WO2003043630A1

WO2003043630A1 - Solid pharmaceutical composition comprising 4-cyano-trifluoro-3-(4-fluorophenyl sulphonyl)-2-hydroxy-2-methylpropiono- m toluidide, pvp, an anti-oestrogen and/or an aromatase inhibitor

Info

Publication number: WO2003043630A1
Application number: PCT/GB2002/005158
Authority: WO
Inventors: Nicola Frances Bateman; Julie Kay Cahill; Neill Hugh Carman; Ian Derek Cockshott
Original assignee: AstraZeneca UK Ltd; AstraZeneca AB
Current assignee: AstraZeneca UK Ltd; AstraZeneca AB
Priority date: 2001-11-16
Filing date: 2002-11-14
Publication date: 2003-05-30
Anticipated expiration: 2004-05-16
Also published as: SE0103838D0; AU2002339169A1

Abstract

The present invention relates to a pharmaceutical formulation comprising the drug 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in a solid dispersion with PVP, the formulation further comprising an anti-oestrogen (eg, tamoxifen citrate) and/or an aromatase inhibitor (eg, anastrozole). The invention also relates to a pharmaceutical dose of the drug and anti-oestrogen/aromatase inhibitor provided by such a formulation. An advantage is the treating and/or preventing of at least one side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, while increasing the bioavailability of the drug; reducing inter-patient variability in plasma concentrations of the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide; enhancing the storage stability of the drug; and/or treating and/or reducing the risk of prostate cancer in a patient.

Description

SOLID PHARMACEUTICAL COMPOSITION COMPRISING 4 -CYAN0-TRIFLU0R0-3- ( 4-FLUOROPHENYL SULPH0NYD -2 -HYDR0XY-2-METHYLPR0PI0N0- M TOLUIDIDE , PVP , AN ANTI -OESTROGEN AND / OR AN AROMATASE INHIBITOR

The present invention relates to a pharmaceutical formulation comprising 4'-cyano- ',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in a

5 solid dispersion with PVP, the pharmaceutical formulation further comprising an anti- oestrogen and/or aromatase inhibitor. In one particular embodiment >50% of the 4'-cyano- α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is provided in the form of the R-enantiomer. The invention also relates to a daily pharmaceutical dose of 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy- 0 2-methylpropiono-m-toluidide provided by such a formulation. In addition, the invention relates to the use of PVP in solid dispersion with 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide, for increasing the bioavailability of the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiόno-m-toluidide; for reducing inter-patient variability in plasma concentrations of s 4'-cyano-α',α', '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide; for enhancing the storage stability of the 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide; or for treating and/or reducing the risk of prostate cancer in a patient. BACKGROUND TO THE INVENTION 0 Bicalutamide, a non-steroidal anti-androgen, is the racemate of 4'-cyano-α',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide.

TM

Bicalutamide is known by the AstraZeneca trade name CASODEX . EP-100172 discloses

4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- - toluidide (named in EP-100172 as 4-cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulphonyl- 5 2-hydroxy-2-methylpropionyl)aniline) as the 8^th compound listed in the table in Example 6. The corresponding structure is shown in formula I:-

Bicalutamide can be used to combat prostate cancer. The properties and usefulness of bicalutamide as an anti-androgen have been reviewed in B J A Furr et al, Urology, 1996, 47 (Suppl. 1A), 13-25, and G J C Kolvenbag et al, Urology. 1996, 47 (Suppl. 1A), 70-79. 4'- cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide can exist in distinct R- and S- enantiomeric forms. The R-enantiomer is the (-) isomer and is the pharmacologically active compound in vivo. For further details of the enantiomers, reference is made to Tucker and Chesterton, J. Med. Chem. 31, pp 885-887 (1988).

The chemical synthesis of racemic 4'-cyano-α', ',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is described in US4636505, and this disclosure is incorporated herein by reference. The R-enantiomer may be obtained by the resolution of enantiomers from the racemate or resolution of precursors of the enantiomers using fractional crystallisation or chromatographic separation of diastereomeric esters of chiral acids. Other methods will, however, be evident to the skilled addressee using routine techniques for the preparation of enantiomers. For example, the R-enantiomer may be prepared by simple crystallisation and chromatographic resolution (see, for example, Wilen and Lochmuller, "Tables of Resolving Agents", J. Chromatography, 113, 283-302 (1975) and E L Eliel, Stereochemistry of Carbon Compounds, McGraw Hill (1962)). Another method involves resolution of the carboxylic acid precursor, 3-(4-fluorophenyl)-2-hydroxy-2- methylpropanoic acid, by fractional crystallisation of diastereomeric salts with chiral amines. The Tucker and Chesterton reference cited above discloses the chromatographic separation of the R-and S- enantiomers from racemic 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide. The method involves the chromatographic separation of R-camphanoyl esters of the racemate and their hydrolysis and oxidation to the R- and S-enantiomers. This disclosure is incorporated herein by reference specifically to provide an illustration of a method of obtaining the enantiomers for use in the present invention.

