from about 2% to about 20 % w/w of the controlled-release composition. More preferably, the amount of the hydrophilic film coating polymer in the first layer ranges from about 2% to about 5 % w/w of the controlled-release composition.
Preferably, the active ingredient, such as tolterodine tartrate, is present at a weight to weight ratio to binder in the second layer from about 1:5 to about 1:10.

4171721 v2 Further, the second layer comprises a binder which is hydroxypropyl cellulose.
More preferably, the amount of the binder in the second layer ranges from about 20% to about 30% w/w of the controlled-release composition.

Preferably, the pH-independent control release polymer of the third layer is selected from the group consisting of: ethyl cellulose, ammonialkyl methacrylate copolymers, methacrylate copolymers, and combinations thereof.

Preferably, the control release polymer of the third layer is ethyl cellulose and the amount of said polymer in the third layer ranges from about 3% to about 15% w/w of the controlled-release composition. More preferably, the amount of said polymer in the third layer ranges from about 3%
to about 5% w/w of the said composition.

Preferably, the hydrophilic polymer in the third layer is hydroxypropyl cellulose and the amount of hydrophilic polymer in the third layer ranges from about 0.4% to about 2%
w/w of the controlled-release composition. More preferably, the amount of hydrophilic polymer in the third layer ranges from about 0.4% to about 0.6% w/w of the said composition.

Preferably, the enteric coating polymer of the fourth layer is selected from the group consisting of:
ammonialkyl methacrylate copolymers, methacrylate copolymers, and combinations thereof. More preferably, the enteric coating polymer of the fourth layer is an aqueous dispersion of anionic polymers with methacrylic acid as a functional group (e.g., Eudragit L30 D-55), and the amount of the enteric coating polymer in the fourth layer ranges from about 0.5 % to about 5% w/w of the controlled-release composition.

Preferably, the third and fourth layers comprise a plasticizer, and more preferably, the plasticizer is triethyl citrate. More preferably, the amount of the plasticizer in the third layer ranges from about 0.4% to about 0.6% w/w and in the fourth layer ranges from about 0.2% to about 2% w/w of the controlled-release composition.

Preferably, the process used for the preparation of a controlled-release pharmaceutical composition is a drug layering process which results in an unique controlled release dosage form of tolterodine extended release capsules which is used for the treatment of urinary incontinence due to overactive bladder.

4171721 v2 Yet another aspect of the present invention is to provide a method of producing of a controlled-release pharmaceutical composition which comprises:
a) providing an inert core;
b) applying a first layer comprising hydrophilic film coating polymer and at least one pharmaceutically acceptable excipient onto the inert core;
c) applying a second layer comprising an active ingredient, a binder and at least one pharmaceutically acceptable excipient onto the first layer;
d) applying a third layer comprising a pH-independent controlled release polymer and at least one pharmaceutically acceptable excipient onto the second layer; and e) applying a fourth layer comprising an enteric coating polymer and at least one pharmaceutically acceptable excipient onto the third layer;
wherein said composition diminishes the food effect when administered to a patient that has eaten.
Preferably, the water insoluble inert core according to the process is microcrystalline cellulose.
More preferably, providing a method of manufacturing of lst layer by adding hydroxypropyl cellulose into purified water, continuously mixing mixture until a clear solution is obtained, and then spraying obtained solution onto about microcrystalline cellulose spheres using a fluid bed bottom spray unit.
Also preferably, providing a method of manufacturing of 2nd layer by adding tolterodine L- tartrate to purified water and continuously mixing mixture until a clear solution is obtained (#1); then adding hydroxypropyl cellulose and colloidal silicon dioxide to purified water in a separate solution (#2), continuously mixing mixture until a suspension is obtained (#2); then mixing solution (#1) and suspension (#2) together for at least 30 minutes, thereby forming suspension (#3), and spraying obtained mixture (#3) on MCC coated spheres of the 1st layer using a fluid bed coater equipped with bottom spray unit.
Also preferably, providing a method of manufacturing of 3rd layer by adding hydroxypropyl cellulose to dehydrated alcohol and continuously mixing mixture until a clear solution is obtained (#1); then adding ethyl cellulose 20cps, colloidal silicon dioxide and triethyl citrate to solution (#1), thereby forming suspension (#2), which is mixing continuously for at least 30 minutes, and spraying suspension (#2) on coated beads of the 2nd layer using, fluid bed coater equipped with bottom spray unit.

4171721 v2 , More preferably, providing a method of manufacturing of 4th layer by adding Triethylcitrate to talc and continuously mixing mixture until a suspension is obtained (#1); then adding Eudragit L3OD
550 to suspension (#1) and continuously stirring, thereby forming suspension (#2) and spraying obtained mixture (#2) on coated beads of the 3rd layer using, fluid bed coater equipped with bottom spray unit.

The present invention is further related to a process for the preparation of a controlled-release pharmaceutical composition, wherein by introducing the fourth layer of Eudragit L3OD 550 over the third layer with ethyl cellulose coated beads the effect of food was diminished when administered to a patient that has eaten.

Preferably, the present invention related to a process for the preparation of a controlled-release pharmaceutical composition, wherein by introducing the fourth layer of Eudragit L3OD 55 over the third layer with ethyl cellulose coated beads, the effect of food was diminished, and exhibits maximum concentrations (Cmax) T/R ratio about 50% and AUCt T/R ratio about 60%
(with 90%
confidence interval).

