NZ613031B2 - Solid molecular dispersion - Google Patents

Abstract

Provided is a solid dispersion comprising 3:97 to 12:88 weight percentage ratio of fesoterodine hydrogen fumarate: an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether or an ester thereof or a mixture of any two or more. Fesoterodine hydrogen fumarate can be stabilised in the dispersion in a form not corresponding to its crystalline or amorphous form. A preferred cellulose ether component is hydroxypropyl methyl cellulose. Further provided is an inert core bead or particle coated with the dispersion, optionally with a modified-release coating on the bead or particle, and a capsule or tablet comprising the beads or particles. The dispersion may be used in the treatment of urinary incontinence. rsion in a form not corresponding to its crystalline or amorphous form. A preferred cellulose ether component is hydroxypropyl methyl cellulose. Further provided is an inert core bead or particle coated with the dispersion, optionally with a modified-release coating on the bead or particle, and a capsule or tablet comprising the beads or particles. The dispersion may be used in the treatment of urinary incontinence.

Description

SOLID MOLECULAR DISPERSION The present invention relates to a solid dispersion comprising from 3:97 to 12:88 weight % ratio of fesoterodine hydrogen fumarate: an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either thereof, or a mixture of any two or more f, in which the fesoterodine hydrogen fumarate is stabilised in the dispersion in a form not corresponding to its crystalline or amorphous form.

The present dispersion achieves comparable or improved al stability in respect of the fesoterodine hydrogen te component to that observed for the commercial xylitol-based tablet ation, in particular by minimising the levels of the two primary degradation products SPM7605 and SPM7675. The present dispersion is believed to achieve this ising effect as it displays the characteristics of a solid lar dispersion.

Preferably, the present invention relates to a solid molecular dispersion comprising from 3:97 to 12:88 weight % ratio of fesoterodine hydrogen fumarate: an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either thereof, or a e of any two or more thereof.

The ion also relates to an inert core bead or particle which is coated with said dispersion, to modified-release coating of such a bead or particle, and to a pharmaceutical capsule formulation comprising such coated beads or les.

The invention further relates to an inert core bead or particle which is coated with said dispersion and to the manufacture of pharmaceutical tablets comprising such beads or particles.

Fesoterodine, that is 2-[(1R)—3-(diisopropylamino)phenylpropyl]—4— (hydroxymethyl)phenyl isobutyrate, R—(+)—2—(3-(diisopropylaminophenylpropyl)- 4-hydroxymethylphenyl isobutyrate or R-(+)-isobutyric acid 2-(3-diisopropylamino- 1-phenylpropyl)-4—hydroxymethylphenyl ester, has the following al structure: Fesoterodine and its physiologically able acid salts are disclosed in W099/58478 for use as antimuscarinic agents that are useful for the treatment of, inter alia, urinary incontinence.

Fesoterodine hydrogen te is disclosed in WOO1/35957A1 and US 685865081 as a preferred crystalline, physiologically compatible, acid addition salt form of rodine.

Fesoterodine per se has only been previously prepared as an unstable oil which presents difficulty for pharmaceutical formulation, processing and use.

Fesoterodine hydrogen fumarate per se is lline and is suitable for pharmaceutical formulation and processing but it requires refrigeration in order to maintain adequate stability on storage for pharmaceutical use.

W02007/141298A1 ses pharmaceutical compositions comprising fesoterodine, or a ceutically acceptable salt thereof, and a pharmaceutically acceptable stabiliser selected from xylitol, sorbitol, polydextrose, isomalt, dextrose, and combinations thereof. Such compositions are suitable for the manufacture of tablets and red tablet compositions bed include those comprising fesoterodine hydrogen fumarate, hydroxypropyl methyl cellulose (HPMC) and xylitol which have shown excellent stability on tablet storage under ambient conditions for over 2 years. Indeed, a tablet composition comprising fesoterodine en fumarate, hydroxypropyl methyl cellulose (HPMC) and xylitol is the drug formulation that is used commercially in view of its acceptable shelf-life. The commercial 4mg dose ation is described in W02007/141298A1 on page 44, Table 1, Example PCT/IBZOIZ/050225 C, and the commercial 8mg dose formulation on page 45, Table 2, Example H.

Studies have shown that the presence of a stabiliser such as xylitol is essential to achieve a ceutically acceptable stability e.

W02010/O43408 describes microencapsulated fesoterodine formulations but does not se formulations containing fesoterodine or a salt thereof, in combination with a ric binder, or a solid molecular dispersion thereof.

There is a need forfurther stable pharmaceutically acceptable formulations comprising fesoterodine hydrogen fumarate. More particularly, there is a need for a further stable formulation comprising fesoterodine hydrogen fumarate that has able, or improved, stability on storage than the current xylitol-based tablet formulation that is sold commercially in which the fesoterodine hydrogen fumarate exists in a crystalline form.

It has now been found that a pharmaceutical formulation comprising a solid dispersion comprising from 3:97 to 12:88 weight % ratio of fesoterodine hydrogen fumarate: an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either thereof, or a mixture of any two or more thereof, in which the fesoterodine hydrogen fumarate is not in crystalline or amorphous form in said dispersion, has comparable or improved stability on storage to the commercial xylitol-based tablet formulation described above. Without g to be bound by theory, it is believed that there exists a solid molecular dispersion of rodine hydrogen te in an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either thereof, or a mixture of any two or more thereof, in said sion.

As such, it has now been found that a pharmaceutical formulation comprising a solid molecular dispersion comprising from 3:97 to 12:88 weight % ratio of fesoterodine en fumarate: an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either thereof, or a mixture of any two or more thereof, has comparable or improved stability on storage to the cial xylitol-based tablet formulation. The observed ity is directly attributable to the solid molecular dispersion present in the formulation. This finding is unexpected in PCT/IBZOIZ/050225 that it has been surprisingly found that fesoterodine hydrogen fumarate can be stabilised in the presence of a polymeric binder (e.g. HPMC) but in the absence of a stabiliser such as xylitol. Such a pharmaceutical formulation is particularly suitable for pment as a modified release, bead-in—capsule formulation of the drug for paediatric use, or for the manufacture of pharmaceutical tablets.

The term “solid sion” refers to a group of solid materials comprising at least two different components, generally a polymeric matrix and a drug. The matrix can be either crystalline or amorphous. The drug molecules can be dispersed throughout the matrix as particles ed of amorphous molecular clusters, or as crystals (highly ordered 3D-molecular arrangement), of the drug. atively, if the drug is sed within the matrix at the molecular level then this is termed a “solid molecular dispersion”. In a solid molecular dispersion the predominant intermolecular interaction is defined as being between each drug molecule and each r molecule, even if the drug les are present as (e.g.) molecular dimers in the solid molecular dispersion. What is essential is that each drug molecule predominantly interacts with a polymeric matrix environment. For a summary of the characteristics of solid sion systems see “Pharmaceutical applications of solid dispersion systems”, Chiou W L, Riegelman S, Journal of Pharmaceutical Sciences (1971), 60(9), 1281—1302.

The present invention relates to a solid molecular dispersion comprising from 3:97 to 12:88 weight % ratio of fesoterodine hydrogen te: an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either f, or a mixture of any two or more thereof.

More ably, the solid molecular dispersion comprises about either a 1:9 or 1:19 weight % ratio of fesoterodine hydrogen te: an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either thereof, or a mixture of any two or more thereof.

Most preferably, the solid molecular dispersion consists essentially of about a 1:9 or 1:19 weight % ratio of fesoterodine hydrogen fumarate: an alkyl PCT/[82012/050225 hydroxyalkylcellulose ether or a yalkylcellulose ether, or an ester of either f, or a mixture of any two or more f.

The alkyl hydroxyalkylcellulose ether or the hydroxyalkylcellulose ether, or an ester of either thereof, that is used as a component of the dispersion is classified as a polymeric binder. A polymeric binder is defined as a ceutically acceptable al consisting of a polymeric material that is generally used to promote adhesion of a drug to itself or to another formulation component, such as the e of an inert core bead or particle. Typical ric binders used in drug layering operations are water soluble to allow application of the mixture of drug and polymeric binder in an aqueous solution, although water insoluble binders can also be used, as appropriate.

