TECHNICAL FIELD OF THE INVENTION
The present invention relates to extended release pharmaceutical composition such as tablets and capsules, and in particular to a matrix tablet composition for oral administration comprising a therapeutically effective quantity of Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof incorporated in a hydrophobic matrix comprising water insoluble polymer such as ethyl cellulose and/or wax such as hydrogenated castor oil and a method for the preparation thereof.

BACKGROUND OF THE INVENTION
Urinary incontinence is the involuntary excretion of urine from one''s body. 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, during its filling phase. The pharmacological treatment in such cases is the administration of muscarinic receptor antagonists such as Oxybutynin and Tolterodine.

Tolterodine is the (R)-N, N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine and is an antimuscarinic drug that is used to treat urinary incontinence and other symptoms of unstable or overactive urinary bladder. It acts on M2 and M3 subtypes of muscarinic receptors whereas most antimuscarinic agents only act on M3 receptors. Tolterodine targets the bladder more than other areas of the body thus lower dose needs to be given daily (due to efficient targeting) and so causing fewer side effects. Nevertheless, commercially sold immediate release formulations of Tolterodine are associated with side effects such as dry mouth, dyspepsia, headache due to high concentration of the drug in a short period of time. In order to overcome this problem extended release formulations have been developed. Extended release dosage forms are widely used for the administration of a variety of drugs since they maintain substantially constant blood levels and avoid the fluctuations associated with the immediate release formulations. Further, the extended release formulations provide many advantages over the immediate release dosage forms, such as increased patients compliance, improved delivery efficiency, decreased total drug requirement and minimization or even elimination of local or systemic side effects.

Various methods are already known for the industrial preparation of extended release oral dosage forms comprising an antimuscarinic agent, and in particular Tolterodine or a pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof as an active ingredient due to its useful therapeutical properties. However, the prior art has encountered substantial difficulties in the production of the oral solid formulations of a desirable dissolution profile and a cost effective manufacturing process.

EP 1 128 819 discloses a formulation containing controlled release beads comprising a core unit of a substantially water soluble or water swellable inert material, a first layer on the core of a substantially water insoluble polymer, a second layer over the first that contains an active ingredient and a third layer of polymer on the second layer effective for controlled release of the active ingredient, wherein the first layer is adapted to control water penetration into the core. This process is very complex, not cost effective and time consuming.

WO 2006/21425 discloses a composition comprising a core coated with an outer layer of a hydrophobic sustained release polymer. Said core is either a matrix core made of a matrix core material, Tolterodine and a binder or an inert core being provided with a layer of Tolterodine and a binder.

US 2009/0192228 A1 discloses a controlled-release composition, comprising: inert core comprising a water insoluble polymer; with a first layer disposed on the inert core, wherein the first layer comprises tolterodine and a binder; and a second layer disposed on the first layer, wherein the second layer comprises a water insoluble polymer, a plasticizer, and a pore-forming agent.

WO 2009/080061 A1 discloses a sustained release composition comprising Tolterodine as an active ingredient and a wetting agent such as Sodium Docusate to improve the release of the active ingredient.

All above prior art discloses coated formulations mainly pellets with functional coating with release controlling polymers which provide sustained release of tolterodine, however such formulations requires specialized and complex techniques and are not cost effective.

Although each of the above patents represents an attempt to overcome the problems associated with extended release composition comprising tolterodine however none of them provide extended release composition for tolterodine which is simple, cost effective and remove complicated process of manufacturing, thus there still exists a need to provide a stable, simple, cost effective extended release composition without producing unwanted pharmaceutical side effects and with improved release rate and low production costs.

None of the prior art discloses an extended release composition for tolterodine comprising matrix composition wherein drug release is solely controlled by hydrophobic matrix comprising water insoluble polymer such as ethyl cellulose and wax such as hydrogenated castor oil, which is capable of releasing drug for about 24 hours without dose dumping.

