1. A process for preparation of controlled release phannaceutical composition of tolterodine comprising: a. an inert core unit, b. a first layer on the inert core unit comprising tolterodine dispersed in a hydrophilic polymer, and c. a second layer of polymer effective for controlled release of active ingredient.

2. The process according to claim 1 wherein the process of preparation of controlled release pharmaceutical composition of tolterodine comprises: a. providing an inert core unit; b. applying a first layer comprising tolterodine and a hydrophilic polymer binder; and drying; c. applying onto said first layer, a second polymer layer effective for controlled release of the active ingredient and drying.

3. The process according to claim 1 or 2 wherein the controlled release pharmaceutical composition is in the form of multiple units.

4. The process according to claim 1 or 2 wherein the inert core may be selected from inert insoluble, inert soluble or swellable and commercially available inert material.

5. The process according to claim 4 wherein insoluble inert cores may be selected from dicalcium phosphate, microcrystalline cellulose and the like.

6. The process according to claim 4 wherein soluble or swellable inert cores may be selected from glucose, mannitol, lactose, xylitol, dextrose, sucrose and the like.

7. The process according to claim 4 wherein commercially available inert material may be selected from sugar sphere, non-pareil seed, celphere and the like.

8. The process according to claim 1 or 2 wherein tolterodine may be selected from tolterodine base, (S)-enantiomer, the racemate and the active 5-hydroxymethyl metabolites, prodrug forms and phannaceutically acceptable salts thereof such as tartarate.

9. The process according to claim 1 or 2 wherein the hydrophilic polymer of the first layer may be selected from polyvinylpyrrolidone, polyalkylene glycol such as polyethylene glycol, gelatin, polyvinyl alcohol, starch and derivatives thereof, cellulose derivatives, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, acrylic acid polymers, polymethacrylates, or any other pharmaceutically acceptable polymer.

10. The process according to claim 1 or 2 wherein the ratio of active ingredient to hydrophilic polymer in the first layer may range from 1:20 to 20:1.

11. The process according to claim 1 or 2 wherein the core may be coated with tolterodine in powder form or sprayed as a solution or dispersion.

12. The process according to claim 1 or 2 wherein polymers used in second layer may be selected from ethyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylates, or mixtures thereof.

13. The process according to claim 1 or 2 wherein the second layer may further comprise modifiers.

14. The process according to claim 13 wherein the modifiers may be selected from hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polymers with pH-dependent solubility, such as cellulose acetate phthalate or ammonio-methacrylate copolymer and methacrylic acid copolymer, or mixtures thereof.

15. The process according to claim 1 or 2 wherein the polymers may be applied as a solution or dispersion in a solvent.

16. The process according to claim 15 wherein the solvent may be selected from water, alcohols like ethyl alcohol or isopropyl alcohol; ketones like acetone or ethylmethylketone; halogenated hydrocarbons like dichloroethane and trichloroethane or mixtures thereof.

17. The process according to claim 1 or 2 wherein the coatings may be applied to the core using any conventional coating technique.

18. The process according to claim 17 wherein the coating technique may be spray coating in a conventional coating pan or fluid bed processor or dip coating.

19. The process according to claim 1 or 2 wherein the second layer constitutes 2 to 50% of the formulation.

20. The process according to claim 1 or 2 wherein coating layers may additionally contain pharmaceutically inert excipients such as plasticizers and lubricants.

21. The process according to claim 20 wherein plasticizers may be selected from propylene glycol, triethylene glycol, oleic acid, ethyleneglycol monoleate, triethyl citrate, triacetin, diethyl phthalate, glyceryl monostearate, dibutyl sebaccate, acetyl triethylcitrate , castor oil and the like.

22. The process according to claim 20 wherein lubricants may be selected from talc, anhydrous colloidal silica, magnesium stearate, glyceryl monostearate, beeswax and the like.

23. The process according to claim 1 or 2 wherein the coated units are filled into hard gelatin capsules or compressed into tablets.