The polymeric binder used in the present ion is an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either thereof, or a mixture of any two or more thereof (referred to herein as the “cellulose ether component”) (see Encyclopaedia of Polymer Science and Technology, John Wiley & Sons, Inc, Vol. 5, 507-532, “Cellulose Ethers”(2002) for general information on cellulose ethers).

Examples of an alkyl hydroxyalkylcellulose ether are hydroxypropyl methyl cellulose (HPMC, compendium name = hypromellose, e.g., Methocel E3 or E5 — trade marks), hydroxyethyl methyl cellulose (HEMC) and hydroxybutyl methyl cellulose (HBMC).

Examples of a hydroxyalkylcellulose ether are hydroxyethylcellulose (HEC) and hydroxypropylcellulose (HPC).

An example of an ester of an alkyl hydroxyalkylcellulose ether is hydroxypropyl methyl ose e succinate (H PMCAS) (see Pharmaceutical Research, 26(6), 1419-1431 (2009).

Most preferably, hydroxypropyl methyl cellulose (e.g. Methocel E5 LV — trade mark) is used as the sole cellulose ether component.

The present solid dispersion/solid molecular dispersion may be prepared by first preparing a solution of fesoterodine hydrogen fumarate and the alkyl PCT/IBZOIZ/050225 hydroxyalkylcellulose ether or yalkylcellulose ether, or an ester of either thereof, or a mixture of any two or more thereof, e.g. hydroxypropyl methyl cellulose alone, in a suitable solvent, e.g. water. This on may be applied to inert core beads or particles and then the coated inert core beads or particles dried to form ate-release (IR) beads or particles/granules. Fluid bed coating of the spouted fluid bed type assisted with a draft tube (such as fluid bed Wurster coating) or tumbling fluid bed coating (such as rotary or tangential granulation) can be used for the coating process (see, e.g., Fukumori, Yoshinobu and Ichikawa, Hideki (2006) 'Fluid Bed Processes for Forming Functional Particles', Encyclopedia of Pharmaceutical Technology, 1: 1, 1773— 1778). Preferably, the fluid-bed coating is ted using a fluid-bed coater in Wurster configuration.

Such inert core beads or particles are preferably comprised of a water-soluble or —swellable material and may be any such al that is conventionally used as inert core beads or les or any other pharmaceutically acceptable water—soluble or water-swellable al that can be made into core beads, particles or pellets.

Preferably, the inert core beads or particles are spheres of e/starch (Sugar Spheres NF — trade mark) or sucrose crystals, or are extruded and dried spheres comprised of excipients such as microcrystalline cellulose or lactose. Preferably, the inert core beads or les are comprised of microcrystalline cellulose alone or in combination with one or more sugars, or are comprised of lactose. Yet more preferably, the inert core beads or particles are comprised of microcrystalline cellulose or lactose alone. Most preferably, the inert core beads or particles are Celphere (trade mark — Asahi Kasei) microcrystalline cellulose spheres of CP-507 grade with a 500-710 micron diameter, or lactose, e.g. Pharmatose 110M (trade mark).

The immediate-release (lR) beads or particles/granules obtained may be coated with a modified-release (MR) layer that provides acceptable control of the release rate of rodine in a t.

The modified-release layer may be a sustained-release (SR) coating which is designed to release the drug at a steady rate. The sustained-release coating may be PCT/132012/050225 a polymer coating such as a cellulose ester, a cellulose ether or an acrylic polymer, or a mixture of any f. red coatings include ethyl cellulose, cellulose acetate or cellulose acetate butyrate, or a mixture of any thereof. The coating may be applied as a solution in an organic solvent or as an aqueous dispersion or latex.

The g may be d using a fluid bed coater, a Wurster coater or a rotary bed coater. if desired the permeability of the coating may be adjusted by blending 2 or more of such coating materials. The porosity of the coating may be tailored by adding a pre-determined amount of a finely-divided, water-soluble material, such as a sugar, salt or water-soluble polymer (e.g. hydroxypropyl cellulose, hydroxypropyl methyl cellulose), to a solution or dispersion of the ne-forming polymer to be used. When the dosage form resulting is ingested into the aqueous medium of the -intestinal tract, these water-soluble additives are d out of the membrane, leaving pores which facilitate release of the drug. The membrane g can also be modified by the addition of a plasticiser such as diethyl phthalate, polyethyleneglycol-400, triacetin, triacetin citrate or propylene glycol. Most preferably, the sustained release coating comprises ethyl cellulose (e.g. Ethocel Standard 10 Premium — trade mark) in ation with hydroxypropylcellulose (e.g.

Klucel EF — trade mark) as a pore former.

In a preferred embodiment of the invention, the modified/sustained-release coating is achieved by first preparing a solution of the selected MR/SR components (e.g. ethylcellulose and hydroxypropylcellulose) in a suitable t, e.g. aqueous isopropanol, and, secondly, by applying this solution to the R beads or particles/granules, e.g. using a fluid bed coater as described above (e.g. using a fluid-bed coater in Wurster configuration), and drying the resulting coated beads or particles/granules. The composition and thickness of the MR/SR coating may be varied to achieve the desired drug release e.

The modified-release layer may be a delayed-release coating which is designed, on dosage form ingestion, to incorporate a delay in time before the onset of drug release. The delayed-release coating may be a pH-sensitive polymer such as cellulose acetate phthalate, cellulose acetate litate, hydroxypropyl methyl PCT/IBZOIZ/050225 cellulose phthalate, polyvinyl acetate phthalate, or may be an anionic acrylic copolymer of methacrylic acid and methyl methacrylate such as those available from RohmPharma, e.g. EUDRAGIT L-1OO (trade mark), EUDRAGIT L-30 D-55 (trade mark), EUDRAGIT 8-100 (trade mark) or IT FS 30D (trade mark), or a mixture of any thereof. The thickness and composition of the delayed-release coating may be adjusted to give the desired delayed-release properties. In general, thicker coatings are more resistant to erosion and, consequently, provide a longer delay in the release of the drug, as do coatings which are designed to ve above ph7. l IR and MR layer coating thicknesses used for the purposes of the present invention are as follows: . IR layer — 10-100 micrometres, preferably 25—30 micrometres . MR layer— 10-100 etres, preferably 10-15, 15-20 or 20—25 micrometres.

The IR or MR beads or particles/granules according to the invention may be filled into drug capsules by conventional techniques. Preferably, gelatin or hydroxypropyl methyl cellulose capsules are used for ceutical formulation Alternatively, the immediate-release beads or particles/granules obtained may be formed into pharmaceutical tablet formulations by conventional techniques.

The solid dispersion, the solid molecular dispersion, the lR/MR beads or les/granules coated therewith, and the pharmaceutical formulations of the invention, may be used as medicaments. In particular, they may be used for the treatment of incontinence, preferably urinary incontinence. Most ably, they may used for the treatment of urge urinary incontinence or mixed urinary inence.

The invention also provides a solid molecular dispersion obtainable by (a) achieving a solution of fesoterodine hydrogen fumarate and an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either f, or a mixture of any two or more thereof, in from 3:97 to 12:88 weight % ratio, and (b) by drying to form said dispersion.

DESCRIPTION OF THE FIGURES Figures 1: (a)-(c) Levels of SPM 7675, SPM 7605 and total degradation products in fesoterodine hydrogen fumarate IR beads (90:10, 85:15 & 80:20 weight % hydroxypropyl methylcellulose — Methocel E5 LV (trade mark): fesoterodine hydrogen fumarate) and the cial tablet ation (Xylitol 1 and 2) when stored at 40°C/75%RH.

Figure 2: (a) crystalline rodine hydrogen fumarate;(b) ous fesoterodine hydrogen fumarate; (c) HPMC- hypromellose—Methocel E5LV.

Figure 2a: Fingerprint region of Figure 2.

Figure 2b: Area for assessment from Figures 2 and 2(a).

Figure 3: FTIR (a) crystalline rodine hydrogen te; (b) amorphous fesoterodine hydrogen fumarate; (c) IR layer from IR beads; (d) HPMC - hypromellose-Methocel E5LV.

