AU726814B2 - Pharmaceutical formulations containing darifenacin - Google Patents

Description

I V I I S F Ref: 405484D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

S.

Name and Address of Applicant: Pfizer Research and Development Company, N.V./S.A.

La Touche House International Financial Services Centre Dublin 1 REPUBLIC OF IRELAND Actual Inventor(s): Thomas Francis Dolan, Michael John Humphrey and Donald John Nichols Address for Service: Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Invention Title: Pharmaceutical Formulations Containing Darifenacin The following statement is a full description of this invention, including the best method of performing 't known to me/us:- 5845 Pharmaceutical Formulations Containing Darifenacin This invention relates to pharmaceutical dosage forms of darifenacin and its pharmaceutically acceptable salts.

Darifenacin is -[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide and is disclosed in European Patent No. 0388054, Examples 1B and 8, and is referred to therein as 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydro-benzofuran-5yl)ethyl]pyrrolidine. It is indicated in the treatment of urinary incontinence and irritable bowel syndrome and has the following structure:

CONH

2

H

Clinical investigations have shown a major metabolite of darifenacin to be the following 3'-hydroxy derivative:

CONH

2 H /OH It appears that the metabolite is 6-fold less selective for muscarinic M3 receptors over M1 receptors in comparison with darifenacin, and so the metabolite is more likely than darifenacin to produce unwanted side-effects such as dry mouth, confusion and blurred vision.

It has now been found that delivering darifenacin and its pharmaceutically acceptable salts to the lower gastrointestinal tract in a sustained release formulation) gives rise to a greater ratio of darifenacin to metabolite in the systemic circulation. This increases the bioavailability of darifenacin, which is likely to minimize any unwanted side-effects. This is surprising because a slower release rate normally leads to a slower delivery to liver enzymes and a greater degree of metabolism of an administered drug.

Thus, according to a first aspect of the present invention, there is provided a rectal formulation adapted for administration to the gastrointestinal tract of a patient, comprising darifenacin, .Bl. \]O'203specl.dc tit 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier; characterized in that the dosage form is adapted to deliver at least 10% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of the patient.

A second aspect of the present invention provides a rectal formulation adapted for administration to the gastrointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier; characterized in that the formulation is adapted to release the darifenacin, or the pharmaceutically acceptable salt thereof, in Apparatus 1 described in USP XXII at page 1578, having baskets of 40 mesh (381p.m apertures), a rotation speed of 100 rpm and a dissolution medium of water at 370C, over a sustained period of time, wherein no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released after 4 hours.

A third aspect of the present invention provides a method of treatment of irritable bowel syndrome or urinary incontinence, which comprises delivering a rectal formulation of darifenacin, or a i pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of a patient in need of such treatment; characterised in that the dosage form is adapted to deliver at least 10% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of the patient.

The dosage forms of the invention may be of the sustained or delayed release type, and so 20 release the darifenacin, or the pharmaceutically acceptable salt thereof, to the gastrointestinal tract of the patient over or after a sustained period of time following administration of the dosage form to the patient. However, when the dosage forms are administered rectally, conventional rectal formulations may be used.

S" By "lower gastrointestinal tract" is meant the portion of the gastrointestinal tract between the region of the ileo-caecal junction and the rectum inclusive.

"Patient" means primarily a human patient, although the formulations of the present invention may be useful in the treatment of non-human animals.

Preferably, the dosage forms of the invention are adapted to deliver at least 25%, and more preferably 50% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the Slower gastrointestinal tract.

Preferably, no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 4 hours after dosing; more preferably no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 8 hours after dosing; and most preferably, no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 16 hours after dosing.

I.IBAlO3203?Opeci doctit 2a The conditions in the gastrointestinal tract are thought to be reproduced in vitro using Apparatus 1 described in USP XXII at page 1578, having baskets of 40 mesh (381 |m apertures), a rotation speed of 100 rpm and a dissolution medium of water at 37 0 C. Therefore, the sustained release formulations of the invention may be defined alternatively as a pharmaceutical dosage form adapted for administration to the gastrointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier; characterized in that the Go *o 9 4 'I.IBA]J(O3203)Spec doc tit dosage form is adapted to release the darifenacin, or the pharmaceutically acceptable salt thereof, in Apparatus 1 described in USP XXII at page 1578, having baskets of mesh (381um apertures), a rotation speed of 100 rpm and a dissolution medium of water at 37 0 C, over a sustained period of time.