24. The process according to claim 23 wherein the coated units further comprise a non-functional coating.

25. The process according to claim 1 or 2 wherein the controlled release pharmaceutical composition shows the following in vitro dissolution profile for tolterodine in 900 ml Phosphate buffer pH 6.8 when tested using USP Apparatus I at 100 rpm: a. not more than 50 percent released in 1 hour. b. between 25 and 85 percent released in 3 hours. c. not less than 50 percent released in 7 hours.

26. A process for preparing controlled release pharmaceutical composition of tolterodine as exemplified and described herein.

The technical field of the present invention pertains to the process for preparation of controlled release phamiaceutical composition of tolterodine. It also relates to the process for preparation of multiple unit pharmaceutical composition of tolterodine.
About 5-10% of the adult population suffers from overactive or unstable urinary bladder, often also referred to as urinary incontinence. The symptoms of an unstable or overactive bladder comprise urge incontinence, urgency and urinary frequency. The prevalence of overactive bladder, particularly urge incontinence, increases with age. It is assumed that unstable or overactive bladder is caused by uncontrolled contractions of the bundles of smooth muscle fibres forming the muscular coat of the urinary bladder (the detrusor muscle) during the filling phase of the bladder. These contractions are mainly controlled by cholinergic muscarinic receptors, and the pharmacological treatment of unstable or overactive bladder has been based on muscarinic receptor antagonists. The drug of choice for a long time has been oxybutynin.
Recently, however, an improved muscarinic receptor antagonist, tolterodine, (R) N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl)-3-phenylpropanamine, has been marketed for the treatment of urge incontinence and other symptoms of unstable or overactive urinary bladder. Both tolterodine and its major, active metabolite, the 5-hydroxymethyl derivative of tolterodine, which significantly contributes to the therapeutic effect, have considerably less side-effects than oxybutynin, especially regarding the tendency to cause dry mouth. While tolterodine is equipotent as oxybutynin in the bladder, its affinity for muscarinic receptors of the salivary gland is eight times lower than that of oxybutynin.
The currently marketed administration form of tolterodine is a film coated tablet containing 1 mg or 2 mg of tolterodine L-tartrate for immediate release in the gastrointestinal tract, the recommended dosage usually being 2 mg twice a day.
Tolterodine tartrate is also marketed by Phamnacia as DETROL LA extended release capsules comprising 2 or 4 mg of the active ingredient.
The PCT application WO 00/12069, filed by Pharmacia and Upjohn discloses treatment of overactive bladder by the administration of a controlled release formulation that delivers
tolterodine, a tolterodlne-related compound, or a pharmacologically acceptable salt thereof such that a substantially constant serum level of the active moiety or moieties is maintained for at least 24 hours.
Another PCT application WO 00/27364, also filed by Pharmacia and Upjohn, relates to a formulation containing said controlled release beads, and to a method of preparing said beads. These beads comprise: (i) a core unit of water-soluble or water-insoluble polymer; (ii) a first layer on the core unit of a substantially water-insoluble polymer; (ill) a second layer covering the first layer and containing the active ingredient and (iii) a third layer on the second layer of polymer effective for controlled release of active ingredient; wherein said first layer Is adapted to control water penetration into the core.
In light of the above it will be appreciated by those versed in the pharmaceutical dispensing art that a need exists for a controlled release pharmaceutical composition that can deliver tolterodine in a controlled, extended dose and at the same time can be formulated by employing a simple process, which involves less number of layering steps.
It has surprisingly been found that controlled release phannaceutical composition of tolterodine may be formulated by layering the core directly with the active Ingredient dispersed in hydrophilic polymer, without the need for a seal-coat or an extra polymer coat between the core and the active layer.
In one general aspect, a simple, economical and easy process for manufacturing controlled release pharmaceutical composition of tolterodine is provided.
In another aspect, a controlled release pharmaceutical composition of tolterodine is provided, which comprises:
i. An inert core unit,
il. a first layer on the inert core unit comprising tolterodine dispersed in a hydrophilic
polymer, and ili. a second layer of polymer effective for controlled release of active Ingredient.
The addition of a hydrophilic polymer in a layer together with the active ingredient imparts desired mechanical properties for withstanding cracking, especially when exposed to mechanical stress during filling in capsules or sachets or during compaction / compression.
Further this new pharmaceutical composition provides excellent multiple unit systems withstanding mechanical stress and giving enough flexibility and plasticity to avoid cracking or rupturing of release controlling layers.
It is another general aspect to provide a process for preparing multiple unit pharmaceutical composition of tolterodine, wherein multiple units are formulated by employing a simple process, which does not involve extra steps of seal coating and are still capable of imparting controlled release properties.
The term "multiple unit pharmaceutical composition" indicates a pharmaceutical composition comprising multiples of individual coated units contained in the formulation in such a form that the individual units will be available from the formulation upon disintegration of the formulation in the stomach. The multiple unit formulation may be a capsule or a tablet, which disintegrate in the stomach to give individual units. The multiple units may be formulated as granules, pellets or beads.