The present invention is further related to use of a therapeutically effective amount of tolterodine or pharmacologically acceptable salt thereof, for the preparation of a pharmaceutical controlled release composition which diminishes the food effect when administered to a patient that has eaten in the treatment of a disorder selected from the group consisting of:
overactive urinary bladder, including urinary incontinence, nocturia and gastrointestinal disorders, wherein said composition exhibits an in vitro release of active ingredient, ranging from about 80% to about 90% after 11 hours, as measured by USP Type 1 Apparatus (rotating basket), with 900 ml of pH 6.8 phosphate buffer at 37 C at a basket speed of 100 rpm., and said composition exhibits maximum plasma concentrations (C.) T/R ratio about 50% and AUCt T/R ratio about 60% (with 90 % confidence interval).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a controlled-release pharmaceutical composition for oral administration comprising a multiple unit formulation, using a drug layering process which allows one to obtain an unique controlled release dosage form of tolterodine extended release capsules which is suitable for the treatment of urinary incontinence due to overactive bladder. Futhermore, the compositions of the present invention diminishes the food effect when administered to a 4171721 v2 patient that has eaten, i.e. the bioavailability of the oral dosage form is relatively uniform, regardless of the fed or fasted state of the patient.
The term "controlled release pharmaceutical composition", as referred to herein, is defined to mean oral pharmaceutical compositions which when administered releases the active ingredient at a relatively constant rate and provide plasma concentrations of the active ingredient that remain substantially invariant over a period of time within the therapeutic range of the active ingredient over a 24-hour period and encompasses "prolonged release", "extended release", "modified release", "delayed release", "long acting" and "sustained release"
compositions.
The compositions according to the present invention deliver a therapeutically effective amount of tolterodine to a patient for 24 hours following a once-daily administration.
The term "therapeutically effective amount" intends to describe an amount of the active agent which stops or reduces the progress of the condition to be treated or which otherwise completely or partly cures or acts palliative on the condition.
The term "active ingredient" and "active pharmaceutical ingredient" refers to an Active Pharmaceutical Ingredients (API) which are active chemicals used in the manufacturing of drugs.
The active agent can be a therapeutic, a prophylactic, or a diagnostic agent.
The term "food effect", as used herein, means a significant difference in the bioavailability of a drug in a patient when the drug is administered in a fasted state compared to a fed state.
"Diminished food effect" means that there is no significant difference in the bioavailability of a drug in a patient when the drug is administered in a fasted state compared to a fed state, i.e. the bioavailability is relatively uniform (there is no significant difference) regardless of the fed or fasted state of the patient.
Drug release and drug release profiles are measures or representations of the manner and timing by which a formulation releases or delivers active ingredients (drug) to a receiving environment (e.g. the stomach, intestines, etc.) upon administration. Various methods are known for evaluating drug release and producing release profiles, including in vitro tests which model the in vivo behavior of a formulation. These include USP dissolution testing for immediate release and controlled release solid dosage forms.

4171721 v2 Drug release profiles are distinct from plasma profiles. A plasma profile is a measure or representation of the dose or level of active ingredient (drug) in the bloodstream of a mammal, e.g.
a patient receiving a drug formulation. Upon release of a drug from a formulation, e.g. into the gut of a mammal, the amount of drag that is present in the bloodstream over time can be determined.

A drug release profile may be designed to produce a desired or targeted plasma profile. Often, but not necessarily, a plasma profile will mimic a release profile. For example, it might be expected that a sustained release of drug is more likely to produce a sustained dose in the plasma, or that a pulsed release would produce a pulsed (peak and valley) plasma profile. This is not necessarily so, however. For example, the half-life of the drug in the blood stream (its rate of decay) may be such that a sustained or continuous plasma profile could result from a pulsed delivery profile. Other factors may also play a role, such as bio- absorption, bioavailability, and first pass effect. The plasma profile produced by a particular release profile may also vary from patient to patient.

Measures of bioavailability are well known in the art and include the area under the plasma concentration-time curve (AUC), the concentration maximum (Cmax), and the time to C. AUC is a measurement of the area under the plasma concentration-time curve, and is representative of the amount of drug absorbed following administration of a single dose of a drug (for example, see Remington: The Science and Practice of Pharmacy, (Alfonso R. Germaro ed.
2000), page 999).

C. is the maximum plasma concentration achieved after oral administration of a drug (Remington, page 999). An oral drug administration results in one Cmax, but may result in greater than one "peak plasma concentration" or "plasma concentration peak" (for example, following the administration of a pulsed dose formulation).

Tmax is the amount of time necessary to achieve the Cmax after oral drug administration, and is related to the rate of absorption of a drag (Remington, page 999).

T/R ratio refers to the Test/Reference ratio. Bioequivalence is the absence of a significantly different rate and extent of absorption in the availability of the active ingredient when administered at the same dose under similar conditions. Bioequivalence can be measured by pharmacokinetic parameters such as, for example, AUC and C.

A controlled release pharmaceutical composition means a pharmaceutical composition including an active pharmaceutical ingredient which is formulated with pharmaceutically acceptable film 4171721 v2 forming polymers and optionally with pharmaceutically acceptable excipients, wherein the pharmaceutical composition shows a pH-dependent or a pH-independent reproducible release profile.
Examples of controlled release pharmaceutical compositions include immediate release pharmaceutical compositions, enteric coated pharmaceutical compositions, pulsed release pharmaceutical compositions or sustained release pharmaceutical compositions.
Controlled release of a pharmaceutical composition may be achieved by different means.
Previously described in the art controlled release was mostly obtained using a hydrophilic matrix agent or a combination of hydrophilic and lipophilic or inert matrix agents.
More commonly, the controlled release was obtained using a coating comprising a combination of water non-dispersible and/or water dispersible polymer.
According to the present invention, the controlled release is achieved by composition containing:
(i) an inert core;
(ii) a first layer disposed over the inert core, wherein the first layer comprises a hydrophilic film coating polymer and at least one pharmaceutically acceptable excipient;
(iii) a second layer disposed over the first layer, wherein the second layer comprises an active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;
(iv) a third layer, disposed over the second layer, wherein the third layer comprises a pH-independent control release polymer and at least one pharmaceutically acceptable excipient; and (v) a fourth layer disposed over the third layer, wherein the fourth layer comprises an enteric polymer and at least one pharmaceutically acceptable excipient.

The present invention provides an advantage for preparing a unique controlled release pharmaceutical formulation of tolterodine (extended release) capsules from a drug layering process which allows one to obtain an unique controlled release dosage form which is suitable for the treatment of urinary incontinence due to overactive bladder and diminishes the food effect when administered to a patient that has eaten.