Bicalutamide (4'-cyano-α', ',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide racemate) is used in conventional oral tablet form (eg, at a daily monotherapy dose of 50mg, 80mg or 150mg) to combat prostate cancer in men. The bioavailability of the bicalutamide to the patient is determined to a certain extent by the dissolution rate and solubility of the drug in the GI tract, which affects absorption across mucosal membranes in the GI tract. The relative bioavailability of bicalutamide for a series of formulations can be assessed by determining the area under the curve (AUC) of a graph of plasma bicalutamide concentration v. time elapsed since administration of the bicalutamide. As a consequence of sub-optimal rates of dissolution and degree of solubility of the drug, there is observed a high degree of inter-patient variability in the bioavailability of bicalutamide administered in conventional tablet form. This may result in sub-optimal treatment efficacy in a proportion of patients. In addition, the maximum systemic exposure achievable after dosing the conventional tablet is limited, such that at conventional tablet doses in excess of 150mg, there is a significant reduction in bicalutamide bioavailability. It would be desirable to extend the therapeutic potential of 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide by increasing the bioavailability of the drug and/or reducing inter-patient variability in plasma concentrations of the drug, relative to conventional bicalutamide, as a result of reduced inter-patient variability in the absorption of the drug.

Such increased bioavailability could be useful in enabling a reduction in the daily dose of 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- - toluidide required to achieve the same level of bioavailability seen with a conventional formulation.

A possible benefit of achieving relatively higher bioavailability could also be the ability to extend treatment to more advanced stages of prostate cancer than are currently treated with the conventional formulations. This could be useful, for example, for treating patients with metastatic prostate cancer, using for example 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide as a monotherapy (ie, not in combination with LHRH analogue therapy or surgical castration).

As another advantage, it would also be desirable to reduce inter-patient variability in plasma concentrations of 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy- 2-methylpropiono- -toluidide as a result of reduced inter-patient variability in the absorption of the drug. This would increase predictability of the treatment and increase uniformity of treatment in a patient population.

It would also be desirable to provide a 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide formulation having good storage stability.

EP-0988863 deals with the issue of increasing the bioavailability of poorly soluble drugs in general. 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono- -toluidide is not specifically addressed. The disclosed solution is to provide a formulation comprising a water-insoluble complex of the drug and a water- insoluble ionic polymer. No specific class of polymer is required, and the polymer can be cationic or anionic, but must have a molecular weight greater than about 80,000 D and a glass transition temperature equal or greater than about 50°C.

EP-1027886 also deals with the issue of increasing the bioavailability of poorly soluble drugs in general. Again, 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2- hydroxy-2-methylpropiono-m-toluidide is not specifically addressed. The disclosed solution is to provide a solid dispersion formulation comprising a low-solubility drug and a polymer. The latter can be one of many possible polymers, as long as it has a glass transition temperature of at least 100°C measured at 50% relative humidity.

Furthermore, it has been observed that the administration of bicalutamide in single agent therapy to humans causes an increase in the amount of testosterone circulating in the blood. Blackledge et al, (Urology, 1996, 47, Suppl. 1 A), pp 44-47) discloses an approximate doubling of the basal level of total testosterone. It is believed that such an increase in the level of testosterone occurs when sufficient of the anti-androgen gains access to the CNS and blocks androgen receptors in the hypothalamus. The consequential lack of feedback of androgen causes additional release of LHRH by the hypothalamus which in turn causes release of luteinising hormone (LH) and follicle stimulating hormone (FSH) by the pituitary gland and production of testosterone in the testes. Aromatase enzyme in fat and other tissues converts some of the increased concentration of testosterone to oestradiol, which results in increased concentrations of oestrogen in the blood. Further discussion of this is provided by C Mahler et al, Clinical Pharmacokinetics, 1998, 34(5), pp 405-417. A disadvantageous effect is produced. Namely, the increase in the levels of circulating oestrogen may cause one or more of the side effects of gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido. A discussion on gynaecomastia can be found in C J Tyrrell, Prostate Cancer and Prostatic Diseases, 1999, 2(4): pp 167-171. It would be further desirable to provide a pharmaceutical product or formulation comprising 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono- -toluidide with a reduction, relative to conventional bicalutamide therapy, of at least one side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, preferably, while also fulfilling at least one of the following aims.

One aim is to improve upon the conventional formulation of bicalutamide (racemic 4'- cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide) by increasing the therapeutic potential of 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide as discussed above. The present invention also aims to provide a 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide formulation having enhanced storage stability. SUMMARY OF THE INVENTION

The present invention fulfils at least one of these aims by providing a pharmaceutical formulation for administration to a patient, the formulation comprising 4'-cyano-α',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in a solid dispersion with PNP, the formulation further comprising an anti -oestrogen or aromatase inhibitor. In one embodiment, wherein >50% of the 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is provided in the form of the R-enantiomer.