SUMMARY OF THE INVENTION
It is, therefore, an object of the present invention to provide an extended release composition for oral administration comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof as an active ingredient, which overcomes the deficiencies of the prior art.

In one aspect the present invention provides a stable extended release solid pharmaceutical dosage formulation for oral administration comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof as an active ingredient, which is bioavailable and effective with sufficient shelf-life, good pharmaceutical properties, enhancing patient compliance and reducing possible side effects.
Moreover, yet another aspect of the present invention is to provide an extended release solid dosage formulation for oral administration comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof as an active ingredient, which can be prepared in dosage forms of different strength by proportionally adjusting the quantities of the excipients and the active ingredient, thereby providing a pharmaceutical linearity, without affecting the dissolution profile and bioavailability of the active ingredient.

In a further aspect of the present invention is to provide a method for the preparation of a extended release solid dosage formulation for oral administration comprising an Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof as an active ingredient, thereby enhancing the release rate of the active ingredient and being stable over a long period of time and improving the pharmaceutical characteristics of the composition.

BRIEF DESCRIPTION OF THE DRAWING
Fig. 1 shows dissolution profiles of the pharmaceutical compositions according to the present invention with different quantities of ethyl cellulose, hydrogenated castor oil in buffer pH 6.8.

DETAILED DESCIPTION OF THE INVENTION
In accordance with the above objects the present invention provides, an extended release pharmaceutical composition for oral administration comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof comprising water insoluble polymer and/or wax.

The above and other objects are further attained and supported by the following some preferred embodiments described herein. However the scope of the invention is not restricted to described embodiments herein after and the complete patent application pursuant here to, will fully and particularly describe the additional preferred embodiments of the present invention.

In yet another embodiment the present invention provides a process of preparing an extended release pharmaceutical composition such as tablets, capsules and sachets, comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof and water insoluble polymer and/or wax.

In yet another embodiment the present invention provides an extended release pharmaceutical composition comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof incorporated in a hydrophobic matrix comprising water insoluble polymer and wax wherein weight ratio of water insoluble polymer to wax is from about 1:100 to about 100:1, preferably from about 1:50 to about 50:1, most preferably from about 1:20 to 20:1.

In yet another embodiment the present invention provides an extended release pharmaceutical composition comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof incorporated in a hydrophobic matrix comprising water insoluble polymer and wax wherein water insoluble polymer is present from about 1 % w/w to about 95 % w/w of the composition.

In yet another embodiment the present invention provides an extended release pharmaceutical composition comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof incorporated in a hydrophobic matrix comprising water insoluble polymer and wax wherein wax is present from about 1 % w/w to about 95 % w/w of the composition.

In yet another embodiment the present invention provides an extended release tablet comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof incorporated in a hydrophobic matrix comprising water insoluble polymer and/or wax.

In yet another embodiment the present invention provides an extended release non-swellable tablet comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof incorporated in a hydrophobic matrix comprising water insoluble polymer and/or wax wherein drug release is solely controlled by hydrophobic matrix without dose dumping.

In yet another embodiment the present invention provides an extended release uncoated matrix tablet comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof incorporated in a hydrophobic matrix comprising a water insoluble polymer such as ethyl cellulose and wax such as hydrogenated castor oil wherein drug release is solely controlled by hydrophobic matrix.

In yet another embodiment the present invention provides, an extended release pharmaceutical composition comprising a hard gelatin capsule with a therapeutically effective number of mini tablets, said mini tablets comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof, and water insoluble polymer and/or wax which is suitable for once daily dosing.

In another embodiment the present invention provides, a stabilized extended release pharmaceutical composition comprising a hard gelatin capsule with a therapeutically effective number of mini tablets, said mini tablets comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof, incorporated in a hydrophobic matrix comprising water insoluble polymer and/or wax.

In yet another embodiment the present invention provides, an extended release pharmaceutical composition comprising a hard gelatin capsule with a therapeutically effective number of mini tablets, said mini tablets comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof, incorporated in a hydrophobic matrix comprising ethyl cellulose and hydrogenated castor oil wherein weight ratio of ethyl cellulose to hydrogenated castor oil is from about 1:100 to about 100:1, preferably 1:50, to about 50:1, most preferably about 1:20 to 20:1.