Particular oral dosage forms include: those in which the darifenacin, or the pharmaceutically acceptable salt thereof, is embedded in a matrix from which it is released by diffusion or erosion; those in which the darifenacin, or the pharmaceutically acceptable salt thereof, is present in a multiparticulate core; those in which there is an impermeable coating provided with an aperture through wnich the darifenacin, or the pharmaceutically acceptable salt thereof, is released; those in which there is a coating of low aqueous solubility; those in which there is a semipermeable coating; those in which the darifenacin is present as an ion exchange resin complex; and pulsatile devices from which the darifenacin is released at specific points in the gastrointestinal tract.

SIt will be apparent to those skilled in the art that some of the above means of achieving 20 sustained release may be combined: for example a matrix containing the active compound may be formed into a multiparticulate and/or coated with an impermeable coating provided with an aperture.

Dealing with each category in turn: 25 In matrix systems, which are preferred, the active compound is embedded or dispersed in a matrix of another material which serves to retard the release of the active .compound into an aqueous environment. Suitable matrix materials include hydroxypropyl methylcellulose and hydroxypropyl cellulose. Matrix formulations accordina to the present invention preferably comprise high molecular weight 85,000-95,000 mass units) .*oo 30 hydroxypropyl methylcellulose.

In multiparticulate cores, the active compound is present in a number of particles which also contain adjuvants, diluents or carriers. Suitable adjuvants, diluents and carriers include microcrystalline cellulose (preferably having a particle size of 50um) and lactose (preferably having a particle size equivalent to 110 mesh (137.5.m apertures)).

Typically, the blended ingredients are formed into a wet mass which is extruded and spheronized to form beads which are then dried.

Impermeable coatings are applied to tablets containing the active compound.

"Impermeable" means that no significant transport of the active compound can take place across the coating during the intended release period of the forr,-ulation. Suitable materials include film-forming polymers and waxes thermoplastic polymers such as poly(ethylene-covinyl acetate), poly(vinyl chloride), ethyl cellulose and cellulose acetate] and the coating thickness is preferably greater than 100pm. The aperture may be formed by drilling, or if the coated formulation is conical, by cutting off the tip.

Coatings of low aqueous solubility include polymers. The solubility of such polymers may be pH-dependent, for example substantially insoluble at pH<5 (so th dissolution does not take part in the stomach) and water soluble at pH>5. Preferred pHsensitive polymers include shellac, phthalate derivatives (including cellulose acetate phthalate, polyvinylacetate phthalate), polyacrylic acid derivatives, and vinyl acetate and crotonic acid copolymers.

Semipermeable membrane coatings allow the active compound to diffuse across the membrane or through liquid filled pores within the membrane. Suitable coating materials include polymers such as cellulose ester or ether, and acrylic polymers.

Preferred materials include ethyl cellulose, cellulose acetate and cellulose acetate 20 butyrate.

Darifenacin resinates may be prepared by treating anionic ion exchange resin beads (for example sodium polystyrene sulphonate) with an acid- addition salt of **darifenacin.

Pulsatile devices have the capacity to release drug at various points of the 25 gastrointestinal tract. They may depend on osmotic potential to trigger release (see US Patent No 3,952,741) or erosion of polymeric material due to changes in pH or microbial degradation. Suitable polymeric materials include pectin [Rubinstein et al. 1991, Pectic salt as a colonic delivery system, Proceed. Intern. Symp. Control. Rel. Bioact. Mater.], methacrylate-galactomannan [Lehman et al, 1991, Methacrylate-galactomannan coating 3 0 for colonic specific drug delivery, ibid], matter containing azobonds [Kopeckova et al, 1991, Bioadhesive polymers for colon specific drug delivery, ibid], chondroitin [Sintov et al, 1991, Colonic administration of indomethacin using modified chondroitin in a cannulated dog model, ibid], dextran hydrogels [Bronsted et al, 1993, A novel hydrogel system designed for controlled drug delivery to the colon, ibid], methacrylic acid copoiymers [Siefke et al, 1993, P-Cyclodextrin matrix films for colon specific drug delivery, ibid], and amylose [Milojevik et al, In vitro and in vivo evaluation of amylose coated pellets for colon specific drug delivery, ibid]. Delivery to specific points of the gastrointestinal tract may also be achieved using multilayered tablets [Gazzaniga et al, 1993, Time dependent oral delivery system for colon specific release, ibid], or hydrogel plugs in a capsule [Binns et al, Application of a pH-independent PEG-based hydrogel to afford pulsatile drug delivery].