Figure 3a: FTIR (a) crystalline fesoterodine hydrogen fumarate; (b) amorphous fesoterodine en fumarate; (c) (d) and (e) IR layer from IR beads (three different samples g sample variability); (f) HPMC- hypromellose-Methocel E5LV.

Figure 4: FTIR (a) crystalline fesoterodine hydrogen fumarate; (b) amorphous fesoterodine hydrogen fumarate; (c) IR layer from 10% MR beads; (d) HPMC-hypromellose-Methocel E5LV.

Figure 4a: FTIR (a) crystalline fesoterodine hydrogen fumarate; (b) amorphous fesoterodine hydrogen fumarate; (c) and (d) IR layer from 10% MR beads (two different samples showing sample variability); (e) HPMC- hypromellose-Methocel E5LV.

Figure 5: FTIR (a) crystalline fesoterodine hydrogen fumarate; (b) amorphous fesoterodine hydrogen fumarate; (c) IR layer from 20% MR beads; (d) HPMC-hypromellose-Methocel E5LV.

(Followed by page 9a) -9a- Figure 5a: FTIR (a) crystalline fesoterodine hydrogen te; (b) amorphous fesoterodine hydrogen fumarate; (c) and (d) IR layer from 20% MR beads (two different samples showing sample variability); (e) HPMC- hypromellose-Methocel E5LV.

Figure 6: FTIR (a) crystalline fesoterodine en te; (b) amorphous fesoterodine hydrogen fumarate; (c) HPMC-hypromellose- (Methocel E5LV);(d) Lactose (Pharmatose 110 mesh).

Figure 6a: FTlR Fingerprint region of Figure 6.

Figure 6b: FTlR Area for assessment in Figures 6 and 6a.

Figure 7: FTIR (a) crystalline fesoterodine hydrogen fumarate; (b) amorphous fesoterodine hydrogen fumarate; (c) 1:9 weight % rodine hydrogen fumarate/HPMC on lactose particles; (d) HPMC-hypromellose- (Methocel E5LV); (e) Lactose (Pharmatose 110 mesh).

Figure 7a: FTIR (a) crystalline fesoterodine hydrogen fumarate; (b) amorphous fesoterodine hydrogen fumarate; (c) (d) and (e) 1:9 weight % fesoterodine hydrogen fumarate/HPMC on lactose particles (three different samples showing sample variability); (f) HPMC-hypromellose- (Methocel E5LV); (g) Lactose (Pharmatose 110 mesh).

Figure 8: FTIR (a) crystalline fesoterodine hydrogen fumarate; (b) amorphous fesoterodine hydrogen fumarate; (c) 1:19 weight % rodine hydrogen fumarate/HPMC on e les; (d) HPMC-hypromellose- (Methocel E5LV); (e) Lactose (Pharmatose 110 mesh).

Figure 8a: FTIR (a) crystalline fesoterodine hydrogen fumarate; (b) amorphous fesoterodine hydrogen fumarate; (c) (d) and (e) 1:19 weight % fesoterodine hydrogen fumarate/HPMC on lactose particles (three different samples showing sample ility); (f) HPMC-hypromellose- (Methocel E5LV); (g) Lactose (Pharmatose 110 mesh).

(Followed by page 10) - 10 _ The following Examples illustrate the invention: EXAMPLE 1 Preparation of a solution of fesoterodine en fumarate and HPMC (hypromellose) Fesoterodine hydrogen fumarate 30.069* Hypromellose (Methocel E5 LV) 270.630* Sterile water for irrigation (to be removed 3995.000* in manufacturing process and does not appear in final product) (*quantities based on dry finished product with no e. Can incorporate 10% overage of the quantities of the coating materials to allow for in-process loss due to tubing s, coating of containers, etc.) o Set-up an overhead stirrer and impeller.

. Weigh out 90 % of water into an appropriate sized vessel.

. Set the agitator speed to produce a suitable vortex and lly add the hypromellose to the water and mix for at least 4 hours, preferably overnight, ensuring the solution does not foam. Cover to prevent evaporation while stirring (ensure there are no lumps after stirring).

. Set-up an overhead stirrer and impeller .Weigh out the ing 10% water into an appropriately sized vessel and add fesoterodine en fumarate under agitation. Mix for 10 s or until the fesoterodine hydrogen fumarate is fully dissolved. Cover to prevent evaporation while ng.

. Add the fesoterodine hydrogen fumarate solution to the hypromellose solution under agitation. 2012/050225 . Mix for a m of 10 minutes or until all lumps have dissolved.

- Determine the quantity of liquid lost due to ation. Replace lost liquid with water, rinsing out the fesoterodine hydrogen fumarate solution-containing vessel.

. Ensure that the solution prepared is protected from sunlight at all times.

EXAMPLE 2 Preparation of a solid molecular dispersion of fesoterodine hydrogen fumarate and HPMC h romellose on microc stalline cellulose beads usin Glatt GPCG 1.1 coater (fesoterodine hydrogen te immediate release (IR) beads) 0 Heat Glatt GPCG 1.1 in 6” Wurster configuration to a product temp of ~ 56 °C. 0 Quickly charge the microcrystalline cellulose spheres (500 — 710um) (Celphere CP-507) (699.301 g/kg - quantity based on dry finished t with no overage. Can incorporate 10% overage of the quantity to allow for in- process loss due to tubing volumes, coating of containers, etc.) into the fluidising chamber of the Glatt GPCG 1.1 coater.

. Once the beads are fully fluidised ce spraying within 1 minute.

. Example target coating conditions for the Glatt GPCG 1.1: Airflow: 80 m3/hr (Set) lnlet Air Temperature: 80°C (Set) Atomisation Pressure: 2.0 Bar (Set) Maximum Spray rate: 12 g/min Nozzle er: 1.2mm Wurster Gap: 20mm Filters: Socks (20pm mesh) Filter shake: 15 secs every 5 mins Tubing: Silicon, 0.125” ID x 0.062” wall Pump: Watson Marlow 505Du peristaltic -12_ o Commence spraying at ~7 g/min (3.9 rpm), after 10 minutes increase the spray rate to ~10g/min (5.6 rpm). After an additional 10 minutes ramp up the spray rate to ~12 g/min (6.9 rpm).

. The product temperature during g (at/near maximum spray rate in steady state) should be approximately 50 °C. 0 Continue spraying until all the theoretical quantity of coating on has been sprayed onto the beads.

. Cover the solution to prevent evaporation while coating. 0 After coating, dry the beads by allowing the product temperature to rise by 2 °C before shutting down the fluidisation air & heat.

. The beads should be sieved through an 850 um sieve to screen out erates.

EXAMPLE 3 Preparation of a solid molecular sion of fesoterodine hydrogen fumarate and HPMC h romellose on microc stalline cellulose beads usin Glatt GPCG 3.1 coater (fesoterodine hydrogen fumarate immediate release (lR) beads) 0 Heat Glatt GPCG 3.1 in 6" Wurster configuration to a product temp of ~ 56 °C.

- Quickly charge the rystalline cellulose spheres (500 — 710pm) (Ceiphere CP-507) (699.301 g/kg — quantity based on dry finished product with no overage. Can incorporate 10% e of the quantity to allow for in- process loss due to tubing volumes, coating of containers, etc.) into the sing chamber of Glatt GPCG 3.1 coater.

. Example target coating conditions for the Glatt GPCG 3.1: Airflow: 50 CFM Inlet Air Temperature: 75 °C (Set) Atomisation Pressure: 2.0 Bar (Set) Maximum Spray rate: ~13.5 g/min WO 98499 Inlet Air Dew Point: 15 °C Nozzle diameter: 1.2 mm Wurster Gap/Partition Height: 30 mm Filters: Socks (20pm mesh) Filter shake: 15 secs every 5 mins : Silicon, 0.125” ID x 0.062” wall Pump: Peristaltic . Commence spraying at ~8 g/min, after 10 minutes increase the spray rate to ~10g/min. After an additional 10 minutes ramp up the spray rate to ~12 g/min.