In yet another embodiment, the present invention provides an extended release pharmaceutical composition comprising from about 0.5% to 50% by weight of Tolterodine or salt thereof and from about 1% to 95% by weight of ethyl cellulose and/or 1% to 95% by weight hydrogenated castor oil and one or more excipients.
Preferred extended release pharmaceutical compositions according to the present invention comprise Tolterodine or salt thereof in an amount approximately 0.5% to 40%, more preferably 0.5% to 25% and most preferably 0.5% to 15%.

In yet another embodiment the present invention provides a process of preparing an extended release pharmaceutical composition comprising Tolterodine or pharmaceutical acceptable salt, derivative, prodrug and metabolite thereof and water insoluble polymer and/or wax wherein process can be selected from direct compression, dry granulation, wet granulation (aqueous/non-aqueous or combination) and melt granulation.

The present invention can be applied in the formulation of tablets, capsules, caplets, sachets or other solid dosage forms for oral administration of an active ingredient.

In the present invention, an extended release composition in the form of a hard gelatin capsule filled with mini-tablets is provided. The use of mini-tablets is beneficial because pharmaceutical linearity between the strength and the formulation is achieved easily by incorporating one or more of the mini-tablets in the capsule. Linearity is highly desired in the pharmaceutical industry for manufacturing, pharmacokinetic and economical reasons.
Tabletting was the chosen production method because it is faster, easier, adds fewer steps to the process and is the most economical. Further, the tabletting method ensures a high production yield, contrary to the manufacture of pellets where the loss of production output is usually much higher. Excipients for the formulation were chosen carefully to give appropriate dissolution rate and stability of the finished dosage form.

The water insoluble polymers according to present invention includes but are not limited to ethyl cellulose, cellulose acetate, cellulose acetate phthalate, polymethyacrylates, calcium silicates and combinations thereof and the like.

The waxes according to present invention include but are not limited to hydrogenated castor oil, hydrogenated vegetable oil, bees wax, carnauba wax and combination thereof and the like.
The extended release pharmaceutical compositions according to present invention further comprises of one or more other excipients such as one or more diluent, one or more binder, one or more glidant, one or more anti-adherent.

Detailed description of the Invention In accordance of the above-mentioned embodiments and others, the present invention in certain embodiments is directed to a extended release pharmaceutical composition comprising Tolterodine or its pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates, enantiomers or racemates, or mixtures thereof.

The term “pharmaceutical composition" herein refers to the combination of one or more drug substances and one or more excipients, "Drug product," "pharmaceutical dosage form," "dosage form," "final dosage form" and the like, refer to a pharmaceutical composition that is administered to a subject in need of treatment and generally may be in the form of tablets, capsules, tablets filled in capsule, mini tablets filled in capsule, sachets containing powder or granules, pellets, liquid solutions or suspensions, patches, and the like

The term "extended release pharmaceutical composition" herein refers to any composition or dosage form that comprises an active drug and which is formulated to provide a longer duration of pharmacological response after administration of the dosage form than is ordinarily experienced after administration of a corresponding immediate release composition comprising the same drug in the same amount. Controlled release compositions include, inter alia, those compositions described elsewhere as "controlled release", "delayed release", "sustained release", "prolonged release", "programmed release", "time release" and/or "rate controlled" compositions or dosage forms.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention.