Preferably, in the dosage forms of the present invention, the darifenacin is in the form of its hydrobromide salt (except when the darifenacin is present as an ion exchange resin complex).

A preferred oral formulation is a tablet consisting essentially of darifenacin hydrobromide in a high molecular weight hydroxypropyl methylcellulose matrix together with anhydrous dibasic calcium phosphate and magnesium stearate. The tablet may be colour coated by conventional methods. Preferably, hydroxypropyl methylcellulose makes up 56-58% w/w of the tablet, magnesium stearate makes up approximately 1% of the tablet, and darifenacin hydrobromide and anhydrous dibasic calcium phosphate make up the balance. The darifenacin hydrobromide content may range from 4mg-54mg per tablet, depending on the dose to be delivered. Such tablets would be suitable for administration once daily.

.Preferably, the dosage forms of the present invention are adapted for oral administration, but they may also be adpated for rectal administration. Rectal suppository formulations may be prepared by dispersing the active ingredient in hardened oils or waxes using conventional methods.

l According to another aspect of the invention, there is provided a method of treatment of irritable bowel syndrome or urinary incontinence, which comprises delivering darifenacin, or a pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of a patient in need of such treatment. The method may be performed by administering a dosage form of the invention to the gastrointestinal tract of a patient in need of such treatment.

The invention is illustrated by the following examples in which the following materials are used: 6 Methocel T M K4M a high molecular weight hydroxypropyl methylcellulose with a number average in molecular weight of 89,000. It is classified in the USP as 2208 and a 2% solution in water has a nominal viscosity of 4000cps. It has a methoxy content of 19-24% and a hydroxypropcxy content of 7-12%; Methocel T M E4M a high molecular weight hydroxypropyl methylcellulose with a number average molecular weight of 93,000. It is classified in the USP as 2910 and a 2% solution in water has a nominal viscosity of 4000cps. It has a methoxy content of 28-30% and a hydroxypropoxy content of 7-12%; Methocel T M K100LV a low molecular weight hydroxypropyl methylcellulose. It is classified in the USP as 2208 and a 2% solution in water has a nominal viscosity of 100cps. It has a methoxy content of 19-24% and a hydroxypropoxy content of 7-12%; Klucel EF TM hydroxy propyl cellulose with a number average molecular weight of 60,000; EthocelTM ethyl cellulose; Avicel T M PH101 microcrystalline cellulose with an average particle size of Lactose regular lactose with a particle size equivalent to 110 mesh (137.5um apertures); Lactose Fast FloTM spray dried lactose; and EmcomPress T M dibasic calcium phosphate (anhydrous).

Aerosil 200 colloidal anhydrous silica 20 Example 1 (comparative) Fast release matrix tablet Ingredient Specification mg/unit (theory) g/batch (actual) Darifenacin hydrobromide Pfizer 23.810 30.19 Methocel K4M Ph Eur 12.000 15.00 Methocel K100LV Premium USP 28.000 35.00 Fast flo Lactose Ph Eur 134.190 167.70 Magnesium Stearate Ph Eur 2.000 2.50 TOTAL 200.000mg The Methocel K4M, K100LV premium, darifenacin and Fast-flo lactose were blended in a Turbula blender for 10 minutes. The mixture was then screened using a 30 mesh (500um apertures) screen and reblended for a further 10 minutes. Magnesium stearate was screened through a 30 mesh (500um apertures) screen and added to the mixture before o••e blending for a further 5 minutes. The blend was then subjected to compression on a tabletting machine using 8mm round normal convex tooling to make 1250 tablets.