. After 1 hour the spray rate can be increased to ~13.5 g/min if the s appears stable with low agglomeration levels.

. The product temperature during coating (at/near m spray rate in steady state) should be approximately 50 °C.

. Continue spraying until all the theoretical quantity of coating solution has been sprayed onto the beads. 0 Cover the solution to prevent evaporation while coating. 0 After g, dry the beads by allowing the product ature to rise by 2 °C before shutting down the fluidisation air & heat.

. The beads should be sieved through an 850 pm (20 Mesh) sieve to screen out agglomerates.

EXAMPLE 4 Preparation of 10% (w/w of final bead) modified release (MR) fesoterodine hydrogen fumarate beads Component Quantity/u nit: (glkg) (Quantities based on dry finished product and do not include overages) Fesoterodine hydrogen fumarate 900.000 immediate release (IR) beads (Example PCT/IBZOIZ/050225 2 or Example 3) Ethylcellulose (Ethocel rd 10 80.000 Premium) ypropylcellulose (Klucel EF) 20 000 Isopropyl alcohol (to be removed in 1327.474 manufacturing process and does not appear in final product) Sterile water for irrigation (to be removed 181019 in manufacturing process and does not appear in final product) TOTAL 1000.000 (a) Modified release on preparation . Calculate MR on components with 10% overage (all components except fesoterodine hydrogen fumarate immediate release beads).

Overall Overall Ethylcellulose Hydroxypropylcellulose solution - solution solution solution theoretical — 10% overage Total Half total - Half water - . Set-up an overhead stirrer and impeller.

ZOIZ/050225 o Weigh out the required quantity of isopropyl alcohol and 50% of the water into an riate sized vessel.

. Set the agitator speed to produce a suitable vortex and gradually add the ellulose to the water and mix for at least 4 hours, ensuring the mixture does not foam. 0 Cover to prevent evaporation while stirring (ensure there are no lumps once stirring has finished).

. Set-up an overhead stirrer and impeller.

. Weigh out the remaining quantity of isopropyl l and 50% of the water into an appropriate sized vessel. 0 Set the agitator speed to produce a suitable vortex and gradually add the hydroxypropylcellulose to the water and mix for at least 4 hours.

. Cover to prevent evaporation while stirring.

. Add the hydroxypropylcellulose solution to the ethylcellulose solution under agitation. Mix for 10 minutes.

. Determine the quantity of liquid lost due to evaporation. Replace lost liquid with an isopropyl alcohol /water ) solution, rinsing out the ypropylcellulose-containing , and mix for 10 mins.

. Cover to prevent evaporation. (b) g of IR beads with modified release layer coating using Glatt GPCG 1.1 fluid bed coater . Heat Glatt GPCG 1.1 in 6” Wurster configuration to a product temperature of ~ 40 °C.

- Quickly charge the fesoterodine hydrogen fumarate immediate release beads into the fluidising chamber of the Glatt GPCG 1.1 fluid bed coater.

. Pre-heat the spheres to ~ 46°C.

. Coat the spheres with the modified release solution (Step (a)) under the following target conditions: -16— Airflow: 80 m3/hr (Set) lnlet Air Temperature: 50°C (Set) Atomisation Pressure: 2.0 Bar (Set) Maximum Spray rate: 13.5 g/min Nozzle diameter: 1.2mm Wurster Gap: 20mm Filters: Bonnets (0.4 mm mesh) Filter shake: 15 secs every 5 mins Tubing: Silicon, 0.125” [D x 0.062” wall Pump: Watson Marlow 505Du peristaltic ce spraying at ~ 9.5 g/min (approximately 6 rpm), after 5 s increase the spray rate to ~11.5g/min ximately 7 rpm). After an additional 5 minutes ramp up the spray rate to ~13.5 g/min (approximately 8 rpm).

The pump rate can be adjusted as necessary to achieve the required spray rates.

The product temperature during g (at/near maximum spray rate in steady state) should be approximately 39 °C.

Continue spraying until all the theoretical ty of modified release solution has been sprayed onto the beads.

Cover the solution to prevent evaporation during spraying.

After coating, dry the beads by allowing the product temperature to rise by 2 °C before shutting down the fluidisation air & heat.

The beads should be sieved through a 1000 um sieve (or US Standard 18 Mesh) to screen out agglomerates. (c) Coating of IR beads with modified release layer coating using Glatt GPCG 3.1 fluid bed coater PCT/[32012/050225 Heat Glatt GPCG 3.1 in 6” Wurster uration to a product temperature of ~ 40 °C Quickly charge the fesoterodine hydrogen fumarate immediate release beads into the fluidising chamber of the Glatt GPCG 3.1 fluid bed coater.

Coat the spheres with the modified release solution (Step (a)) under the following target conditions: Airflow: 50 CFM Inlet Air Temperature: 50 °C (Set) Atomisation Pressure: 2.0 Bar (Set) Maximum Spray rate: 16 g/min Inlet Air Dew Point: 15 °C Nozzle diameter: 1.2 mm Wurster Gap/Partition height: 30 mm Filters: Bonnets (0.4 mm mesh) Filter shake: 15 secs every 5 mins Tubing: Silicon, 0.125” ID x 0.062” wall Pump: Peristaltic Commence spraying at ~ 11.0 g/min, after 5 s increase the spray rate to ~14.0 g/min. After an additional 5 minutes ramp up the spray rate to ~16.0 g/min.

The t temperature during g (at/near maximum spray rate in steady state) should be approximately 39 °C.

Continue spraying until all the theoretical quantity of coating solution has been sprayed onto the beads.

Cover the on to prevent evaporation during spraying.

After coating, dry the beads by allowing the product temperature to rise by 2 °C before ng down the fluidisation air & heat.

The beads should be sieved through a 1000 pm sieve (or US Standard 18 Mesh) to screen out agglomerates. _ 13 _ EXAMPLE 5 Preparation of 15% (w/w of final bead) modified release (MR) fesoterodine hydrogen fumarate beads These are prepared by a similar process to that of Example 4 using the following components.

Component Quantity/unit: (glkg) (Quantities based on dry finished product and does not include overages) Fesoterodine hydrogen fumarate 0 immediate release (IR) beads (Example 2 or Example 3) Ethylcellulose (Ethocel Standard 10 0 Premium) Hydroxypropylcellulose (Klucel EF) 30.000 lsopropyl alcohol (to be dIn 1991 2.11 cturing process and does not appear in final product) Sterile water for irrigation (to be removed 271.529 in manufacturing process and does not appear in final product) TOTAL 1000.000 EXAMPLE 6 Preparation of 20% (w/w of final bead) modified release (MR) rodine hydrogen fumarate beads PCT/[82012/050225 These are prepared by a similar process to that of Example 4 using the ing components.

Component Quantity/unit: (glkg) (Quantities based on dry finished product and does not include overages) Fesoterodine hydrogen fumarate 800.000 immediate release (IR) beads (Example 2 or Example 3) Ethyl cellulose el Standard 10 160.000 Premium) Hydroxypropylcellulose(Klucel EF) 40.000 lsopropyl alcohol (to be removedin 2654.942 manufacturing process and does not appear in final t) Sterile water for irrigation (to be removed 362.038 in cturing process and does not appear in final product) TOTAL 1000.000 Preparation of capsules containing modified release fesoterodine hydrogen fumarate beads . Charge beads into a suitable encapsulator (e.g. Bosch GKF 400) . Charge suitable capsules into the encapsulator (e.g., gelatine size 3) PCT/1B2012/050225 o Encapsulate the beads by filling an appropriate amount of MR beads into each e using the bead filling station of the encapsulator and ensuring the capsules are closed properly . Clean or polish the capsules as appropriate using a standard capsule polisher -21_ EXAMPLE 8 Chemical stabiliy studies for IR beads coated with a solid molecular dispersion of fesoterodine hydrogen fumarate and ellose (hydroxypropyl methylcellulose — Methocel E5 LV (trade mark)) Solutions of 90:10, 85:15 and 80:20 weight % hydroxypropyl methylcellulose — Methocel E5 LV (trade mark): fesoterodine hydrogen fumarate (equivalent to 1:9, 1:57 and 1:4 weight % fesoterodine hydrogen fumarate : hydroxypropyl methylcellulose — Methocel E5 LV (trade mark), respectively) were prepared and coated onto microcrystalline cellulose (MCC) beads at potencies of approximately 3.0, 3.6 and 4.2% weight% (based on final lR bead) in the following manner.