Example 1

B. No. 047/003
Ingredients Weight (mg)

Intra-granular
Tolterodine Tartrate 4.0
Lactose Monohydrate 60.0
Microcrystalline Cellulose 80.0
Ethyl Cellulose 10.0
Alcohol q.s.
Extra-granular
Hydrogenated Castor Oil 25.0
Ethyl Cellulose 20.0
Magnesium Stearate 1.0
Total 200.0

Manufacturing Procedure:
1. Sift Tolterodine Tartrate, Lactose monohydrate through suitable sieve.
2. Geometrically mix tolterodine tartrate with lactose monohydrate.
3. Sift Microcrystalline Cellulose and ethyl cellulose through suitable sieve.
4. Mix Step 3 with step 2
5. Granulate step 4 blend by using sufficient quantity of Alcohol.
6. Dry the granules in oven at temperature NMT 50°C.
7. Pass the dried granules through a suitable sieve.
8. Sift Hydrogenated castor oil and ethyl cellulose through suitable sieve.
9. Mix step 7 granules with step 8
10. Sift magnesium Stearate through suitable sieve and lubricate the step 9 blend.
11. Compress the step 10 lubricated blend into tablets/minitablets using suitable punches and/or fill the blend/minitablets into capsules.

Example 2

B. No. 047/007
Ingredients Weight (mg)
Intra-granular
Tolterodine Tartrate 4.0
Lactose Monohydrate 455.0
Ethyl Cellulose 64.0
Alcohol q.s.
Extra-granular
Hydrogenated Castor Oil 80.0
Ethyl Cellulose 32.0
Magnesium Stearate 5.0
Total 640.0

Manufacturing Procedure:
1. Sift Tolterodine Tartrate, Lactose monohydrate through suitable sieve.
2. Geometrically mix tolterodine tartrate with lactose monohydrate.
3. Sift Ethyl Cellulose through suitable sieve.
4. Mix Step 3 with step 2
5. Granulate step 4 blend by using sufficient quantity of Alcohol.
6. Dry the granules in oven at temperature NMT 50°C.
7. Pass the dried granules through a suitable sieve.
8. Sift Hydrogenated castor oil and ethyl cellulose through suitable sieve.
9. Mix step 7 granules with step 8
10. Sift magnesium stearate through suitable sieve and lubricate the step 9 blend.
11. Compress the step 10 lubricated blend into tablets/minitablets using suitable punches and/or fill the blend/minitablets into capsules.

Example 3
B. No. 047/011
Ingredients Weight (mg)
Intra-granular
Tolterodine Tartrate 4.0
Lactose Monohydrate 487.0
Ethyl Cellulose 32.0
Alcohol q.s.
Extra-granular
Hydrogenated Castor Oil 80.0
Ethyl Cellulose 32.0
Magnesium Stearate 5.0
Total 640.0

Manufacturing Procedure:
1. Sift Tolterodine Tartrate, Lactose monohydrate through suitable sieve.
2. Geometrically mix tolterodine tartrate with lactose monohydrate.
3. Sift Ethyl Cellulose through suitable sieve.
4. Mix Step 3 with step 2
5. Granulate step 4 blend by using sufficient quantity of Alcohol.
6. Dry the granules in oven at temperature NMT 50°C.
7. Pass the dried granules through a suitable sieve.
8. Sift Hydrogenated castor oil and ethyl cellulose through suitable sieve.
9. Mix step 7 granules with step 8
10. Sift magnesium stearate through suitable sieve and lubricate the step 9 blend.
11. Compress the step 10 lubricated blend into tablets/minitablets using suitable punches and/or fill the blend/minitablets into capsules.

Example 4

B. No. 047/019
Ingredients Weight (mg)
Intra-granular
Tolterodine Tartrate 4.0
Lactose Monohydrate 122.0
Microcrystalline Cellulose 50.0
Ethyl Cellulose 12.5
Alcohol q.s.
Extra-granular
Hydrogenated Castor Oil 25.0
Ethyl Cellulose 25.0
Magnesium Stearate 1.5
Total 240.0

Manufacturing Procedure:
1. Sift Tolterodine Tartrate, Lactose monohydrate through suitable sieve.
2. Geometrically mix tolterodine tartrate with lactose monohydrate.
3. Sift Ethyl Cellulose and microcrystalline cellulose through suitable sieve.
4. Mix Step 3 with step 2
5. Granulate step 4 blend by using sufficient quantity of Alcohol.
6. Dry the granules in oven at temperature NMT 50°C.
7. Pass the dried granules through a suitable sieve.
8. Sift Hydrogenated castor oil and ethyl cellulose through suitable sieve.
9. Mix step 7 granules with step 8
10. Sift magnesium stearate through suitable sieve and lubricate the step 9 blend.
11. Compress the step 10 lubricated blend into tablets/minitablets using suitable punches and/or fill the blend/ minitablets into capsules.