The invention also provides a daily pharmaceutical dose of 4'-cyano-α',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide mucosally administrable to a patient for treating and/or reducing the risk of prostate cancer in the patient, wherein the dose comprises 10 to 600mg of 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide in a solid dispersion with PNP, the dose further comprising an anti-oestrogen or an aromatase inhibitor. In one embodiment, wherein >50% of the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)- 2-hydroxy-2-methylpropiono-m-toluidide is provided in the form of the R-enantiomer. Further aspects of the invention relate to the use in the manufacture of a pharmaceutical product of an anti-oestrogen or an aromatase inhibitor and 4'-cyano-α',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide or a pharmaceutically acceptable salt or solvate thereof, for simultaneous or sequential administration to a patient, for treating and/or reducing the risk of prostate cancer in the patient and treating and/or preventing at least one side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, the 4'-cyano-α',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide being in solid dispersion with PVP, and optionally wherein >50% of the the 4'-cyano-α',α',α'-trifluoro-3- (4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is provided in the form of the R-enantiomer.

As explained further below, an additional advantage of the present invention for solid dispersions with relatively high drug loads is an improvement in drug dissolution compared with similar solid dispersions where a higher proportion of the drug is provided in the S-form.

FIGURES

Fig. 1 Dissolution of bicalutamide (ie, racemic 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide) from various solid dispersion formulations (50mg bicalutamide in 900ml of media).

Key:

Diamonds - conventional bicalutamide tablet formulation Triangles - PEG4000

Rectangles - PVP

Crosses - PLA:PEG [2kDa:2kDa]

Fig. 2 Dissolution of bicalutamide from solid dispersion formulations (50mg bicalutamide in 900ml of media) with or without SDS.

Key:

Circles - with 5% SDS

Squares - without SDS

Fig. 3 Dissolution of bicalutamide and optically pure R-4'-cyano-α',α\α'-trifluoro-3- (4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide from solid dispersion formulations (50mg 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in 900ml of media, 1:3 drug : PVP ratio).

Key:

Diamonds - bicalutamide Squares - R-4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2- hydroxy-2-methylpropiono-m-toluidide Triangles - conventional bicalutamide tablet formulation

s Fig. 4 Dissolution of bicalutamide and pure R-4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-/n-toluidide from solid dispersion formulations (50mg 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in 900ml of media, 1:1 drug : PVP ratio). 0

Key:

Diamonds - bicalutamide

Squares - R-4 '-cyano-α', α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2- hydroxy-2-methylpropiono- -toluidide s Triangles - conventional bicalutamide tablet formulation

DETAILED DESCRIPTION OF THE INVENTION

The inventors chose to investigate solid dispersion formulations as a possible means of fulfilling at least one of the aims stated above. In terms of the aim of increasing the 0 therapeutic potential of 4'-cyano-α',α\α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy- 2-methylpropiono-m-toluidide, the inventors sought to increase the therapeutic potential by achieving one or both of an increase in the bioavailability of 4'-cyano-α\α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide and a decrease in inter- patient variability in plasma concentrations of 4'-cyano-α',α',α'-trifluoro-3-(4- 5 fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide, relative to treatment with conventional bicalutamide formulations.

The prior art teaches a very wide range of possible polymers for solid dispersion, in order to increase the bioavailability of drugs in general. The inventors have now surprisingly found that the therapeutic potential of 4'-cyano-α',α',α'-trifluoro-3-(4- 0 fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-/n-toluidide can be increased by formulating 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide in a solid dispersion specifically with PVP. In one embodiment, wherein >50% of the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide is provided in the form of the R-enantiomer. As the non-limiting example section below demonstrates, such an increase in therapeutic potential for 4'-cyano- α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is not achieved with various other polymers. PVP is also known by various other names, such as polyvinylpyrrolidone, poly[l-(2- oxo-l-pyrrolidinyl)ethylene], polyvidone and l-vinyl-2-pyrrolidinone polymer. PVP is available in various grades as shown in the following table.

In one embodiment, the present invention uses PVP having a K-value <90. For example, the PVP has a K-value range <60, or <30, but >15, >17 or >25. In one example, the K-value is selected from 25, 17, 15 and 12.

In one embodiment, the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2- hydroxy-2-methylpropiono- -toluidide is in a solid dispersion with at least one PVP polymer. Thus, it is contemplated that a mixture of two or more PVP polymers differing in K-values can be used.

The term "solid dispersion" is a well-known term in the art, which refers to a dispersion of one or more active ingredients in an inert carrier or matrix at solid state, typically, but not exclusively, prepared by conventional melting (fusion), solvent, or melting- solvent methods. Terms also used to describe this type of approach are solid solutions, coevaporates and coprecipitates (W.L. Chiou and S. Riegelman, "Applications of Solid Dispersion Systems", J. Pharm. Sci. 60:1281-1302, 1971). In one embodiment the dispersion is manufactured by melt extrusion. A preferred ratio of 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide: PVP by weight is from 1:0.25 to 1:10. More preferably the lower limit of this range is 1:1, 1:2, 1:3 or 1:>3. Preferably, the upper limit of this range is 1:<3, 1:5 or 1:7. Particularly preferred ratios are 1:5, 1:4 and 1:3. In one embodiment, the range is 1:>3 to 1:10. In another embodiment, the range is 1:0.25 to 1:<3 and the solid dispersion includes a wetting agent. Further discussion of wetting agents appears below.