Solution Preparation and Coating Process Conditions All solutions were prepared in the same manner following a dedicated solution preparation sheet by a similar method to that of Example 1. A hydroxypropyl cellulose — Methocel E5 LV (trade mark) and water solution was ed at least 4 hours in advance of coating (normally the afternoon prior to commencement of coating), with the fesoterodine hydrogen te portion of the solution in water being prepared on the day of coating then mixed with the hydroxypropyl methylcellulose — el E5 LV (trade mark) solution, prior to g. The coating conditions are summarised in Table 1.

Table 1. Coating Conditions Eouipment Parameter: kg startino batch scale Fluidised bed e uiment Iatt GPCG 1.1 t container er inch chlick, 970 series, form 84 Liouid insert diameter mm A 2 ——E0 Fixed arameters: — . Start at ~8g/min & Spray rate acceleration ramp up at 10 minute intervals Atomisino air oressure Bar .

Stabilig Studies In order to assess the al stability of the fesoterodine hydrogen fumarate IR beads red as above at ratios of 90:10, 85:15 and 80:20 weight % hydroxypropyl methylcellulose — Methocel E5 LV (trade mark): fesoterodine en fumarate) batches of each were subdivided into approximately 59 lots, transferred to 600C HDPE (high density polyethylene) bottles and then stored at the accelerated storage conditions of 40°C/75%RH (RH=re|ative humidity). s were withdrawn after 4, 8 and 12 weeks storage and analysed by HPLC (using similar conditions to those shown in Table 2 with the difference that 75 microlitre injection volumes were used) with focus on the two key degradation products SPM 7675 and SPM 7605 (the chemical structures of which are shown below) and the total level of ation products observed.

SPM 7675 SPM 7605 Summary plots showing the levels of SPM 7675, SPM 7605 and the total ation products observed in the IR beads , 85:15 and 80:20 weight % hydroxypropyl methylcellulose — Methocel E5 LV (trade mark): fesoterodine en fumarate) when stored at 40°C/75%RH are shown in Figures 1(a)—(c).

For comparative purposes, Figures 1 (a)—(c) also include data on the levels of SPM 7675, SPM 7605 and total degradation products present in the fesoterodine hydrogen fumarate commercial xylitol-based tablet formulation (Xylitol 1* and Xylitol 2**) stored under similar accelerated stability conditions.

In summary, it can be seen that the fesoterodine hydrogen fumarate IR beads prepared with a ratio of 90:10 weight % ypropyl methylcellulose — Methocel E5 LV (trade mark): fesoterodine hydrogen fumarate have a comparable chemical stability to the cial xylitol tablet formulation.

(*Xylitol 1 — sample of 4mg fesoterodine commercial tablets (see W02007/141298A1 on page 44, Table 1, Example C) packaged in blisters in accordance with European Union regulatory requirements . The ing material is a laminated aluminium foil, mouldable for bottoms of push—through packages. The composite film consists of the following materials: - Oriented polyamide (oPA), ess of about 25 um - Aluminium, thickness of about 45 pm - PVC, thickness of about 60 um) (**Xy|itol 2 — sample of 4mg fesoterodine commercial tablets (see W02007/141298A1 on page 44, Table 1, Example C) from a package ning 90 tablets per bottle each with a desiccant canister filled with 3 g of silica gel. ) PCT/lBZOlZ/050225 EXAMPLE 9 Chemical stability and dissolution s for IR beads coated with a solid molecular dispersion of 1:9 weight% fesoterodine hydrogen fumaratezhypromellose h drox ro l meth Icellulose — Methocel E5 LV — trade mark and for sustained release (SR, i.e. MR) coated bead formulations thereof Process Description — Immediate Release (IR) Beads These were prepared by a similar process to that described in Example 2.

Process Description — 10% and 20% Sustained Release (SR) Beads These were prepared by a similar process to that described in Example 4 and 6, respectively, using a Glatt GPCG 1.1 fluid bed coater.

Stability Studies for fesoterodine hydrogen fumarate Immediate Release (IR) and Sustained e (SR) beads Stability s were ted on both fesoterodine en fumarate IR beads and fesoterodine hydrogen fumarate SR beads (10% and 20% w/w of final bead).

Fesoterodine hydrogen fumarate IR and SR beads (10% and 20% SR coat) were packaged in sealed double polyethylene bags with desiccant in between liners inside a fibreboard drum and stored at 5°C, 25°C / 60% relative humidity (RH) and °C / 75% RH.

Visual appearance, chemical stability (degradation products by HPLC) and dissolution were tested initially, after 3 and 6 months e at 5°C, and after 6 weeks and 3 months storage at 25°C / 60% RH and 30°C / 75% RH. -25_ Analytical Methods (a) Degradation Products by HPLC The method for the determination of the degradation products of fesoterodine hydrogen fumarate IR and SR beads was a reversed-phase HPLC method with conditions as described in Table 2. fication was accomplished by comparing retention times of the impurity markers and s. Quantification of specified and unspecified degradation products was achieved by the comparison of peak area response in a test sample with that of an al standard solution. Total degradation products is the sum of all specified and unspecified degradation products by HPLC, excluding Process d Impurities, present above the reporting threshold of 0.05%.

Table 2. Chromatographic Conditions Mobile gohase A (MPA) 0.1 % trifluoroacetic acid aq) Mobile phase B (MPB 0.1% trifluoroacetic acid (far UV Acetonitrile UV absorbance at 220nm Injection s REF MIX TEST Column temperature Auto samoler tem-erature_5°C Flow Rate 1. n Mode mum-n19-1 MPA (% MPB % Column Stationary Phase Spheribond CN 5 pm or Waters Spherisorb CN 5 pm or equivalent (b) Dissolution The rate of dissolution of fesoterodine hydrogen fumarate IR and SR beads is determined using a rotating paddle procedure (USP Apparatus 2) in 900 mL of USP ~26- ate buffer dissolution medium. The amount of fesoterodine hydrogen fumarate dissolved in the dissolution medium is ined by a reversed-phase HPLC method with conditions as described in Table 3.

Table 3. Chromatographic Conditions Mobile phase A (MPA) Potassium phosphate buffer @ pH ~6.5 + 5% far UV acetonitrile Elution Mode tic MPA % MF’B % Water XBridge C18 5 pm or equivalent Results Stability data for rodine hydrogen fumarate IR beads are presented in Tables 4 to 6, for fesoterodine fumarate SR beads (10% SR coat) in Tables 7 to 9, and for fesoterodine fumarate SR beads (20% SR coat) in Tables 10 to 12.

The immediate e (IR) beads coated with a solid molecular dispersion of 1:9 weight% fesoterodine hydrogen fumaratezhypromellose (hydroxypropyl methyl cellulose — Methocel E5 LV— trade mark) showed no significant increase in the levels of degradation products after 6 months storage at 5°C and only small and acceptable increases after 3 months storage at 25°C / 60% RH and 30°C / 75% RH.

Similarly, the sustained release (SR) beads (at both 10 and 20% SR coating levels) showed no significant increase in the levels of degradation products after 6 months storage at 5°C and only small and able increases after 3 months storage at 25°C / 60% RH and 30°C / 75% RH.

PCT/[82012/050225 Dissolution es of both the IR and SR beads were satisfactory at all storage conditions.

Table 4. Stability of fesoterodine hydrogen fumarate IR Beads stored at 5°C _——m_ Off white free flowing beads. No evidence of visible foreion matter or contamination. Test Test —_—_ -———— Dissolution __-—_ NT 1 1 1 1 12 Table 5. Stability of fesoterodine hydrogen te IR Beads stored at °CI60%RH Off white free flowing beads. No evidence Meets Test Meets Test Test 1.4% a 0.71% Dissolution _-—— ———-z_ —_—m_ “—12- Table 6. Stability of rodine hydrogen fumarate IR Beads stored at °C/75%RH ———m_ Off white free flowing beads. No evidence of visible foreign matter or contamination. Test Test _—_— 0.1 .