The inert core may be selected from pharmaceutically inert insoluble or soluble or swellable material. Alternatively, the inert core may also be a commercially available product. The insoluble inert cores are composed of dicalcium phosphate, microcrystalline cellulose and the like, either alone or in combination. The soluble inert cores are composed of sugar selected from glucose, mannitol, lactose, xylitol, dextrose, sucrose and the like. Commercially available inert cores are selected from sugar sphere, non-pareil seed, celphere and the like. The cores may be of any geometric shape, though spheres are preferred for the ease of uniform coating.
The first layer containing the active ingredient may be comprised of tolterodine with a polymer. The polymer is usually hydrophilic but may be water-soluble or water-insoluble. Exemplary polymers to be used in the first layer containing the active ingredient are
hydrophilic polymers such as polyvinylpyrrolidone, polyalkylene glycol such as polyethylene glycol, gelatin, polyvinyl alcohol, starch and derivatives thereof, cellulose derivatives, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxyethylcellulose, carboxy-methyl-hydroxy-ethyl cellulose, acrylic acid polymers, polymethacrylates, or any other pharmaceutically acceptable polymer.
Tolterodine for the purpose of the present invention may be selected from tolterodine base, 1. e. (R)-N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl)-3phenylpropanamine, as well as the corresponding (S)-enantiomer, the racemate and the active 5-hydroxymethyl metabolites, prodrug forms and pharmaceutically acceptable salts thereof such as tartarate. Tolterodine used in the pharmaceutical compositions described herein can be prepared by any known method, such as, for example, using either of the procedures disclosed in U.S. Patent No. 5,382,600 or U.S. Patent No. 5,922,914. Both of these patents are incorporated herein in their entirety by reference.
The ratio of active ingredient to hydrophilic polymer in the first layer may be in the range of 1:20 to 20:1 (w/w).
The core particles may be coated with the active ingredient dispersed in the hydrophilic polymers by powder layering technique, i.e. the active ingredient is applied to the core in dry form as powder. Alternatively, the polymer is sprayed onto the cores as a solution or dispersion in such a way that solvent, preferably water, is evaporated, and the polymer is applied to the cores together with the active ingredient, i.e. forming a homogenous dispersion. The pharmaceutically active ingredient is applied onto the core material preferably by spraying an aqueous/non aqueous solution/suspension in a fluidized bed with wurster or top spray technique.
The drug layered cores may be coated with a polymeric layer for modifying and controlling the drug release. Suitable polymers may be selected from water-insoluble polymers or polymers with pH dependent or independent solubility, for example, ethyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate
trimellitate, polymethacrylates, or mixtures thereof. Optionally, the controlled release layer may comprise, in addition to the above polymers, modifier (s) with different solubility characteristics, to adjust the pemneability, and thereby the release rate, of the controlled release layer.
Exemplary polymers that may be used as a modifier include: hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polymers with pH-dependent solubility, such as cellulose acetate phthalate or ammonio methacrylate copolymer and methacrylic acid copolymer, or mixtures thereof. Additives such as sucrose, lactose and phamnaceutical grade surfactants may also be included in the controlled release layer, if desired.
The polymers may be applied as a solution or dispersion in a solvent. The solvent may be selected from water, alcohols like ethyl alcohol or isopropylalcohol; ketones like acetone or ethylmethylketone; halogenated hydrocarbons like dichloroethane and trichloroethane or mixtures thereof.
Any conventional coating equipment may be employed to facilitate coating such as centrifugal fluidized bed coating apparatus or a pan coating apparatus. The coating may be applied using a conventional coating pan, a spray coater, rotating perforated pan or an automated system. The coated multiple units may be dried in an oven or in a fluidized bed.
The coating may constitute about 2-50% w/w of the formulation.
The coating layers may additionally contain pharmaceutically inert excipients such as plasticizers and lubricants.
Suitable plasticizers include propylene glycol, triethylene glycol, oleic acid, ethyleneglycol monoleate, triethyl citrate, triacetin, diethyl phthalate, glyceryl monostearate, dibutyl sebacate, acetyl triethylcitrate , castor oil and the like.
Suitable lubricants may be selected from talc, anhydrous colloidal silica, magnesium stearate, glyceryl monostearate, beeswax and the like.
Optionally, multiple units may comprise a non-functional coating over the second layer.
The coated multiple units are filled into hard gelatin capsules or compressed into tablets, which disintegrate in the stomach to make available a multiplicity of individually coated units.
In another aspect, a process is provided for preparing controlled release pharmaceutical composition of tolterodine, which comprises:
(a) providing an inert core unit;
(b) applying a first layer comprising an active ingredient and a hydrophilic polymer binder; and drying;
(c) applying onto said first layer, a second polymer layer effective for controlled release of the active ingredient and drying.
The controlled-release composition shows the following in vitro dissolution profile for tolterodine in 1000 ml Phosphate buffer pH 6.8, when tested using USP Apparatus I at 100 rpm:
a. not more than 50 percent released in 1 hour.
b. between 25 and 85 percent released in 3 hours.
c. not less than 50 percent released in 7 hours.
The following examples illustrate various aspects of the present invention. These examples are for illustration only and should not be construed as limiting the scope of the invention.
EXAMPLE 1
(TABLE REMOVED)