4171721 v2 Furthermore, the present invention particularly provides a more conventional manufacturing process, which is less time consuming, is very simple and can be easily transferred to commercial manufacturing.
The pharmaceutical composition according to the present invention comprises: a water insoluble inert core, which is preferably microcrystalline cellulose, and a first layer disposed over the inert core comprising a hydrophilic film coating polymer which is selected from the group consisting of:
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose ethers, povidone, and copovidone or a combination comprising at least one of the foregoing polymers.
Preferably, the hydrophilic film coating polymer in the first layer of the said pharmaceutical composition is hydroxypropyl cellulose.
Also preferably, the amount of the film coating polymer in the first layer ranges from about 2% to about 20% w/w of the controlled-release composition. More preferably the amount of the film coating polymer in the first layer ranges from about 2% to about 5% w/w of the controlled-release composition.
Preferably, the active pharmaceutical ingredient is selected from the group consisting of:
tolterodine, the 5-hydroxymethyl metabolite of tolterodine, the (S)-enantiomer of tolterodine, the 5-hydroxymethyl metabolite of the (S)-enantiomer of tolterodine, the racemate of tolterodine, its prodrug forms and pharmacologically acceptable salts thereof. Even more preferably, the pharmaceutically active ingredient is tolterodine or a pharmacologically acceptable salt thereof.
And more preferably, the active ingredient is tolterodine tartrate.
Preferably, the active ingredient, such as tolterodine or a pharmaceutically acceptable salt thereof, is present in a weight to weight ratio to binder in the second layer from about 1:5 to about 1:10.
The pharmaceutical composition of the present invention, in addition to the active ingredient, contains pharmaceutically acceptable excipients added to the composition for a variety of purposes. At least one pharmaceutically acceptable excipient may be present in the composition of the present invention, such as for example diluents, binders, lubricants, disintegrants, glidants, and acidifying agents. As understood by a person skilled in the art, these excipients are conventional excipients which are well known in the pharmaceutical art.

4171721 v2 Preferably, the binder in the second layer is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylates, and a combination thereof.
More preferably, the binder in the second layer is hydroxypropyl cellulose and the amount of the binder in the second layer ranges from about 20% to about 30% w/w of the controlled-release composition.
The pharmaceutical composition according to the present invention comprises a pH-independent control release polymer in the third layer which is selected from the group consisting of: ethyl cellulose, amrnonialkyl methacrylate copolymers, methacrylate copolymers, and combinations thereof.
Preferably, the pH-independent control release polymer of the third layer is ethyl cellulose, and the amount of the control release polymer in the third layer ranges from about 3%
to about 15% w/w of the controlled-release composition. More preferable the amount of ethyl cellulose ranges from about 3% to about 5% w/w of the said composition.
In addition to the control release polymer, the third layer of the said pharmaceutical composition contains at least one pharmaceutically acceptable excipient. Preferably, at least one pharmaceutically acceptable excipient is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, polym.ethacrylates, and a combination thereof.
More preferably, the hydrophilic polymer in the third layer is hydroxypropyl cellulose and the amount of said excipient ranges from about 0.4% to about 2% w/w of the controlled-release composition. More preferably, the amount of hydroxypropyl cellulose in the third layer ranges from about 0.4% to about 0.6% w/w of the said composition.
The pharmaceutical composition according to the present invention comprises an enteric coating polymer in the fourth layer which is selected from the group consisting of:
ammonialkyl methacrylate copolymers, methacrylate copolymers, and combinations thereof.
Preferably, the enteric coating polymer of the fourth layer is Eudragit L3OD 558. More preferably, the amount of 4171721 v2 the enteric coating polymer in the fourth layer ranges from about 0.5% to about 5% w/w of the controlled-release composition.
Preferably, the third and fourth layers comprise a plasticizer, and more preferably, the plasticizer is selected from the group consisting of: diethyl phthalate, dibutyl phthalate,dibutyl sebacate, tributyl citrate, triethyl citrate, acetyl tributyl citrate, castor oil, mineral oil, glyceryl monostearate, and a combination thereof.
More preferably, the plasticizer in the third and in the forth layers is triethyl citrate and wherein the amount of the plasticizer in the third layer ranges from about 0.4% to about 2% w/w and in the fourth layer ranges from about 0.2% to about 2% w/w of the controlled-release composition.
Oral dosage forms which may be employed with the present invention include granules, spheroids or pellets in a capsule or in any other suitable solid form. Preferably, however the oral dosage form is a capsule.
In a preferred embodiment of the invention, the oral controlled release composition comprises contains a 4 mg dose of tolterodine tartrate.
The controlled release composition can be manufactured in accordance with conventional techniques in which the first layer of hydrophilic polymer is applying to non pareils (MCC beads), then applying onto first layer, a second layer comprising the active ingredient, such as tolterodine tartrate, and hydroxypropyl cellulose as binder; then applying onto the second layer, a third pH-independent polymer layer effective for controlled release of the active ingredient, wherein the polymer used is to control the release is ethylcellulose; and applying over the third layer, a fourth layer effective for controlled release of the active ingredient, herein the polymer used is to control the release is Eudragit 30D 55 .
According to an aspect of the present invention, the process for the manufacturing of a controlled-release pharmaceutical composition comprising: an inert core, an active ingredient, a hydrophilic film coating polymer, a pH-independent controlled release polymer, an enteric coating polymer and at least one pharmaceutically acceptable excipient, wherein said process comprises following steps:
1. Manufacturing process of 1st layer:
a) adding hydroxypropyl cellulose into purified water;

4171721 v2 b) mixing continuously the prepared mixture until a clear solution is obtained;
c) spraying obtained solution over microcrystalline cellulose spheres (also known as beads) using a fluid bed bottom spray unit.