Example 5

B. No. 047/027
Ingredients Weight (mg)
Intra-granular
Tolterodine Tartrate 4.0
Lactose Monohydrate 81.0
Microcrystalline Cellulose 108.0
Ethyl Cellulose 10.0
Ethyl Cellulose (aqueous dispersion) 15.0
Purified Water q.s.
Extra-granular
Hydrogenated Castor Oil 35.0
Ethyl Cellulose 14.5
Magnesium Stearate 2.5
Total 270.0

Manufacturing Procedure:
1. Sift Tolterodine Tartrate, Lactose monohydrate through suitable sieve.
2. Geometrically mix tolterodine tartrate with lactose monohydrate.
3. Sift Ethyl Cellulose and microcrystalline cellulose through suitable sieve.
4. Mix Step 3 with step 2.
5. Granulate step 4 blend by using ethyl cellulose aqueous dispersion and purified water.
6. Dry the granules in oven at temperature NMT 50°C.
7. Pass the dried granules through a suitable sieve.
8. Sift Hydrogenated Castor Oil and Ethyl Cellulose through suitable sieve.
9. Mix step 7 granules with step 8.
10. Sift magnesium stearate through suitable sieve and lubricate the step 9 blend.
11. Compress the step 10 lubricated blend into tablets/minitablets using suitable punches and/or fill the blend/minitablets into capsules.

Example 6

B. No. 047/031
Ingredients Weight (mg)
Intra-granular
Tolterodine Tartrate 4.0
Lactose Monohydrate 100.0
Microcrystalline Cellulose 203.5
Ethyl Cellulose 10.0
Ethyl Cellulose (aqueous dispersion) 15.0
Hydrogenated Castor Oil 35.0
Purified Water q.s.

Extra-granular
Magnesium Stearate 2.5
Total 270.0

Manufacturing Procedure:
1. Sift Tolterodine Tartrate, Lactose monohydrate through suitable sieve.
2. Geometrically mix tolterodine tartrate with lactose monohydrate.
3. Sift Ethyl Cellulose, Hydrogenated Castor Oil and microcrystalline cellulose through suitable sieve.
4. Mix Step 3 with step 2.
5. Granulate step 4 blend by using ethyl cellulose aqueous dispersion and purified water.
6. Dry the granules in oven at temperature NMT 50°C.
7. Pass the dried granules through a suitable sieve.
8. Sift magnesium stearate through suitable sieve and lubricate the step 7 blend.
9. Compress the step 8 lubricated blend into tablets/minitablets using suitable punches and/or fill the blend/minitablets into capsules.

The formulations of Example 1 to Example 2 were subjected to in-vitro dissolution studies and the results obtained are presented below table:
Dissolution Studies Dissolution Media: 900ml, pH 6.8 Phosphate Buffer, USP I, 100 RPM
Time (hrs) % Drug Released
Formulation Example 1 Example 2 Example 3 Example 4 Example 5 Example 6
1 34 22 15 23 28 19
2 52 29 20 34 39 29
3 63 34 25 40 46 36
5 74 42 30 48 57 45
7 81 47 35 54 63 50
10 86 52 39 58 70 59
12 88 55 43 60 73 65
14 90 58 45 63 78 68
18 93 63 50 66 83 74
20 95 65 53 68 87 77
24 96 68 57 70 92 83

While this provisional patent application contains the description of the principal inventive concepts. The complete patent application pursuant here to, will fully and particularly describe the preferred embodiments of the present invention.

Dated this the 23rd day of November, 2009

Figure 1