One aspect of the invention provides a pharmaceutical dose of 10 to 600mg, or 25 to 600mg, of 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide administrable to a patient for treating and/or reducing the risk of prostate cancer in the patient, wherein the dose comprises 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in a solid dispersion comprising PVP, and optionally, wherein >50% of the 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is provided in the form of the R-enantiomer. Preferably, the dose comprises an upper limit of 1000, 500, 450, 400, 300, 200, 150, 125, 100, 75, 50mg 25mg or lOmg of 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide. In one example, the dose comprises 450mg of 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide.

Additional excipients may be included in the formulation or dose. For example, the formulation or dose may comprise one or more fillers, binders, disintegrants and/or lubricants. Suitable fillers include, for example, lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g. microcrystalline cellulose, cellulose), calcium sulphate, xylitol and lactitol.

Suitable binders include, for example, polyvinylpyrrolidone, lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymefhylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatin and sodium alginate.

Suitable disintegrants include, for example, crosscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycollate, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Suitable lubricants include, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnuba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and sodium stearyl fumarate.

Additional conventional excipients which may be added include preservatives, stabilisers, anti-oxidants, silica flow conditioners, antiadherents or glidants.

Other suitable fillers, binders, disintegrants, lubricants and additional excipients which may be used are described in the Handbook of Pharmaceutical Excipients, 3rd Edition; The Theory and Practice of Industrial Pharmacy, 3rd Edition 1986; Pharmaceutical Dosage Forms 1998; Modern Pharmaceutics, 3rd Edition 1995; Remington's Pharmaceutical Sciences 20th Edition 2000.

Preferably, the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide will be present in an amount of 1 to 80%, and preferably from 1 to 50% (more preferably 2 to 20% or 2 to 15%) by weight of the solid dispersion.

Preferably, one or more fillers will be present in an amount of 1 to 70% by weight of the formulation or dose.

Preferably, one or more binders will be present in an amount of 2 to 40% by weight of the formulation or dose.

Preferably, one or more disintegrants will be present in an amount of 0.5 to 25%, and especially 4 to 10% by weight of the formulation or dose. It will be appreciated that a particular excipient may act as both a binder and a filler, or as a binder, a filler and a disintegrant. Typically the combined amount of filler, binder and disintegrant comprises, for example, 1 to 90% by weight of the formulation or dose.

Preferably, one or more lubricants will be present in an amount of 0.25 to 5%, and especially 1 to 2% by weight of the formulation or dose. Preferably, one or more wetting agents will be present in the solid dispersion in an amount of 0.1 to 5% (eg, 1 to 2%) by weight of the solid dispersion. The presence of a wetting agent provides a further enhancement of the increase in therapeutic potential achieved with the present invention. Examples of suitable wetting agents include sodium dodecyl sulphate (sodium lauryl sulphate); docusate sodium; polyoxyethylen sorbitan fatty acid esters, eg polysorbates 20, 40, 60 and 80; polyoxyethylene castor oil derivatives, eg Cremophor

TM

RH40 ; and poloxamers.

Methods for preparing solid dispersions are known in the art and typically comprise the steps of dissolving the drug and the polymer in a common solvent and evaporating the solvent. The solvent can be routinely selected according to the polymer used. Examples of solvents are: acetone/dichloromethane, methanol/dichloromethane, acetone/water, acetone/ethanol, dichloromethane/ethanol or ethanol/water. Methods for evaporating solvent include rotary evaporation, spray drying, lyophilisation and thin film evaporation. Other techniques may be used such as melt extrusion, solvent controlled precipitation, pH controlled precipitation and supercritical fluid technology.

When referring to a solid dispersion we do not exclude the possibility that a proportion of the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- m-toluidide may be dissolved within the PVP, the exact proportion, if any, will depend upon the particular PVP polymer selected.

In the formulations of the invention, at least some of the 4'-cyano-α',α',α'-trifluoro-3- (4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide may be present in amorphous form in the solid dispersion with the PVP. The provision of the 4'-cyano- α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in amorphous form is additionally advantageous, since it further increases the solubility and dissolution rate of the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-rn-toluidide, thereby enhancing the increase in therapeutic potential achieved with the present invention. Whether or not drug is present in amorphous form can be determined by conventional thermal analysis or X-ray diffraction. In one embodiment, at least 25% of the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide in the formulation is present in amorphous form. More preferably, this amount is at least 30%, 40%, 50%, 75%, 90%, 95% or 99%. The most preferred embodiment is where 100% of the 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in the formulation is in amorphous form. The amorphous form applies to the bicalutamide drug as a whole, thus the proportion of amorphous drug can be S-enantiomer or R-enantiomer or both.

The formulations and doses are mucosally administrable, ie administrable to mucosal membranes for absorption across the membranes. To this end, suitable routes of administration include administration by inhalation, as well as oral, intranasal and rectal administration. Oral administration is particularly preferred. A tablet or other form of the formulation would be chosen by the skilled addressee according to the route of administration. The 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide is useful to provide an anti-androgenic effect, in that this compound blocks androgen activity in a patient. The anti-androgenic effect is useful for treating cancer, for example prostate cancer. Particular examples are advanced prostate cancer and early prostate cancer. The anti-androgenic effect may be useful for prophylaxis, in order to reduce the risk of prostate cancer occurrence in patients or re-occurrence (eg, following prostatectomy or radiation therapy aimed at curing the patient). This could be especially useful in men genetically pre-disposed to prostate cancer. Conventional methods are available to classify patients according to their risk of contracting prostate cancer, for example by assessment of family history and measurements over time of particular blood proteins such as prostate specific antigen (PSA). Other uses for the anti-androgenic effect are the treatment of a non-malignant disease of the prostate gland (eg, benign prostatic hyperplasia or hypertrophy), testotoxicosis, hirsutism and acne. These conditions, in conjunction with prostate cancer, will be referred to herein as prostatic disorders. The patient can be a human male, eg an adult, but the treatment of other mammals is also contemplated.