2. Manufacturing process of 2nd layer:
a) adding the active ingredient, such as Tolterodine L- Tartrate, to purified water b) mixing continuously prepared mixture until a clear solution is obtained solution (#1);
c) adding hydroxypropyl cellulose and colloidal silicon dioxide to purified water in a separate suspension ( #2);
d) mixing mixture until a suspension is obtained (#2).
e) mixing solution (#1) and suspension (#2) together for at least 30 minutes, thereby forming mixture (#3).
f) spraying mixture (#3) over MCC coated spheres of the 1st layer using a fluid bed coater equipped with bottom spray unit.
3. Manufacturing Process of 3rd layer a) adding hydroxypropyl cellulose to dehydrated alcohol.
b) mixing continuously mixture until a clear solution is obtained (#1);
c) adding ethylcellulose 20cps, colloidal silicon dioxide and triethyl citrate to solution (#1), thereby forming suspension (#2);
d) mixing suspension (#2) continuously for at least 30 minutes;
e) spraying suspension (#2) over the coated beads of the 2nd layer using, fluid bed coater equipped with bottom spray unit.

4. Manufacturing Process of 4th layer a) adding Triethylcitrate to talc to purified water while continuously mixing;
b) mixing continuously mixture until a clear solution is obtained (#1);
c) adding Eudragit L3OD 55 to mixture (#1) d) continuously stirring, thereby forming mixture (#2);
e) spraying mixture (#2) over the coated beads of the 3rd layer using, fluid bed coater equipped with bottom spray unit.

4171721 v2 The following examples illustrate the preferred embodiments and various aspects of the present invention and are not be considered as limiting the invention in any way.

Example 1. FORMULATION AND METHOD OF PRODUCING A CONTROLLED-RELEASE
COMPOSITION FOR TOLTERODINE EXTENDED RELEASE CAPSULES.

Manufacturing process of 1st layer:
The required quantity of hydroxypropyl cellulose is added into purified water and continuously mixed until a clear solution is obtained (solution #1). This solution (#1) is sprayed onto microcrystalline cellulose spheres (also known as beads) using a fluid bed bottom spray unit.

Manufacturing process of 2nd layer:
The required quantity of Tolterodine L-Tartrate is added to purified water and continuously mixed until a clear solution is obtained (solution #1). Preparing binding solution adding hydroxypropyl cellulose and colloidal silicon dioxide to purified water, continuously mixing until a suspension is obtained (suspension #2). Solution (#1) and suspension (#2) are then mixed together for at least 30 minutes, thereby forming mixture (#3). Mixture #3 is sprayed onto the MCC
coated spheres of the 1st layer using a fluid bed coater equipped with bottom spray unit.
Manufacturing Process of 3rd layer:
The required quantity of hydroxypropyl cellulose is added to dehydrated alcohol and continuously mixed until a clear solution is obtained (solution #1). Ethylcellulose 20cps, colloidal silicon dioxide and triethyl citrate are added to solution (#1), thereby forming suspension (#2), which is continuously mixed for at least 30 minutes before using it. Suspension (#2) is then sprayed onto coated beads of the 2nd layer using fluid bed coater equipped with bottom spray unit.

Manufacturing Process of 4th layer:
The required quantity of triethylcitrate is added to talc and continuously mixed with purified water until a clear solution is obtained (solution #1). Eudragit L3OD 55 is added to solution (#1) while continuously stirring, thereby forming suspension (#2). Suspension (#2) is then sprayed onto coated beads of the 3rd layer using, fluid bed coater equipped with bottom spray unit.

The formulation of Example 1 is set out in Table 1 below.

4171721 v2 Table 1. The formulation of Example 1 for a controlled-release composition.

1st LAYER COMPOSITION: seal coating-performed on non pareils (MCC beads) No. Description mg/capsules %(w/w) 1 MCC-Spheres 72.73 53.76 2 Hydroxypropylcellulose-Type-L 5.09 3.76 3 Colloidal Silicon Dioxide 2.18 1.61 4 Dehydrated alcohol--Sub-total 80.0 -2nd LAYER COATING: drug layering performed on 1st layer coated beads No. Description mg/capsules %(w/w) - 1 Tolterodine-L-Tartrate 4.0 2.96 2 Hydroxypropyl cellulose- Type- 28.0 20.7 L
3 Colloidal silicon dioxide 8.4 6.21 - 4 Purified water --Sub-total 120.4 -3rd LAYER COATING: controlled release coating- performed on 2nd layer coated beads No. Description mg/capsules %(w/w) 1 Ethylcellulose 20cps 5.50 4.07 2 Colloidal Silicon dioxide 1.41 1.04 3 Hydroxypropyl Cellulose Type- 0.82 0.61 L
4 Tri-ethyl Citrate 0.69 0.51 5 Dehydrated Alcohol --Sub-total 128.82 -4171721 v2 4th LAYER COATING: enteric polymer coating-coating performed on 3rd layer coated beads.
No. Description mg/capsules %(w/w) 1 Methacrylic acid Copolymer 3.169 2.34 2 Triethyl citrate 0.381 0.28 3 Talc LM 2.898 2.14 4 Purified water S.Total 135.27 100 6 Capsules size 3 white opaque 48.0 Total 183.27 The pharmaceutical composition obtained from above mentioned Example 1 was subsequently tested for in vitro dissolution rate, measured by USP Type 1 Apparatus (rotating basket), using the 5 following parameters:
Basket speed - 100 rpm Media - pH 6.8 phosphate buffer Dissolution medium - 900m1 Temperature - 37 C
Time -1, 3, 7 and 11 hrs.
The dissolution results are set out in Table II below.
Table II. DISSOLUTION DATA
No. Time (hrs) Example 1 (%) Example 2. THE FORMULATION FOR A CONTROLLED-RELEASE COMPOSITION.
The procedure of the above Example 1 is followed in this example, wherein the present example is controlled-release pharmaceutical composition of tolterodine without the 4th enteric polymer coating.