SPM 7675 0.19% 0.12% 0.29% Recort Result Time Point minutes _— _-§_ PCT/IBZOlZ/050225 —__—__ Table 7. Stability of fesoterodine hydrogen te SR Beads (10% SR Coat) stored at 5°C “_mm fiAcceptance criteria —m_ Appearance Off white free flowing beads. No evidence Meets Test Meets Meets of visible foreign matter or contamination. Test Test Deradation Products ——— SPM 7605 0.11% 0.13% 0 1 SPM 7675 0.21% 0.14% 0.16% 0.60% 0.69% Dissolution Report Result Time Point hours) ——— —__-l- —_-E- —m-_82_77 Table 8. Stability of fesoterodine en fumarate SR Beads (10% SR Coat) stored at 0%RH Acceptance Criteria i Off white free g beads. No evidence of visible forei-n matter or contamination. Test ———— Dissolution —-—_- Table 9. Stability of fesoterodine hydrogen fumarate SR Beads (10% SR Coat) stored at 30°Cl75%RH Timepoint— eweeks smonths Test % Appearance Off white free flowing beads. No evidence of vistble foreign matter or contamination. Test Test _-—_ -_—__—SPM7675 0.21% 0.16% 0.30% 090% W0 2012/098499 PCT/[32012/050225 Dissolution Report Result Time Point hours) __— Table 10. ity of fesoterodine hydrogen fumarate SR Beads (20% SR Coat) stored at 5°C ———Efi_ Off white free g beads. No evidence of visible foreion matter or contamination. Test Test ———— Dissolution -_-—_— —-__3—4 —““_ Table 11. Stability of fesoterodine hydrogen fumarate SR Beads (20% SR Coat) stored at 25°CI60%RH —_—II6 weeks 3 months Acceptance Criteria i of visible foreign matter or contamination. Test Test ———_ Dissolution __-—__ —__-_ —‘-_13.2- PCT/IBZOIZ/050225 Table 12. Stability of fesoterodine hydrogen fumarate SR Beads (20% SR Coat) stored at 30°CI75%RH ————_m Aceptance Critea —3sm_ Appearance Off white free flowing beads. No evidence Meets Test Meets Meets of e forei an matter or contamination. Test Test Degradation Products ——— Dissolution -—-—__ —-__7—3 —-__“ NT= Not tested a) lsopropyl l (IPA) used in the sample dilution solvent was found to enhance the level of an uns-ecified impurity. IPA was re-laced by methanol as the dilution solvent from the 3M time ' PCT/[32012/050225 EXAMPLE 10 Preparation of s containing a solid molecular dispersion of 1:19 or 1:9 weight % fesoterodine hydrogen fumarate: HPMC (hygromellose) on lactose particles using a Glatt GPCG 1.1 coater a) Preparation of a solution of fesoterodine hydrogen fumarate and HPMC (hygromellose) —1:9 Formulation 1:19 Formulation Quantity per tablet (mg) Quantity per tablet (mg) Fesoterodine hydrogen fumarate Lactose atose 65.853 65.853 1 10M) (*quantities based on dry ed product with no overage. Can incorporate 10% overage of the quantities of the coating materials to allow for in-process loss due to tubing volumes, coating of containers, etc.) . Calculate amounts of materials to use based on a 3009 starting charge of e in the coater.

. Set-up an overhead stirrer and er.

. Weigh out 50 % of water into an appropriate sized vessel. 0 Dissolve fesoterodine hydrogen fumarate in water a Mix remainder of water with isopropanol (IPA) 2012/050225 . Set the agitator speed to produce a suitable vortex and gradually add the HPMC to the IPA/water and mix for a suitable time ensuring that the solution does not foam. Cover to prevent evaporation while stirring (ensure there are no lumps after stirring).

. Add the remaining water/API solution to the HPMC on with agitation b) Preparation of a solid molecular dispersion of fesoterodine hydrogen fumarate and hypromellose on lactose powder using Glatt GPCG 1.1 coater . Heat Glatt GPCG 1.1 in 6” Wurster configuration to a product temp of ~ 30 °C.

. Charge the lactose powder (300 g) into the coater . Once the powder is fully fluidised commence spraying within 1 minute.

. The product temperature during g (at/near maximum spray rate in steady state) should be approximately 30 °C. 0 Continue spraying until all the theoretical quantity of coating solution has been sprayed onto the . 0 Cover the solution to prevent evaporation while coating. 0 After coating, dry the granules by ng the product temperature to rise by 2°C before shutting down the fluidisation air & heat. 0) Preparation of tablets containing the granules from step (b) —1:9Formulation 1:19 Formulation ty per tablet (mg) Quantity per tablet (mg) rodine Granules 145.853 225.853 Hypromellose (Methocel 78.137 120.995 K100M) Glyceryl Behenate 6.512 10.084 Com oritol 888 PCT/IBZOlZ/050225 . Blend fesoterodine granules and hypromellose in a suitable blender. 0 Add Compritol and talc to the r and blend.

. Compress tablets using a suitable tablet press and appropriately sized tooling.

EXAMPLE 11 Determination of the comparative chemical stabiliy of samples of fesoterodine hydrogen fumarate with HPMC and other polymeric binders on lactose particles a) Sample preparation The 1:19 and 1:9 HPMC samples were prepared as described in Example 10, steps (a) and (b).

The non-HPMC samples were prepared by a r method to that described in e 10, steps (a) and (b), using the specified non-HPMC polymeric binder. All non-HPMC samples contained 1:9 weight % of fesoterodine hydrogen fumarate: polymeric binder. b) iy data The analytical methodology employed for the determination of the degradation products SPM-7605 and SPM 7675 (see al structures in Example 8) in s of fesoterodine hydrogen fumarate and HPMC/other polymeric binder on lactose was similar to that described in Example 9 with minor modifications to the HPLC conditions as described in Table 13. 0.1 % trifluoroacetic acid a ueous 0.1% trifluoroacetic acid far UV acetonitrile UV ance at 220nm Test _ 1-2 mL/min 45 minutes Elution Mode Gradient MPA % 12 week chemical ity data were ted on the samples after storage at 4OC/75% RH under closed conditions using induction sealed HDPE bottles and using a 1g desiccant cartridge. The results obtained are summarised in Table 14.

TABLE 14: Polymeric binder used in sample“2 (on lactose particles) Eudragit L Eudragit NE 30D Eudragit RS 30D WO 98499 PCT/132012/050225 Eudragit RS PO HPMC (1:19) 0.18 98.36 ' 8 Xylitol (reference)3 .37 0.51 92.77 1 All formulations were in a 1:9 wt % ratio of fesoterodine hydrogen fumaratezpolymeric binder except where noted 2 See Table for specific details of the polymeric binders used. 3 1:9 weight % of fesoterodine hydrogen fumaratezxylitol.

TABLE 15: Eudragit NE 30D 30% PCT/[32012/050225 ‘ mmonio Methacrylate Evonik Copolymer Dispersion ype B ‘ mmonio Methacrylate Evonik Eudragit RS PO Copolymer Type B NF it RS PO HPMC (119) Hypromellose USP Methocel E5 -9) Hypromellose USP Methocel E5 Polyvinyl acetate DJ>U) 'TI nyl e/ on>(I) '11 _——UJCI) 'l'l letol ylitol USP ylisorb 90IiRoquette 0) Results It is clearly evident from Table 14 that of the polymeric binder samples analysed, only fesoterodine and HPMC samples (in ratios of either 1:19 or 1:9 wt. %) provided acceptable chemical stability as judged by the levels observed for the key SPM 7605and SPM 7675 degradants when the samples as described were stored for 12weeks at 40°C/75% R.H.