In one embodiment of the formulation or dose, >50%, >60%, >70%, >80%, >85%, >90%, >95%, >98% or >99% or thereabout of the 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is provided in the form of the R-enantiomer. In a preferred embodiment, 100% or substantially 100% of the 4'-cyano- α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide is provided in the form of the R-enantiomer. By "substantially 100%" we mean that the 4'- cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide is provided as the pure R-enantiomer, or there is a trace (<1%) of the S-enantiomer present. As the experimental section below shows, the predominance of the R-enantiomer in the present invention provides for a 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)- 2-hydroxy-2-methylpropiono-m-toluidide formulation with good storage stability and an enhanced therapeutic potential.

To fulfil the aim of providing a pharmaceutical product comprising bicalutamide with reduced side effects relative to conventional bicalutamide pharmaceutical product, the present invention provides a pharmaceutical product for administration to a patient, the formulation comprising 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide, or a pharmaceutically acceptable salt or solvate thereof, in a solid dispersion comprising PVP, the formulation further comprising an anti-oestrogen (eg, tamoxifen or a pharmaceutically acceptable salt or solvate thereof, eg, tamoxifen citrate). It is contemplated that one or a mixture of such PVP polymers can be used. Further details of suitable solid dispersions is given in the general description above (with the exception that the 5 present aspect is not limited to the use of a drug proportion of >50% of the 4'-cyano-α^',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide being provided in the form of the R-enantiomer).

The anti -oestrogen prevents oestrogen activity. The anti-oestrogenic effect is useful for treating and/or preventing a side effect selected from gynaecomastia, breast tenderness, 10 hot flushes, impotence, reduction in libido, nausea, vomiting, fatigue and diarrhoea. Such side effects have been observed with monotherapy use of anti-androgens. Preferably, the side effect is one or both of gynaecomastia and breast tenderness.

Tamoxifen, an anti-oestrogen, is known by the AstraZeneca trade name

TM

NOLVADEX . Tamoxifen is the trans isomer of l-(p-beta-dimethylaminoethoxyphenyl)-

15 1,2-diphenylbut-l-ene, which is disclosed in US-4,536,516. An alternative name is (Z)-2-[p- (l,2-diphenylbut-l-enyl)phenoxy]ethyldimethylamine. The corresponding structure is shown in formula I:-

I

20 Preferably, the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide and anti -oestrogen are provided in a ratio respectively of 25 to 350 (preferably the lower end of the range being 50; preferably the upper end of the range being 300, 150 or 50; suitable values in the ranges being 150 or 50) : 0.5 to 100 (preferably the lower end of the range being 1, 2.5 or 5; preferably the upper end of the range being 40,

25 20 or 10; a suitable value in the range being 2.5, 5, 7.5, 8, 9, 10, 15 or 20).

The invention also provides a pharmaceutical product for mucosal administration to a patient, the formulation comprising 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)- 2-hydroxy-2-methylpropiono-m-toluidide, or a pharmaceutically acceptable salt or solvate thereof, in solid dispersion comprising PVP, the formulation further comprising an aromatase inhibitor (eg, anastrozole, letrozole or exemestane, or a pharmaceutically acceptable salt or solvate thereof). It is contemplated that one or a mixture of such PVP polymers can be used. Further details of suitable solid dispersions is given in the general description above. In one embodiment, >50% of the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2- hydroxy-2-methylpropiono-m-toluidide is provided in the form of the R-enantiomer.

The aromatase inhibitor inhibits conversion of testosterone to oestradiol by aromatase enzyme. The aromatase inhibition is useful for treating and/or preventing a side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence, reduction in libido, nausea, vomiting, fatigue and diarrhoea. Such side effects have been observed with monotherapy use of anti-androgens. Preferably, the side effect is one or both of gynaecomastia and breast tenderness.

Anastrozole, an aromatase inhibitor, is known by the AstraZeneca trade name

TM

ARΓMIDEX . Anastrozole is known as 2,2'-[5-(lH-l,2,4-triazol-l-ylmethyl)-l,3- phenylene]di(2-methyl-propionitrile), which is disclosed in US re-issue No. 36,617. An alternative name is 2,2'-dimethyl-2,2'-[5-(lH-l,2,4-triazol-l-ylmethyl)-l,3- phenylene]bis(propiononitrile). The corresponding structure is shown in formula II:-

Letrozole, an aromatase inhibitor, is known by the trade name FEMARA . Letrozole is known by the alternative names 4,4'-(lH-l,2,4-triazol-l-ylmethylene)-bisbenzonitrile; 1- [bis(4-cyanophenyl)methyl]-l,2,4-triazole; and 4-[l-(4-cyanophenyl)-l-(l,2,4-triazol-l- yl)methyl]benzonitrile. Letrozole is disclosed in US 4,978,672. The corresponding structure is shown in formula III:-

III

Exemestane, an aromatase inhibitor, is known by the trade name AROMASIN and is marketed by Pharmacia and Upjohn. Exemestane is known by the alternative name 6- methylenandrosta-l,4-diene-3,17-dione. Further reference is made to US-4,808,616 and US- 4,904,650.