4171721 v2 The formulation of Example 2 is set out in Table III below.
TABLE III: Example 2 1st LAYER COMPOSITION: seal coating-performed on non pareils (MCC beads) No. Description mg/capsules % (w/w) 1 MCC-Spheres 72.73 53.76 2 Hydroxypropylcellulose-Type-L 5.209 3.76 3 Colloidal Silicon Dioxide 2.18 1.61 4 Dehydrated alcohol - -Sub-total 80.0 -2nd LAYER COATING: drug layering performed on 1st layer coated beads No. Description mg/capsules % (w/w) 1 Tolterodirte-L-Tartrate 4.0 2.96 2 Hydroxypropyl cellulose- Type- 28.0 20.70 L
3 Colloidal silicon dioxide 8.4 6.21 4 Purified water- -Sub-total 120.38 -3rd LAYER COATING: controlled release coating- performed on 2nd layer coated beads No. Description mg/capsules % (w/w) 1 Ethylcellulose 20cps 5.50 4.07 2 Colloidal Silicon dioxide 1.41 1.04 3 Hydroxypropyl Cellulose Type- 0.82 0.61 L
4 Tri-ethyl Citrate 0.69 0.51 5 Dehydrated Alcohol - -Sub-total 128.80 -4171721 v2 4th LAYER COATING: enteric polymer coating-coating performed on 3rd layer coated beads.
No. Description mg/capsules /0(w/w) 1 Methacrylic acid Copolymer 2 Triethyl citrate 3 Talc LM
4 Purified water Capsules size 3 white opaque Total 128.80 The pharmaceutical composition obtained from above mentioned Example 2(without enteric polymer coating) was subsequently tested in a bioequivalence study performed against DETROL
LA , wherein said composition provides maximum plasma concentrations (Cmax) T/R ratioof about 246% and AUCt T/R ratio of about 140.8 % (with 90 % confidence interval).
The bioequivalence study data of Example 2 is set out in Table IV below.

Table IV. BIOEQUIVALENCE FED STUDY DATA - T/R RATIOS
No. DESCRIPTION NO ENTERIC COAT
1 Cmax 246.2%
2 AUCt 140.8%

Example 3. FORMULATION FOR A CONTROLLED-RELEASE COMPOSITION OF
TOLTERODINE CAPSULES.
The procedure of manufacturing of the above Example 1 is followed in this example, wherein the present example is controlled-release pharmaceutical composition of tolterodine tartrate coated with about 6 % w/w enteric polymer coating performed on 3rd layer coated beads.
The formulation of Example 3 is set out in Table V below.

4171721 v2 TABLE V: Example 3.
1st LAYER COMPOSITION: seal coating-performed on non pareils (MCC beads) No. Description mg/capsules 1)/0(w/w) 1 MCC-Spheres 72.73 53.76 2 Hydroxypropykellulose-Type-L 5.209 3.76 3 Colloidal Silicon Dioxide 2.18 1.61 4 Dehydrated alcohol Sub-total 80.0 2nd LAYER COATING: drug layering performed on 1st layer coated beads No. Description mg/capsules %(w/w) 1 Tolterodine-L-Tartrate 4.0 2.96 2 Hydroxypropyl cellulose- Type-28.0 20.70 3 Colloidal silicon dioxide 8.4 6.21 4 Purified water Sub-total 120.38 3rd LAYER COATING: controlled release coating- performed on 2nd layer coated beads No. Description mg/capsules %(w/w) 1 Ethylcellulose 20cps 5.50 4.07 2 Colloidal Silicon dioxide 1.41 1.04 3 Hydroxypropyl Cellulose Type-0.82 0.61 4 Tri-ethyl Citrate 0.69 0.51 Dehydrated Alcohol Sub-total 128.80 4th LAYER COATING: enteric polymer coating-coating performed on 3rd layer coated beads.
No. Description mg/capsules %(w/w) 1 hudragit L3OD 55 5.42 3.97 4171721 v2 24 4th LAYER COATING: enteric polymer coating-coating performed on 3rd layer coated beads.
No. Description mg/capsules %(w/w) 2 Triethyl citrate 1.65 1.20 3 Talc LM 0.65 0.47 4 Purified water Total 136. 52 The pharmaceutical composition obtained from above mentioned Example 3 (with about 6 % w/w enteric polymer coating performed on 3rd layer coated beads) was subsequently tested in a bioequivalence study performed against DETROL LA , wherein said composition provides maximum plasma concentrations (C.) T/R ratio about 51% and AUCt T/R ratio about 63.8 %
(with 90 % confidence interval).
The bioequivalence study data of Example 3 is set out in Table VI below.

Table VI. BIOEQUIVALENCE FED STUDY DATA - T/R RATIOS
No. Description About 6% (w/w) enteric coat J. Cmax 51.0%

2 AUCt 63.8%

Example 4 FORMULATION FOR A CONTROLLED-RELEASE COMPOSITION OF
TOLTERODINE CAPSULES.
The procedure of manufacturing of the above Example 1 is followed in this example, wherein the present example is controlled-release pharmaceutical composition of Tolterodine tartrate coated with about 4 % w/w enteric polymer coating performed on 3rd layer coated beads.
The formulation of Example 4 is set out in Table VII below.