EXAMPLE 12 PCT/132012/050225 Comparative chemical stabiliy of s containing solid molecular dispersions of 1:19 or 1:9 weight % fesoterodine hydrogen fumarate: HPMC (hypromellose) on lactose particles versus the commercial xylitoI-based tablet a) Sample preparation The tablets containing the 1:19 and 1:9 HPMC dispersions on lactose were ed as described in Example 10, steps (a), (b) and (c) b) Stabiliy data The analytical methodology ed for the determination of the degradation products 5 and SPM7675 (see chemical structures in Example 8) in samples of fesoterodine en fumarate in HPMC dispersions on lactose was similar to that described in Example 9 with minor modifications to the HPLC conditions as described in Table 16.

Table 16: Mobile chase A MPA .1 % trifluoroacetic acid a.

Mobile phase B (MPB .1% trifluoroacetic acid far UV Acetonitrile) V ence at 220nm In'ection Volume EST 75 uL Column temperature Auto sampler temerature 403 Flow Rate AA5 s Elution Mode Gradient Column Stationary Phase Spheribond CN 5 pm or Waters Spherisorb CN 5 pm or eouivalent The comparative stability of tablets containing 1:19 or 1:9 HPMC dispersions on lactose versus the commercial xylitol-based tablet (8mg strength) was assessed by PCT/132012/050225 storage of samples for 10 days at the purposefully selected, stressed (high temperature), storage conditions of 60°C/30% RH, 50°C/50%RH and 50°C/30%RH.

The results are summarised in Tables 17, 18 and 19.

Table 17. Stability of fesoterodine hydrogen fumarate cial xylitol-based 8mg tablets stored at stressed conditions —'__— ________,_ Degradation 7605 % 7675 %_- T_ta|%__--— Table 18. ity of tablets containing 1:9 wt % fesoterodine en fumarate:HPMC on lactose particles stored at stressed conditions _69°C/3Q°H 0H 7,30%R Degradation Products SPM 0.22 122145 2.37 1.48 SPM 0.26 0.29 0.29_ 7675 % Total % 23 4.3 4.3 Table 19. Stability of tablets containing 1:19 wt % fesoterodine hydrogen fumarate:HPMC on lactose particles stored at stressed conditions —__60°C/30%RH 50°C/50%RH 0%RH Degradation Products —__-_Od 7605% _m-- 7675% _otal%_4%__—_— it is clearly evident from Tables 17, 18 and 19 that the levels of SPM 7605 and SPM 7675 in s containing 1:9 or 1:19 wt % fesoterodine en fumarate:HPMC on lactose particles were less than levels observed for the commercial xylitol-based tablet under all three storage conditions used.

PCT/[32012/050225 ANALYSIS 1. Analysis of IR layer of IR and MR beads comprising a solid molecular dispersion of fesoterodine hydrogen fumarate and HPMC mellosel on microcrystalline cellulose beads by Fourier Transform Infrared (FTIRI spectroscopy IR and MR bead sample ation (a) IR beads (see Examples 2 and 3) The beads were cut in half with a scalpel after which the IR layer was peeled off using a scalpel and tweezers. The peeled off IR layers were lightly pressed down onto a glass slide with a glass cover slip, after which they were transferred to the Attenuated Total Reflection (ATR) window for analysis. IR layers of five or six half beads were used for the collection of one spectrum. (b) MR beads (see Examples 4 and 6) The beads were cut in half with a l after» which the MR layer was peeled off using a scalpel and tweezers. Then the IR layer was peeled off. The peeled off IR layers were lightly pressed down onto a glass slide with a glass cover slip, after which they were transferred to the ATR window for analysis. For the 20% MR coated beads (see Example 6), IR layers of one or two half beads were used for the collection of one spectrum. For the 10% MR coated beads (see Example 4), IR layers of five half beads were used for the tion of one spectrum.

Cmstalline fesoterodine hydrogen fumarate reference This was obtained by the method bed in US6858650B1, Preparation 6.

Preparation of amorphous fesoterodine hydrogen fumarate reference PCT/132012/050225 Crystalline fesoterodine hydrogen fumarate (see above) was cryogenically ball milled using a Retsch MM301 mill and 1.5mL Retsch stainless steel mill chamber and ball. Each milling session lasted 10 minutes and the mill speed was set at 30Hz.

The mill chamber with sample inside was cooled in liquid nitrogen for 5 minutes before milling, and between each subsequent milling session. The sample was milled for 50 s in total, after which a PXRD pattern was collected to confirm that the sample was amorphous fesoterodine hydrogen fumarate.

FTIR The infrared spectra were acquired using a ThermoNicolet Nexus FTIR spectrometer equipped with a ‘DurasampllR’ single reflection ATR accessory (diamond surface on zinc selenide substrate) and d-TGS KBr detector. The spectra were collected at 2cm"1 resolution and a co-addition of 512 scans. enzel apodization was used. Using ATR FTIR will cause the relative intensities of infrared bands to differ from those seen in a transmission FTIR um using KBr disc or nujol mull sample preparations. Due to the nature of ATR FTIR, the bands at lower wavenumber are more intense than those at higher wavenumber.

FTIR data treatment Spectra were transferred into ance units within the ThermoNicolet Omnic 6.1a Results Figures 2-5a inclusive show the FTIR ATR spectra obtained for . crystalline fesoterodine hydrogen fumarate . ous fesoterodine en fumarate 2012/050225 0 IR layer of IR beads comprising a solid molecular dispersion of fesoterodine hydrogen fumarate and hypromellose (see Example 2 or 3) . IR layer of 10% MR beads comprising a solid molecular dispersion of fesoterodine hydrogen fumarate and hypromellose (see Example 4) . IR layer of 20% MR beads comprising a solid molecular dispersion of fesoterodine hydrogen fumarate and hypromellose (see e 6) The results show that . when assessing infrared peak frequency positions and intensities obtained by analysis of the IR layers of IR and MR beads, there are peaks that overlap with the peaks seen for amorphous fesoterodine fumarate as well as those seen for crystalline fesoterodine hydrogen fumarate, and there are peaks with different frequency ons and intensities that can be used to characterise the IR layers of IR and MR beads, amorphous fesoterodine fumarate and crystalline fesoterodine hydrogen fumarate. . in the spectra obtained from the samples of the IR layers of IR and MR beads, the absence of some of the more intense, characteristic peaks ed in the spectra obtained from samples of lline fesoterodine hydrogen fumarate and amorphous fesoterodine hydrogen fumarate. . there are obvious changes in relative intensities of peaks in the spectra obtained from the samples of the IR layers of IR and MR beads in ison to the peaks in the spectra obtained from samples of crystalline fesoterodine hydrogen fumarate and amorphous fesoterodine hydrogen fumarate. t being bound by theory, it is believed that these changes in peak frequency on and intensity observed show that there is a clear interaction of fesoterodine hydrogen te with the HPMC polymeric binder in the IR layers of IR and MR beads. These effects are similar to those described by Konno and Taylor, J.Pharm.Sci (2006) 95, 12, 705. These s are believed to be caused by the presence of a solid molecular dispersion of rodine hydrogen fumarate in the HPMC polymeric binder in the IR layers of the IR and MR beads analysed. In other words it is believed that neither amorphous molecular clusters, nor crystals, of fesoterodine hydrogen fumarate in the HPMC polymeric binder could be detected in the IR layers of the IR and MR beads analysed. 2. Analysis of IR granules comprising a solid molecular sion o_f fesoterodine hydrogen fumarate and HPMC (hypromellose) on lactose particles by Fourier Transform Infrared (FTIR) spectroscopy The IR granules were prepared as described in Examples 10a and 10b.

Sample ation No sample ation was performed. The sample was placed onto the ATR crystal and pressure was applied.

FTIR The ed spectra were acquired using a ThermoNicolet Nexus FTIR spectrometer equipped with a ‘DurasampllR’ single reflection ATR (attenuated total reflection) accessory (diamond surface on zinc selenide substrate) and d-TGS KBr detector. The reference spectra for crystalline and amorphous fesoterodine hydrogen te, HPMC (Methocel E5LV) and lactose (Pharmatose — trade mark) were collected using the ing experimental settings: Sample Resolution (cm‘ ) Crystalline fesoterodine hydrogen fumarate ——128 Amorphous fesoterodine hydrogen fumarate ——256 HPMC (Methocel E5LV) _128 PCT/IBZOlZ/050225 Lactose (Pharmatose 110 mesh) For the sample containing a solid molecular dispersion of 1:9 weight % fesoterodine hydrogen fumarate/HPMC on lactose particles the spectra were collected at 4cm'1 resolution and a co-addition of 512 scans.