Process:
Hydroxypropyl methylcellulose and tolterodine tartrate were dissolved in water and the solution obtained was sprayed onto non-pareil beads and the coating was dried. Drug coated beads were further coated with a solution of ethyl cellulose and hydroxypropyl methylcellulose in a mixture of Isopropyl alcohol and water (83:17). The coated beads were dried and filled into capsules.
Table 1 shows the dissolution data of Tolterodine tartrate 4.0 mg capsules prepared as per composition of Example 1. The dissolution was carried out in 1000ml phosphate buffer pH 6.8 using USP Apparatus Type I (basket) at a speed of 100 rpm.
Table 1: Comparative in vitro release of tolterodine extended release capsules of Example 1 and Detrol LA capsules (4 mg; marketed by Pharmacia)
(TABLE REMOVED)

EXAMPLE 2
(TABLE REMOVED)

Process:
The process followed is similar to that followed in Example 1.
EXAMPLE 3
(TABLE REMOVED)

Process:
Hydroxypropyl methylcellulose and tolterodine tartrate were dissolved in water and the solution obtained was sprayed onto microcrystalline cellulose beads and the coating was dried. Drug coated beads were further coated with a dispersion of ethyl cellulose and hydroxypropyl methylcellulose in a mixture of Isopropyl alcohol and water. The coated beads were dried, lubricated and filled into capsules.
While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. For example, polyvinyl pyrrolidone, carboxymethyl cellulose, hydroxypropyl cellulose can be used as hydrophilic polymers for the first layer. Further, it is contemplated that any single feature or any combination of optional features of the inventive variations described herein may be specifically excluded from the claimed invention and be so described as a negative limitation. Accordingly, it is not intended that the Invention be limited, except as by the appended claims.