4171721 v2 TABLE VII: Example 4.
1st LAYER COMPOSITION: seal coating-performed on non pareils (MCC beads) No. Description mg/capsules %(w/w) 1 MCC-Spheres 72.73 53.76 2 Hydroxypropylcellulose-Type-L 5.209 3.76 3 Colloidal Silicon Dioxide 2.18 1.61 4 Dehydrated alcohol Sub-total 80.0 2nd LAYER COATING: drug layering performed on 1st layer coated beads No. Description mg/capsules %(w/w) 1 Tolterodine-L-Tartrate 4.0 2.96 2 Hydroxypropyl cellulose- Type-28.0 20.70 3 Colloidal silicon dioxide 8.4 6.21 4 Purified water Sub-total 120.38 3rd LAYER COATING: controlled release coating- performed on 2nd layer coated beads No. Description mg/capsules %(w/w) 1 Ethylcellulose 20cps 4.48 3.38 2 Colloidal Silicon dioxide 1.15 0.87 3 Hydroxypropyl Cellulose Type-0.67 0.50 4 Tri-ethyl Citrate 0.56 0.42 Dehydrated Alcohol Sub-total 127.24 4.171721 v2 26 4th LAYER COATING: enteric polymer coating-coating performed on 3rd layer coated beads.
No. 'Description mg/capsules (w/w) 1 Eudragit L3OD 55 2.138 1.61 2 Triethyl citrate 2.949 2.22 3 Talc LM 0.257 0.19 4 Purified water Total 132.584 The pharmaceutical composition obtained from above mentioned Example 4 (with about 4 % w/w enteric polymer coating performed on 3rd layer coated beads) was subsequently tested in Bioequivalence study performed against DETROL LA , wherein said composition provides maximum plasma concentrations (C.) T/R ratio about 135 % and AUCt T/R ratio about 129 %
(with 90 % confidence interval).

The bioequivalence study data of Example 4 is set out in Table VIII below.

Table VIII. BIOEQUIVALENCE FED STUDY DATA - T/R RATIOS
No. Description About 4 % (w/w) enteric coat 1 Cmax 135.0 %
2 AUCt 129.0 %

Example 5 FORMULATION FOR A CONTROLLED-RELEASE COMPOSITION OF
TOLTERODINE LA CAPSULES - COMPARATIVE STUDY
The procedure of manufacturing of the above Example 1 is followed in all these examples, wherein the present example is comparative study of the controlled-release pharmaceutical composition of tolterodine tartrate capsules (4mg).

The results of comparative study on those formulations are set out in Table IX
below.

4171721 v2 TABLE IX: Example 5.
1st LAYER COMPOSITION: seal coating-performed on non pareils (MCC beads) No. Description No enteric coat, 6% (w/w) enteric 4.2 ')/0 (w/w) enteric mg/caps. coat, mg/caps. coat, mg/caps.
1 MCC-Spheres 72.73 72.73 72.73 2 Hydroxypropylcellulose-Type- 5.209 5.209 5.209 3 Colloidal Silicon Dioxide 2.18 2.18 2.18 4 Dehydrated alcohol Sub-total 80.0 80.0 80.0 2nd LAYER COATING: drug layering performed on 1st layer coated beads No. Description No enteric coat, 6% (w/w) enteric 4.2 "/0(w/w)enteric mg/caps. coat, mg/caps. coat, mg/caps.
1 Tolterodine-L-Tartrate 4.0 4.0 4.0 2 Hydroxypropylcellulose-Type- 28.0 28.0 28.0 3 Colloidal silicon dioxide 8.4 8.4 8.4 4 Purified water Sub-total 120.38 120.38 120.38 3rd LAYER COATING: controlled release coating- performed on 2nd layer coated beads No. Description No enteric coat, 61)/0(w/w) enteric 4.2 % (w/w) enteric mg/caps. coat, mg/caps. coat, mg/caps.
1 Ethylcellulose 20cps 5.5 5.5 4.48 2 Colloidal Silicon dioxide 1.41 1.41 1.15 3 Hydroxypropylcellulose Type- 0.82 0.82 0.67 4 Tri-ethyl Citrate 0.69 0.69 0.56 4171721 v2 3rd LAYER COATING: controlled release coating- performed on 2nd layer coated beads No. Description No enteric coat, 6%(w/w) enteric 4.2 % (w/w) enteric mg/caps. coat, mg/caps. coat, mg/caps.
Dehydrated Alcohol Sub-total 128.80 128.80 127.24 4th LAYER COATING: enteric polymer coating-coating performed on 3r layer coated beads.
No. Description No enteric coat, 6% (w/w) enteric 4.2 % (w/w) enteric mg/caps. coat, mg/caps. coat, mg/caps.
1 Eudragit L3OD 55 5.42 2.138 2 Triethyl citrate 1,65 2. 949 -3 Talc LM
0.65 0. 257 - 4 Purified water Total 128.80 136.52 132. 584 The pharmaceutical composition obtained from above mentioned Examples was subsequently 5 tested in a bioequivalence study performed against DETROL LA , wherein said composition provides maximum plasma concentrations (Cmax) T/R ratio from about 50% to about 135% and AUCt T/R ratio from about 60 % to about 125 % (with 90 % confidence interval).
The bioequivalence comparative study data is set out in Table X below.

Table X. BIOEQUIVALENCE COMPARATIVE FED STUDY DATA - T/R RATIOS
No. Description No enteric coat 6%
(w/w)* 4.2 /0(w/w)*
enteric coat enteric coat 1 Cmax 246.2%
51.0% 135%
- 2 AUCt 140.8%
63.8% 129%
*Along with percentage change, the coating compositions were also different.

The bioequivalence summary of main study results on Tolteraodine L-Tartrate extended release capsules 4 mg (Fed) is set out in Table XI below.

4171721 v2 Table XI. SUMMARY OF THE MAIN STUDY RESULTS ON BIOEQUIVALENCE
TOLTERODINE L-TARTRATE LA CAPSULES 4 MG (FED) PARAMETER MEAN TEST C.V. (%) MEAN C.V.
(%)REFERENCE
Cmax (pg/mL) 2864.583 41.3 2077.000 22.0 ln (Cmax) 7.960 3.7 7.639 3.1 'L., (hours) * 4.50 12.5 5.00 27.6 AUCT (pg b/mL) 28215.213 50.0 24964.825 51.8 ln (AUCT) 10.248 3.9 10.125 3.9 AUCD (pg h/mL) 28423.363 49.6 25477.133 49.6 In (AUC.) 10.255 3.9 10.146 3.9 AUCTiu (%) 99.110 0.5 96.819 5.3 Ka (hours-l) 0.132 23.5 0.123 24.6 T1/2,1 (hours) 5.467 22.7 5.945 26.2 * median is presented 4171721 v2

Claims

1. A controlled-release composition for oral administration, comprising:
(i) an inert core;
(ii) a first layer disposed over the inert core, the first layer comprising a hydrophilic film coating polymer and at least one pharmaceutically acceptable excipient;
(iii) a second layer disposed over the first layer, the second layer comprising an active pharmaceutical ingredient, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient;
(iv) a third layer, disposed over the second layer, the third layer comprising a pH-independent control release polymer and at least one pharmaceutically acceptable excipient;
and (v) a fourth layer disposed over the third layer, the fourth layer comprising an enteric polymer and at least one pharmaceutically acceptable excipient, wherein administration of the composition to a human patient allows for relatively constant bioavailability of the active pharmaceutical ingredient, regardless of the fasted or fed state of said patient.