Example 2 Medium release matrix tablet The Methocel K4M, E4M, darifenacin and Fast-flo lactose were blended in a suitable blender for 10 minutes. The mixture was then screened using a 30 mesh (500~m apertures) screen and reblended for a further 10 minutes. Magnesium stearate was screened through a 30 mesh (500tm apertures) screen and added to the mixture before blending for a further 5 minutes. The blend was then subjected to compression on a tabletting machine using 8mm round normal convex tooling to make 1250 tablets.

r r Example 3 Slow release matrix tablet Ingredient Specification mg/unit (theory) Darifenacin hydrobromide Pfizer 23.810 g/batch (actual) 30.19 74.70 nnyarous dibasic calcium phosphate Methocel K4M

USP

59.790 Ph Eur 114.400 143.00 Magnesium Stearate I Ph Eur I

TOTAL

2.000 2.50 200.000 The Methocel K4M, darifenacin and anhydrous dibasic calcium phosphate were blended in a Turbula blender for 10 minutes. The mixture was then screened using a 30 mesh 8 (500p.m apertures) screen and reblended for a further 10 minutes. Magnesium stearate was screened through a 30 mesh (500um apertures) screen and added to the mixture before blending for a further 5 minutes. The blend was then subjected to compression on a tabletting machine using 8mm round normal convex tooling to make 1250 tablets.

Example 4 Encapsulated coated core multiparticulates Preparation of uncoated cores Ingredient Specification g/kg (theory) g/batch (actual) Darifenacin hydrobromide Pfizer 119.048 119.76 Avicel PH101 Ph Eur 359.499 359.50 Lactose Regular Ph Eur 359.499 359.50 Fumaric acid NF 161.954 161.95 Purified water Ph Eur (500.000) 500.0 TOTAL 1000.000g 1000.71 The Avicel PH101, lactose regular, darifenacin and fumaric acid were blended in an Apex 2L Y cone for 10 minutes. The mixture was then screened using a 30 mesh (500um apertures) screen and re-blended for 10 minutes. Purified water was added to form a wet mass amenable to extrusion. The resultant wet mass was extruded using an Nica E 140 extruder (1mm screen) and then spheronised using a Caleva spheroniser to form multiparticulate beads. The beads were then dried using a bed temperature of 50°C for 1 hour to remove excess moisture.

Preparation of final formulation Ingredient Specification mg/unit (theory) g/batch (actual) Darifenacin uncoated cores Pfizer 200.000 150.30 Ethyl cellulose N-10 NF 17.750 13.32 Klucel EF NF 7.250 5.44 Ethyl Acetate NF 237.500 178.2 Isopropyl alcohol NF 237.500 178.1 TOTAL 225.000 Filled into white size 2 gelatine capsule shells.

C.

C

S

Ethyl acetate and isopropyl alcohol were stirred in a suitable vessel to ensure thorough mixing. To this mixture the Klucel EF and ethyl cellulose N10 were added and the solution stirred until complete dissolution had taken place. The uncoated beads were added to a fluidised bed coater and using an inlet temperature of 40 0 C the beads were coated with the solution containing the Klucel EF and ethylcellulose N10. On completion of coating the beads were dried for 10 minutes using a bed temperature of approximately The coated beads were filled into capsule shells prior to administration.

Example Ion exchange resin formulation Ingredient g/batch Darifenacin hydrobromide 60.39 Sodium polystyrene sulphonate 187.00 Disodium edetate, dihydrate 1.53 Water 2000.00 The disodium edetate and sodium polystyrene sulphonate were suspended in water. This suspension was then heated to 50°C whilst stirring. The darifenacin hydrobromide was then added to the suspension and the suspension stirred for a further 2 hours at 15 The darifenacin polystyrene sulphonate was then filtered off and washed until free of bromide ions. The darifenacin resinate was then dried under vacuum at 250C for approximately 16 hours.