Preferably, the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide and aromatase inhibitor are provided in a ratio respectively of 25 to 350 (preferably the lower end of the range being 50; preferably the upper end of the range being 300, 150 or 50; suitable values in the ranges being 150, 80 or 50) : 0.005 to 100 (preferably the lower end of the range being 0.05 or 0.5; preferably the upper end of the range being 50, 10 or 1; the most preferred range being 0.5 to 1; a suitable value in the range being

1).

The invention also provides a pharmaceutical dose of 10 to 600 mg, or 25 to 600mg, of 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide administrable to a patient for treating and/or reducing the risk of prostate cancer in the patient, wherein the dose comprises 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide, or a pharmaceutically acceptable salt or solvate thereof, in a solid dispersion comprising PVP, the dose further comprising an anti-oestrogen. A suitable pharmaceutical dose has from 0.5 to 200 mg of the anti-oestrogen.

Preferably, the lower end of the range is 1, 5, 10, 15 or 20 mg; preferably the upper end of the range is 80, 60, 40, 20 or 10 mg; a suitable value in the range being 10 or 20 mg. The dose or the regimen has from 10 to 600 mg of the compound 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide or a pharmaceutically acceptable salt or solvate thereof. Preferably the lower end of the range is 10 mg; preferably the upper end of the range is 300, 150 or 50 mg; suitable values in the ranges are 150 or 50 mg. In one example, the dose is 150 mg of 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide or a pharmaceutically acceptable salt or solvate thereof and 1, 2.5, 5, 7.5, 8, 9, 10, 15 or 20 mg of the anti -oestrogen (eg, tamoxifen citrate).

In addition, the invention provides a pharmaceutical dose of 25 to 600 mg of 4'-cyano- α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide administrable to a patient for treating and/or reducing the risk of prostate cancer in the patient, wherein the dose comprises 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2- hydroxy-2-methylpropiono-m-toluidide, or a pharmaceutically acceptable salt or solvate thereof, in a solid dispersion comprising PVP, the dose further comprising an aromatase inhibitor.

A suitable pharmaceutical dose has from 0.005 to 200 mg of the aromatase inhibitor. Preferably, the lower end of the range is 0.05 or 0.5 mg; preferably the upper end of the range is 50, 10 or 1 mg; the most preferred range is 0.5 to 1 mg; a suitable value in the range being 1 mg. The dose or the regimen has from 10 to 600 mg of the compound 4'-cyano-α',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide or a pharmaceutically acceptable salt or solvate thereof. Preferably the lower end of the range is 10 mg; preferably the upper end of the range is 300, 150 or 50 mg; suitable values in the ranges are 150 or 50 mg. In one example, the dose is 150 mg of 4'-cyano-α',α',α'-trifluoro- 3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide or a pharmaceutically acceptable salt or solvate thereof and 0.1, 0.25, 0.5 or 1 mg of the aromatase inhibitor (eg, anastrozole).

The anti-oestrogen/aromatase inhibitor and the 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide are preferably administered daily. Another possible regime would be dosing of the 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide on alternate days and dosing of the anti-oestrogen/aromatase also on (the same or different) alternate days. To this end, the pharmaceutical product may include administration instructions. Preferably, the 4'- cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-/n- toluidide is administered every 3, 4, 5, 6 or 7 days and the anti-oestrogen/aromatase is administered every 3, 4, 5, 6 or 7 days (eg, on the same day as the 4'-cyano-α',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide). Further aspects of the invention relate to the use in the manufacture of a pharmaceutical product of an anti -oestrogen and 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-/n-toluidide or a pharmaceutically acceptable salt or solvate thereof, for simultaneous or sequential administration to a patient, for treating and/or preventing at least one side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, and

(a) increasing the bioavailability of 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)- 2-hydroxy-2-methylpropiono-m-toluidide in the patient; or

(b) treating and/or reducing the risk of prostate cancer in the patient. As explained below, reducing the risk of prostate cancer includes reducing the risk of re-occurrence of prostate cancer, the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide being in solid dispersion with PVP.

By "treating" the side effect(s), we mean reducing the severity of a side effect or eliminating a side effect already being experienced by a patient. By "preventing" the side effect(s), we mean suppressing increase in the incidence or severity of a side effect.

In addition, the invention relates to the use in the manufacture of a pharmaceutical product of an anti-oestrogen and 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2- hydroxy-2-methylpropiono-m-toluidide or a pharmaceutically acceptable salt or solvate thereof, for simultaneous or sequential administration to patients, for reducing inter-patient variability in plasma concentrations of 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide in the patient and treating and/or preventing at least one side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, the 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide being in solid dispersion with PVP.