2. The controlled-release composition according to claim 1, wherein the in vitro dissolution profile of the composition provides from about 80% to about 90 % of the active ingredient released after 11 hours, as measured by USP Type 1 Apparatus (rotating basket), with 900 ml of pH 6.8 phosphate buffer, at 37°C, at a basket speed of 100 rpm.

3. The controlled-release composition according to any one of claims 1 to 2, wherein the active pharmaceutical ingredient is tolterodine or a pharmaceutically acceptable salt thereof.

4. The controlled-release composition according to claim 3, wherein the active pharmaceutical ingredient is tolterodine tartrate.

5. The controlled-release composition according to any one of claims 1 to 4, wherein said composition is suitable for use in the treatment of a disorder selected from the group consisting of:
overactive urinary bladder, including urinary incontinence, nocturia and gastrointestinal disorders.

6. The controlled-release composition for oral administration according to any one of claims 1 to 5, wherein the active pharmaceutical ingredient exhibits the following in vitro dissolution:
.cndot. from 1% to about 20% of the pharmaceutically active ingredient is released after 1 hour;
.cndot. from about 20% to about 50% of the pharmaceutically active ingredient is released after 3 hours;
.cndot. from about 50% to about 80 % of the pharmaceutically active ingredient is released after 7 hours; and .cndot. from about 80% to about 90 % of the pharmaceutically active ingredient is released after 11 hours, as measured by USP Type 1 Apparatus (rotating basket), with 900 ml of pH 6.8 phosphate buffer at 37°C, at a basket speed of 100 rpm.

7. The controlled-release composition according to any one of claims 1 to 6, wherein administration of the composition to a patient provides maximum plasma concentrations (C max) in a Test/Reference ratio from about 50% to about 135% and AUC t in a Test/Reference ratio from about 60 % to about 125 % (with a 90% confidence interval) in a study comparing the composition to a reference product.

8. The controlled-release composition according to any one of claims 1 to 7, wherein said composition exhibits a value of a maximum plasma concentrations (C max) in a Test /Reference ratio as follows: from about 250% when there is no enteric coat to about 50% when said composition comprises about 6% w/w of the enteric coat.

9. The controlled-release composition according to any one of claims 1 to 7, wherein said composition exhibits a value of a maximum plasma concentrations (C max) in a Test /Reference ratio as follows: from about 250% when there is no enteric coat to 135% when said composition comprises about 4% w/w of the enteric coat.

10. The controlled-release composition according to claim 3, wherein the composition comprises about 4 mg of the active pharmaceutical ingredients; and wherein the administration of said composition results in a maximum plasma concentration of tolterodine ranging from about 1200 pg/ml to about 5000 pg/ml.

11. The controlled-release composition according to any one of claims 1 to 10, wherein the AUC t T/R ratio of unbound pharmaceutically active ingredient exhibits a value as follows: from about 140% when there is no enteric coat to about 60% when said composition comprises about 6% w/w of enteric coat over the third layer.

12. The controlled-release composition according to any one of claims 1 to 10, wherein the AUC t T/R ratio of unbound pharmaceutically active ingredient exhibits a value as follows: from about 140% when there is no enteric coat to about 125% when said composition comprises about 4% w/w of enteric coat over the third layer.

13. The controlled-release composition according to claim 3, wherein the composition comprises about 4 mg of the active pharmaceutical ingredient; and wherein the administration of said composition results in the area under the curve from time 0 to the last measured time (AUC t) ranging from about 15000 pg .cndot.hr/m1 to about 32000 pg .cndot.hr/ml.

14. The controlled-release composition according to claim 3, wherein the composition comprises about 4 mg of the active pharmaceutical ingredient; and wherein administration of said composition results in the area under the curve from time 0 to time infinity (AUC0-inf) after administration of a 4 mg dose of the pharmaceutical composition to a human patient ranges about 15000 pg .cndot.hr/m1 to about 32000 pg .cndot.hr/ml.

15. The controlled-release composition according to claim 1, wherein the composition comprises about 4 mg of the active pharmaceutical ingredient; and wherein the T max ranges from about 4 to about 8 hours after administration of the pharmaceutical composition to a human patient.

16. The controlled-release composition according to any one of claims 1 to 15, wherein the inert core consists of microcrystalline cellulose.

17. The controlled-release composition according to any one of claims 1 to 16, wherein the hydrophilic film coating polymer of the first layer is selected from the group consisting of:
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose ethers, povidone, copovidone and combinations thereof.33

18. The controlled-release composition according to claim 17, wherein the hydrophilic film coating polymer in the first layer is hydroxypropyl cellulose.

19. The controlled-release composition according to claim 17 or 18, wherein the hydrophilic film coating polymer in the first layer is present at a concentration ranging from about 2% to about 20%
w/w of the controlled-release composition.

20. The controlled-release composition according to any one of claims 1 to 19, wherein the weight to weight ratio of pharmaceutically active ingredient to binder in the second layer ranges from about 1:5 to about 1:10.

21. The controlled-release composition according to any one of claims 1 to 20, wherein the binder of the second layer is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylates, and combination thereof.

22. The controlled-release composition according to claim 21, wherein the binder in the second layer is hydroxypropyl cellulose.