WE CLAIM:
1. A process for preparation of controlled release phannaceutical composition of
tolterodine comprising:
a. an inert core unit,
b. a first layer on the inert core unit comprising tolterodine dispersed in a
hydrophilic polymer, and
c. a second layer of polymer effective for controlled release of active
ingredient.
2. The process according to claim 1 wherein the process of preparation of
controlled release pharmaceutical composition of tolterodine comprises:
a. providing an inert core unit;
b. applying a first layer comprising tolterodine and a hydrophilic polymer
binder; and drying;
c. applying onto said first layer, a second polymer layer effective for
controlled release of the active ingredient and drying.
3. The process according to claim 1 or 2 wherein the controlled release pharmaceutical composition is in the form of multiple units.
4. The process according to claim 1 or 2 wherein the inert core may be selected from inert insoluble, inert soluble or swellable and commercially available inert material.
5. The process according to claim 4 wherein insoluble inert cores may be selected from dicalcium phosphate, microcrystalline cellulose and the like.
6. The process according to claim 4 wherein soluble or swellable inert cores may be selected from glucose, mannitol, lactose, xylitol, dextrose, sucrose and the like.
7. The process according to claim 4 wherein commercially available inert material may be selected from sugar sphere, non-pareil seed, celphere and the like.
8. The process according to claim 1 or 2 wherein tolterodine may be selected from tolterodine base, (S)-enantiomer, the racemate and the active 5-hydroxymethyl metabolites, prodrug forms and phannaceutically acceptable salts thereof such as tartarate.
9. The process according to claim 1 or 2 wherein the hydrophilic polymer of the first layer may be selected from polyvinylpyrrolidone, polyalkylene glycol such as polyethylene glycol, gelatin, polyvinyl alcohol, starch and derivatives thereof, cellulose derivatives, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, acrylic acid polymers, polymethacrylates, or any other pharmaceutically acceptable polymer.
10. The process according to claim 1 or 2 wherein the ratio of active ingredient to hydrophilic polymer in the first layer may range from 1:20 to 20:1.
11. The process according to claim 1 or 2 wherein the core may be coated with tolterodine in powder form or sprayed as a solution or dispersion.
12. The process according to claim 1 or 2 wherein polymers used in second layer may be selected from ethyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylates, or mixtures thereof.
13. The process according to claim 1 or 2 wherein the second layer may further comprise modifiers.
14. The process according to claim 13 wherein the modifiers may be selected from hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polymers with pH-dependent solubility, such as cellulose acetate phthalate or ammonio-methacrylate copolymer and methacrylic acid copolymer, or mixtures thereof.
15. The process according to claim 1 or 2 wherein the polymers may be applied as a solution or dispersion in a solvent.
16. The process according to claim 15 wherein the solvent may be selected from water, alcohols like ethyl alcohol or isopropyl alcohol; ketones like acetone or ethylmethylketone; halogenated hydrocarbons like dichloroethane and trichloroethane or mixtures thereof.
17. The process according to claim 1 or 2 wherein the coatings may be applied to the core using any conventional coating technique.
18. The process according to claim 17 wherein the coating technique may be spray coating in a conventional coating pan or fluid bed processor or dip coating.
19. The process according to claim 1 or 2 wherein the second layer constitutes 2 to 50% of the formulation.
20. The process according to claim 1 or 2 wherein coating layers may additionally contain pharmaceutically inert excipients such as plasticizers and lubricants.
21. The process according to claim 20 wherein plasticizers may be selected from propylene glycol, triethylene glycol, oleic acid, ethyleneglycol monoleate, triethyl citrate, triacetin, diethyl phthalate, glyceryl monostearate, dibutyl sebaccate, acetyl triethylcitrate , castor oil and the like.
22. The process according to claim 20 wherein lubricants may be selected from talc, anhydrous colloidal silica, magnesium stearate, glyceryl monostearate, beeswax and the like.
23. The process according to claim 1 or 2 wherein the coated units are filled into hard gelatin capsules or compressed into tablets.
24. The process according to claim 23 wherein the coated units further comprise a non-functional coating.
25. The process according to claim 1 or 2 wherein the controlled release pharmaceutical composition shows the following in vitro dissolution profile for tolterodine in 900 ml Phosphate buffer pH 6.8 when tested using USP Apparatus I at 100 rpm:
a. not more than 50 percent released in 1 hour.
b. between 25 and 85 percent released in 3 hours.
c. not less than 50 percent released in 7 hours.

26. A process for preparing controlled release pharmaceutical composition of tolterodine as exemplified and described herein.