Furthermore, the invention relates to the use in the manufacture of a pharmaceutical product of an aromatase inhibitor and 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide or a pharmaceutically acceptable salt or solvate thereof, for simultaneous or sequential administration to a patient, for treating and or preventing at least one side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, and (a) increasing the bioavailability of 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)- 2-hydroxy-2-methylpropiono-m-toluidide in the patient; or

(b) treating and/or reducing the risk of prostate cancer in the patient. As explained below, reducing the risk of prostate cancer includes reducing the risk of re-occurrence of prostate cancer, the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- - toluidide being in solid dispersion with an PVP.

In addition, the invention relates to the use in the manufacture of a pharmaceutical product of an aromatase inhibitor and 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide or a pharmaceutically acceptable salt or solvate thereof, for simultaneous or sequential administration to patients, for reducing inter-patient variability in plasma concentrations of 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in the patient, relative to conventional bicalutamide pharmaceutical product, and treating and/or preventing at least one side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide being in solid dispersion comprising PVP.

The term "product" is intended to mean either a combination of the solid dispersion formulation and the anti-oestrogen/ aromatase inhibitor (eg, provided as a capsule or tablet containing both the solid dispersion and the anti-oestrogen/aromatase inhibitor) or a kit comprising separate amounts of the solid dispersion and the anti-oestrogen/ aromatase inhibitor (eg, a set of tamoxifen citrate tablets and a separate set of tablets of the solid dispersion). The latter product can be used for simultaneous or sequential (ie, temporally spaced) administration of the agents to the patient, while the combination is for simultaneous administration. Factors such as the rate of absorption, metabolism and the rate of excretion of each agent will affect their presence at the tumour site. Such factors are routinely considered by, and are well within the ordinary skill of, the clinician when he contemplates the treatment of a medical condition which requires the conjoint administration of two agents in order to obtain a beneficial effect. In one embodiment, the anti-oestrogen/aromatase inhibitor is provided in the solid dispersion, along with the 4^'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2- hydroxy-2-methylpropiono-m-toluidide. Production of this embodiment entails the formation of a solution comprising the anti-oestrogen/aromatase inhibitor, the polymer and the A'- cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide prior to spray drying (or other method described above for removing the solvent).

In another embodiment, the solid dispersion of the polymer and the 4'-cyano-α',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is produced and then mixed with the anti-oestrogen aromatase inhibitor. Routine considerations of a person skilled in the art would be the particle size, particle size distribution, particle morphology and powder flow properties of the anti-oestrogen/aromatase inhibitor. The anti- oestrogen/aromatase inhibitor would be mixed with the solid dispersion using conventional mixing methods such as trituration or ordered mixing to attain the required content uniformity. Further details of these routine considerations is given in Pharmaceutics, The science of dosage form design, Edited by M E Aulton 1988.

As noted above, in one embodiment of the pharmaceutical product and doses according to the invention, >50% of the 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-/7ϊ-toluidide is provided in the form of the R-enantiomer. In this embodiment, preferably about >50, >60%, >70%, >80%, >85%, >90%, >95%, >98% or >99%, or substantially 100% of the 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is provided in the form of the R-enantiomer.

In another embodiment, the racemate of 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is used.

According to another aspect of the invention there is provided a method for preparing a pharmaceutical formulation comprising 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide with reduced inter-patient variability in plasma concentrations of 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide and/or increased bioavailability of 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide and/or a reduced side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, in the patient comprising forming a solid dispersion of PVP with 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2- hydroxy-2-methylpropiono-m-toluidide, the formulation further comprising an antioestrogen. In one particular embodiment the antioestrogen is tamoxifen, in a further embodiment, greater than 50% of the 4^'-cyano-α^',α^',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide is provided in the form of the R-enantiomer. In a further embodiment greater that 30% of the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)- 2-hydroxy-2-methylpropiono-/n-toluidide is in amorphous form.

Each of these aspects of increased bioavailability, enhanced storage stability and reduced interpatient variability are either relative to the same bioequivalent dose of conventional bicalutamide or relative to a non-solid dispersion formulations of bicalutamide. The products and doses may be in a form suitable for oral use (for example as tablets, capsules, aqueous or oily suspensions, emulsions or dispersible powders or granules), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions; for example for use within a transdermal patch), for parenteral administration (for example as a sterile aqueous or oily solution or suspension for intravenous, subcutaneous, intramuscular or intravascular dosing), or as a suppository for rectal dosing. Preferably a form suitable for oral administration is used, for example as tablets or capsules.

The products and doses may also use conventional pharmaceutically-acceptable diluents or carriers that are well known in the art. Suitable pharmaceutically-acceptable diluents or carriers for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such such as croscarmellose sodium, sodium starch glycollate,corn starch or alginic acid; binding agents such as Polyvinylpyrrolidone, gelatin or starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, silica flow conditioners, antiadherents or glidants and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art. Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil. EXPERIMENTAL A: Comparative Examples

The following examples are not according to the present invention, but are included to provide a suitable context for the interpretation of the examples according to the present invention (see section B). In Vitro Assessment of Various Solid Dispersion Formulations

The inventors prepared a formulation of a solid dispersion of bicalutamide (racemic 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- - toluidide) with a representative PVP polymer (in this case PVP K-25) and compared this against solid dispersions using several different polymers with bicalutamide. A conventional bicalutamide tablet formulation was also included for comparison. The formulations were assessed for an improvement in therapeutic potential using an in vitro dissolution test.