Example 6 (comparative) S' 20 Immediate Release Caosule Ingredient Specification mg/unit theory g/batch (actual) Darifenacin hydrobromide Pfizer 8.929 547.46 Lactose Ph Eur 104.453 6267.20 Maize starch Ph Eur 34.818 2089.10 Aerosil 200 Ph Eur 0.300 18.00 Magnesium stearate Ph Eur 1.500 84.88 TOTAL 150.000 I 1 467.2g of the lactose was added to all of the darifenacin hydrobromide and blended in an Apex 8L double cone tumbling blender for 20 minutes. This was then milled using a Fitzmill (hammers forward, high speed) through a 1mm screen and the mill washed with the remaining lactose (4800.0g). This lactose, Aerosil 200 and maize starch were then added to the darifenacin hydrobromide/lactose preblend prepared initially and blended for minutes in a Gardner 28L double cone tumbling blender. This blend was then passed through a 1mm screen using a Fitzmill (knives forward, slow speed) and then blended for a further 20 minutes using the 28L blender. Magnesium stearate (88.88g) was then added and blending continued using the 28L blender for 5 minutes. The final blend was then encapsulated into size 2 hard gelatin capsule shells using a Zanasi capsule filling machine.

Example 7 Measurement of in vitro release rates Dissolution methods Dissolution of the formulations of Examples 1-4 was performed using a rotating basket apparatus (Apparatus 1, USPXXII, p. 1578). The formulations were placed in baskets mesh, 381pm apertures) using a rotation speed of 100rpm in 900ml water at 37°C 20 0.5°C. At specified time intervals, 10ml aliquots were removed from the dissolution vessel from a zone midway between the surface of the dissolution medium and the top of the basket not less than 1cm from the vessel wall. The first 7ml is discarded and the remaining solution transferred to an HPLC vial for subsequent analysis.

25 The release of darifenacin from the formulation of Example 5 was determined according to USP XXIII Apparatus 4 (page 1794). Using a flow rate of 250ml/hour solutions at 37°C of the following pH were used to assess release: 0-1hr pH 1.5; 1-2hr pH 2.5; 2-3.5hr pH4.5; 3.5-5hr pH 6.9; 5-24hr pH 7.2.

*l Dissolution of the formulation of Example 6 was performed using a rotating basket apparatus (Apparatus 1, USPXXII, p 1578). The formulations were placed in baskets 381 m apertures) using a rotation speed of 100rpm in 900ml water at 370C At specified time intervals a 20ml aliquot of dissolution media was removed from a zone midway between the surface of the dissolution media and the top of the basket not less than 1cm from the vessel wall. The aliquots were filtered (0.45um, Acrodisc) and the first 5ml of filtrate discarded. 5ml of the remaining filtrate was then diluted to 25ml using a 1:1 solution of water/methanol prior to analysis by HPLC.

Analysis For the formulations of Examples 1-5, High Performance Liquid Chromatography

(HPLC)

was performed using a BDS Hypersil C18 column. The mobile phase used was an aqueous 0.03M potassium dihydrogen orthophosphate at pH 3.5/methanol, (1000:800 v/v) using a flow rate of 1.5ml/min at 37°C and a sample size of 20pL. Detection was by fluorescence operating at an excitation wavelength of 288nm (slit width 18nm) and an emission wavelength of 320nm (slit width 18nm).

For the formulation of Example 6, High Performance Liquid Chromatography (HPLC) was performed using a Novapack C18 column. The mobile phase was aqueous 0.01M sodium acetate containing 0.2%v/v triethylamine at pH 6 .0/methanol/acetonitrile (45:54:1, v/v/v) using a flow rate of 1.Oml/min and a sample size of 50pl. Detection was by ultraviolet spectroscopy at 230nm.

Results Example 1 formulation (comparative) 20 Time release (range) S1 65 (52-81) 2 80 (72-92)

S

4 91 (87-96) 25 Example 2 formulation Time release 1 41 (38-46) 4 77 (73-81) 8 95 (94-96) Example 3 formulation Time release 1 6 (5-7) 8 42 (36-44) 16 67 (59-70) Example 4 formulation Time release 1 11 (9-15) 4 58 (50-70) 8 98(95-103) Example 5 formulation Time release 1 11 (10-12) 2 25 (24-27) 6 55 (51-59) 12 79 (77-82) 18 90(89-91) 24 94 (93-95) Example 6 formulation (comparative) Time release 0.25 94 99 20 0.75 98 Example 7 Suppository (mg/unit) Specification s Darifenacin HBr- 35.7 Pfizer S' PEG 1000 1290.2 Ph. Eur.

PEG 4000 430.1 Ph. Eur.