23. The controlled-release composition according to any one of claims 1 to 22, wherein the binder in the second layer is present at a concentration ranging from about 20% to about 30% w/w of the controlled-release composition.

24. The controlled-release composition according to any one of claims 1 to 23, wherein the pH-independent control release polymer of the third layer is selected from the group consisting of:
ethyl cellulose, ammonialkyl methacrylate copolymers, methacrylate copolymers, and combinations thereof.

25. The controlled-release composition according to claim 24, wherein the pH-independent control release polymer of the third layer is ethyl cellulose.

26. The controlled-release composition according to any one of claims 1 to 27, wherein the pH-independent control release polymer in the third layer is present at a concentration ranging from about 3% to about 15% w/w of the controlled-release composition.

27. The controlled-release composition according to any one of claims 1 to 26, wherein the third layer further comprises a hydrophilic polymer selected from the group consisting of:
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, polymethacrylates, and combinations thereof.

28. The controlled-release composition according to claim 27, wherein the hydrophilic polymer is hydroxypropyl cellulose.

29. The controlled-release composition according to claim 27 or 28, wherein the hydrophilic polymer in the third layer is present at a concentration ranging from about 0.4% to about 2% w/w of the controlled-release composition.

30. The controlled-release composition according to any one of claims 1 to 29, wherein the enteric coating polymer of the fourth layer is selected from the group consisting of:
ammonialkyl methacrylate copolymers, methacrylate copolymers, and combinations thereof.

31. The controlled-release composition according to claim 30, wherein the enteric coating polymer of the fourth layer comprises an aqueous dispersion of anionic polymers with methacrylic acid as a functional group.

32. The controlled-release composition according to any one of claims 1 to 31, wherein the enteric coating polymer in the fourth layer is present at a concentration ranging from about 0.5% to about 6 % w/w of the controlled-release composition.

33. The controlled-release composition according to any one of claims 1 to 32, wherein the third and the forth layers further comprises a plasticizer selected from the group consisting of: diethyl phthalate, dibutyl phthalate, dibutyl sebacate, tributyl citrate, triethyl citrate, acetyl tributyl citrate, castor oil, mineral oil, glyceryl monostearate, and combinations thereof.

34. The controlled-release composition according to claim 33, wherein the plasticizer is triethyl citrate.

35. The controlled-release composition according to any one of claims 1 to 34, wherein the plasticizer in the third layer is present at a concentration ranging from about 0.4% to about 0.6%
w/w and in the fourth layer ranging from about 0.2% to about 2% w/w of the controlled-release composition.

36. The controlled-release composition according to any one of claims 1 to 35, wherein the fourth layer accounts for about 4 to about 8% w/ w of said composition.

37. The controlled-release composition according to claim 36, wherein the fourth layer accounts for about 4.5 to about 5.5 % w/w of said composition.

38. The controlled-release composition according to claim 36, wherein the fourth layer accounts for about 5% w/w of said composition

39. A multiple unit formulation comprising a controlled release composition according to any one of claims 1 to 38.

40. The multiple unit formulation according to claim 39, wherein said composition is in the form of a capsule.

41. A controlled release bead composition of tolterodine or a pharmaceutically acceptable salt thereof, for oral administration, comprising an enteric polymer and/or at least one pharmaceutical acceptable excipient.

42. A controlled-release composition for oral administration comprising:
a pharmaceutically effective amount of tolterodine or a pharmaceutically acceptable salt thereof;

at least one hydrophilic film coating polymer in an amount ranging from about 2% to about 20% w/w of the composition;
at least one pH-independent control release polymer in an amount ranging from about 3%
to about 15% w/w of the composition;
at least one enteric coating polymer in an amount ranging from about 0.5 % to about 10%
w/w of the composition;
and at least one pharmaceutically acceptable excipient;
wherein the in vitro dissolution profile of the composition provides from about 80% to about 90 % of the active ingredient released after 11 hours, as measured by USP Type 1 Apparatus (rotating basket), with 900 ml of pH 6.8 phosphate buffer, at 37°C, at a basket speed of 100 rpm;
wherein administration of the composition to a patient provides maximum plasma concentrations (C max) in a Test/Reference ratio of about 50% and AUC t in a Test/Reference ratio of about 60% (with a 90% confidence interval) in a study comparing the composition to a reference product; and wherein administration of the composition allows for relatively constant bioavailability of the active pharmaceutical ingredient, regardless of the fasted or fed state of said patient.

43. A method of producing a controlled-release composition according to anyone of claims 1 to 38, comprising the steps of:
a) providing an inert core;
b) applying a first layer comprising an hydrophilic film coating polymer and at least one pharmaceutically acceptable excipient onto the inert core;
c) applying a second layer comprising an active pharmaceutical ingredient, a binder and at least one pharmaceutically acceptable excipient onto the first layer;
d) applying a third layer comprising a pH-independent controlled release polymer and at least one pharmaceutically acceptable excipient onto the second layer; and e) applying a fourth layer comprising an enteric coating polymer and at least one pharmaceutically acceptable excipient onto the third layer.

44. Use of a therapeutically effective amount of tolterodine or a pharmaceutically acceptable salt thereof, for the preparation of a controlled release composition for oral administration suitable for use in the treatment of a disorder selected from the group consisting of:
overactive urinary bladder, including urinary incontinence, nocturia and gastrointestinal disorders;37 wherein administration of the composition to a human patient allows for relatively constant bioavailability of the tolterodine, or a pharmaceutically acceptable salt thereof, regardless of the fasted or fed state of said patient.

45. The use according to claim 44, wherein the in vitro dissolution profile of the composition provides from about 80% to about 90 % of the active ingredient released after 11 hours, as measured by USP Type 1 Apparatus (rotating basket), with 900 ml of pH 6.8 phosphate buffer, at 37°C, at a basket speed of 100 rpm; and wherein administration of the composition to a patient provides maximum plasma concentrations (C max) in a Test/Reference ratio of about 50% and AUC t in a Test/Reference ratio of about 60% (with a 90% confidence interval).