For the sample containing a solid molecular dispersion of 1:19 weight % fesoterodine hydrogen fumarate/HPMC on lactose particles the a were collected at 8cm'1 resolution and a co-addition of 512 scans.

Happ—Genzel apodization was used. Using ATR FT—IR will cause the relative intensities of ed bands to differ from those seen in a transmission FT—IR spectrum using KBr disc or nujol mull sample preparations. Due to the nature of ATR FT-IR, the bands at lower wavenumber are more intense than those at higher wavenumber.

The FTIR spectra ed are shown In Figures 6, 6a, 6b, 7, 7a, 8 and 8a.

FTIR data treatment Spectra were transferred into absorbance units within Nicolet Omnic 6.1a software and saved as .spc files. The spectra were then opened in Grams/Al 8.0 where a peak fit was performed using 4 peaks in the region 17920m'1 to 1521cm' 1, using a mixture of an/Lorentzian peak shape and 50 iterations for the fit.

Evidence for the presence of a solid lar dispersion rather than a physical mixture of amorphous or cmstalline domains in a .

When assessing ed peak positions for the samples containing a solid dispersion of fesoterodine hydrogen fumarate/HPMC on lactose particles there are peaks that overlap with those for amorphous fesoterodine hydrogen fumarate as well as those for crystalline fesoterodine hydrogen fumarate.

However, the absence of some of the more intense, characteristic peaks seen for the amorphous and crystalline rodine hydrogen fumarate samples in the spectra for the fesoterodine hydrogen fumarate/HPMC on lactose particle samples analysed, as well as the obvious changes in relative intensities and shifts compared to the amorphous and crystalline fesoterodine hydrogen fumarate samples, allows a conclusion that there is a clear interaction of the fesoterodine hydrogen fumarate with the HPMC matrix in the fesoterodine hydrogen fumarate/HPMC on lactose particle samples. This ction causes typical shifts in the infrared frequencies of certain onal groups, as described in the literature by Konno and Taylor, J.Pharm.Sci, 95, 12, 705 (2006).

Therefore we can conclude that rodine hydrogen te is present in the fesoterodine hydrogen fumarate/HPMC on lactose particle samples as a solid lar dispersion. 3. Analysis of IR granules sing fesoterodine hydrogen fumarate and either PVA or methyl methacmlate (Eudragit) on lactose particles by Fourier Transform Infrared (FTIR) oscopy and PXRD PXRD Capillary PXRD data was collected on the samples of fesoterodine en fumarate and either PVA or methyl methacrylate git NE 30D or Eudragit RS PO) on lactose particles prepared as in Example 11.

PXRD data was collected using a Bruker-AXS Ltd D8 Advance powder X-ray diffractometer fitted with a capillary stage, a theta—theta goniometer, a KA-1 (Cu) primary monochromator and a Braun position sensitive detector. The sample was mounted in a 1.0 or 1.5mm quartz capillary. The sample was rotated whilst being irradiated with copper K—alpha1 X-rays (wavelength = 1.5406 Angstroms) with the X- ray tube operated at 40kV/40mA. The analysis was performed with the goniometer running in continuous mode set for a 6 second count per 0.011° step over a two theta range of 2 to 55°.

PCT/IBZOlZ/050225 The patterns that were collected show no evidence for crystalline fesoterodine hydrogen fumarate in the samples. It would have been expected that PXRD would be capable of detecting crystalline rodine hydrogen fumarate at the API concentration levels (ca. 5% w/w%) in these samples and hence it is concluded that the samples ed did not contain lline fesoterodine hydrogen fumarate.

FTIR FTIR ATR analysis was carried out on the above samples of fesoterodine hydrogen fumarate and either PVA or methyl methacrylate (Eudragit) on lactose particles in an attempt to determine if the fesoterodine hydrogen fumarate was present in either an amorphous state or as a solid molecular dispersion with the polymeric binder used.

The region of the spectra where important information on teristic fesoterodine hydrogen fumarate functional groups is obtained spans from 1800- 1500cm'1. unately methyl methacrylate (Eudragit) itself displays a very intense peak around 1724cm'1 that masks l teristic fesoterodine hydrogen fumarate peaks leaving only one observable characteristic fesoterodine en fumarate peak around 1581cm'1. Unfortunately this peak is not effective alone in distinguishing the existence of fesoterodine hydrogen fumarate in an amorphous state from the existence of fesoterodine hydrogen fumarate in solid molecular dispersion in the sample of fesoterodine hydrogen fumarate and methyl methacrylate (Eudragit) on lactose particles.

For the sample of fesoterodine hydrogen fumarate and PVA on lactose particles, FTIR ATR analysis showed that there are dominant PVA peaks ranging from 1731 - 1568cm'1 leaving no clear region to assess peaks characteristic of fesoterodine hydrogen te and to distinguish the existence of fesoterodine hydrogen fumarate in an amorphous state from the existence of fesoterodine hydrogen PCT/[32012/050225 fumarate in solid molecular dispersion in the sample of rodine hydrogen fumarate and PVA on lactose particles.

In summary, despite use of best efforts, it could not be determined if the samples of fesoterodine en fumarate and either PVA or methyl methacrylate (Eudragit) on lactose particles contained fesoterodine hydrogen fumarate in an amorphous state or fesoterodine hydrogen fumarate in a solid molecular dispersion. _ 49 -

Claims (14)

1. A solid molecular sion comprising from 3:97 to 12:88 weight % ratio of fesoterodine hydrogen fumarate: an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either thereof, or a mixture of any two or more thereof.

2. A solid dispersion comprising from 3:97 to 12:88 weight % ratio of fesoterodine hydrogen fumarate: an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose 10 ether, or an ester of either thereof, or a mixture of any two or more thereof, in which the fesoterodine hydrogen fumarate is stabilised in the dispersion in a form not corresponding to its crystalline or amorphous form.

3. A dispersion as claimed in claim 1 or 2 comprising about a 1:9 weight % ratio of 15 fesoterodine en fumarate: an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either thereof, or a mixture of any two or more thereof.

4. A sion as claimed in claim 3 consisting ially of about a 1:9 weight % 20 ratio of fesoterodine hydrogen fumarate: an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either thereof, or a mixture of any two or more thereof.

5. A dispersion as claimed in claim 1 or 2 comprising about a 1:19 weight % ratio of 25 fesoterodine hydrogen fumarate: an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either thereof, or a mixture of any two or more thereof.

6. A sion as claimed in claim 5 consisting essentially of about a 1:19 weight % 30 ratio of rodine hydrogen fumarate: an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either thereof, or a mixture of any two or more thereof.

7. A dispersion as claimed in claim 1 or 2 consisting essentially of fesoterodine hydrogen fumarate, and an alkyl hydroxyalkylcellulose ether or a hydroxyalkylcellulose ether, or an ester of either f, or a mixture of any two or more thereof.

8. A dispersion as claimed in any one of claims1 to 7 wherein the cellulose ether 10 component is selected from hydroxypropyl methyl cellulose (HPMC), hydroxyethyl methyl cellulose , hydroxybutyl methyl cellulose (HBMC), yethylcellulose (HEC), hydroxypropyl cellulose (HPC) or hydroxypropyl methyl cellulose acetate succinate (HPMCAS): or is a e of any two or more thereof. 15

9. A dispersion as claimed in claim 8 wherein the ose ether component is hydroxypropyl methyl cellulose alone.

10. A dispersion as claimed in any one of claims 1 to 9 for use as a medicament. 20

11. A dispersion as d in any one of claims 1 to 9 for use in the treatment of urinary incontinence.

12. An inert core bead or particle which is coated with a dispersion as claimed in any one of claims 1 to 9.

13. An inert core bead or particle as claimed in claim 12 wherein the core bead or particle comprises microcrystalline cellulose.

14. An inert core bead or particle as d in claim 12 wherein the core bead or 30 particle comprises lactose. _51