Example 8 formulation Clinical Pharmacokinetics Study A four way, multiple dose crossover study to investigate the bioavailability of darifenacin and its 3'-hydroxy metabolite when given as a sustained release formulation compared with an immediate release formulation was carried out. Thirteen normal males received the formulations of Examples 1- 3 od each for 6 days as well as the formulations of Example 6 three times a day. Plasma samples for drug and metabolite assay were taken over 24 hours on the last day of dosing for each period of the study. The pharmacokinetic parameters (area under the concentration-time curve over 24 hours, I1< 1 o2t)3j ecC doc ill l2a AUC, maximum concentration and concentration at 24 hours post dose) were obtained for both drug and metabolite. The tabie below shows the ratio of AUG values for darifenacin and metabolite (A UCda rifenain'A UC metaoWite) and the relative bioavailability of darifenacin (Frei darifenacin) and metabolite (F relI metabolite) for the formulations versus an immediate release capsule.

06 9 9 *6 000 '9 '0 *0 .0 JR \1,113 tit 13 Ratio of AUC of darifenacin: metabolite and relative bioavalklty_ eI versus an immediate release capsule na Not applicable These data indicate that the relative bioavailability of darifenacin over the metabolite is increased when darifenacin is administered in a sustained release formulation according to the invention.

4'9 9* 4' a *4' 4'*4'4' 4'* 4' 4'.

4' 4' a 4'*4'4' *e.4' a 4'* 4' 4' a

Claims (17)

1. A rectal formulation adapted for administration to the gastrointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier; characterized in that the formulation is adapted to deliver at least 10% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of the patient.

2. A formulation as claimed in claim 1, which is adapted to deliver at least 50% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract.

3. A formulation as claimed in claim 1 or claim 2, which is adapted to release the ,!arifenacin, or the pharmaceutically acceptable salt thereof, to the gastrointestinal tract of the patient, over or after a sustained period of time wherein no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 4 hours after administration of the dosage form to the patient.

4. A formulation as claimed in claim 3, wherein no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 8 hours after dosing.

5. A formulation as claimed in claim 4, wherein no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released 16 hours after dosing.

6. A rectal formulation adapted for administration to the gastrointestinal tract of a patient, comprising darifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier; characterized in that the formulation is adapted to release the darifenacin, or the pharmaceutically acceptable salt thereof, in Apparatus 1 described in USP XXII at page 1578, having baskets of 40 mesh 3 81,im apertures), a rotation speed of 100 rpm and a dissolution medium of water at 37°C, over a sustained period of time, wherein no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released after 4 hours.

7. A formulation as claimed in claim 6, wherein no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released after 8 hours.

8. A formulation as claimed in claim 6, wherein no more than 90% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, is released after 16 hours.

9. A formulation as claimed in any one of the preceding claims, wherein the darifenacin is in the form of its hydrobromide salt.

A formulation as claimed in any one of claims 1 to 9, which is a suppository.

11. A formulation as claimed in claim 10 wherein the darifenacin or the pharmaceutically acceptable salt thereof, is dispersed in a hardened oil or wax.

12. A process for the preparation of a formulation as defined in claim 11 which comprises dispersing darifenacin or a pharmaceutically acceptable salt thereof, in a hardened oil or wax.

13. A rectal formulation adapted for administration to the gastrointestinal tract of a patient, substantially as hereinbefore described with reference to Example 7.

14. A method of treatment of irritable bowel syndrome or urinary incontinence, which comprises delivering a rectal formulation of darifenacin, or a pharmaceutically acceptable salt thereof, io the lower gastrointestinal tract of a patient in need of such treatment; characterised in that the dosage form is adapted to deliver at least 10% by weight of the darifenacin, or the pharmaceutically acceptable salt thereof, to the lower gastrointestinal tract of the patient.

A rectal formulation according to any one of claims 11 to 13, when used for the treatment of irritable bowel syndrome or urinary incontinence in a patient in need of such treatment.

16. A method as claimed in claim 14, which comprises administering a rectal formulation as defined in any one of claims 1 to 11 or 13 to the gastrointestinal tract of a patient in need of such !reatment. Dated

17 August, 2000 Pfizer Research and Development Company, N.V./S.A Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 9* I,,