Each formulation had a weight ratio of bicalutamide:polymer of 1 :5. The following polymers were used to produce solid dispersions:- polyethylene glycol (PEG) 4000, PLA:PEG [2kDa, 2kDa] (a di-block copolymer of poly(lactide):polyethylene glycol) and PVP K-25. Preparation of Solid Dispersion Formulations

Solid dispersions having a 1:5 ratio by weight of bicalutamide:polymer were prepared as follows, 0.5g of bicalutamide and 2.5g of polymer were weighed directly into a 250ml round bottom flask and dissolved in 80ml of acetone:dichloromethane (3:1). The solvent was removed on a rotary evaporator or by spray drying. The formulation was placed in a vacuum oven and dried under high vacuum at 40°C for 24 hours.

The formulation was retrieved from the flask and dry milled using a Fritsch mill. The formulation was then dried for a further 24 hours under high vacuum at 40°C.

In order to produce formulations having ratios other than 1:5, weights and volumes in the process should be adjusted so that they are pro-rata to those described above. In vitro Dissolution Test

(a) PVP Solid Dispersion v. Solid Dispersion With Other Polymers The formulations were weighed into hard gelatin capsules (equivalent to 50mg drug) and dissoluted in 900ml media [0.25% sodium dodecyl sulphate solution] for one hour at 37°C (paddle speed 75rpm). 5ml samples were then removed with a plastic syringe at 5, 10, 20, 30, 45 and 60 minutes. Each sample was centrifuged (14,000rpm) at ambient temperature for 15 minutes and then analysed by HPLC using the following conditions:-

Eluent: 58% ACN/42% water/0.2% formic acid

Column: 15cm Luna 5um, 3mm id column (with guard)

Detection wavelength: 270nm Flow rate: lml/min

Temperature: ambient

Injection: lOul

Retention time: approximately 2 minutes

Figure 1 shows the results of in vitro dissolution tests performed on the various solid dispersions. As Fig.l shows, 100% of bicalutamide in solution was achieved with the PVP solid dispersion and supersaturation was maintained over the 60 minute test (ie, no drug precipitation was observed). Compare this against the results for the PLA:PEG solid dispersion, which did not show any improvement over the conventional tablet formulation. The PEG4000 solid dispersion also was much inferior to the PVP formulation, the former achieving only approximately 50% of bicalutamide in solution for a 1:5 ratio. Enhancement of Therapeutic Potential Using A Wetting Agent

Solid dispersions were prepared using a spray drying method for solvent removal with and without 5% sodium dodecyl sulphate (SDS) as a wetting agent. The solid dispersions had a 1:3 ratio by weight of bicalutamide:polymer. Preparation of Solid Dispersions

(a) without SDS

3.0g of drug (bicalutamide) and 9.0g of PVP K-25 polymer were added to 400ml of the solvent mixture, Acetone/Dichloromethane (3:1). Complete dissolution was achieved with stirring. The solution was delivered to the spray dryer and the solvent removed. The product was a free flowing white powder.

(b) with 5% SDS

0.6g of SDS was added to 400ml of the solvent mixture, Acetone/Dichloromethane (3:1). Complete dissolution was achieved by stirring and heat. The solution was cooled before the addition of 3.0g of drug (bicalutamide) and 9.0g of PVP K-25 polymer complete dissolution was achieved with stirring. The solution was delivered to the spray dryer and the solvent removed. The product was a free flowing white powder. In vitro Dissolution Test The test was performed following the protocol above. Figure 2 shows a comparison of cumulative % bicalutamide released v. time for the two formulations. As Fig. 1 shows, for solid dispersions having a 1:3 ratio by weight of bicalutamide:polymer. the formulation including SDS displayed enhanced bicalutamide release compared to the formulation that did not include SDS. B: Examples in accordance with the invention Enhancement of therapeutic potential provided by the R-enantiomer (i) At a 1;3 ratio

A solid dispersion was made that had a 1:3 ratio by weight of R-4'-cyano-α',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide (100% of the R-enantiomer): PVP K-25 polymer. Production was by a spray drying method for solvent removal with 5% sodium dodecyl sulphate (SDS) as a wetting agent. A second solid dispersion was also made by a spray drying method with 5% SDS, but this solid dispersion had a 1:3 ratio by weight of bicalutamide (ie, racemic R-4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide) : PVP K-25 polymer. In vitro Dissolution Test

The test was performed following the protocol above. Figure 3 shows a comparison of cumulative % 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono- -toluidide released v. time for the two formulations and for a conventional 50mg bicalutamide tablet formulation. As Fig. 3 shows, the solid dispersion according to the invention, which had 100% of the R-enantiomer, displayed enhanced drug release compared to the conventional formulation. The enhancement was similar to that achieved by the bicalutamide solid dispersion. (ii) At a 1:1 ratio

The protocol in part (i) was followed, with the exception that the drug : PVP ratio for both formulations was changed to 1:1. In vitro Dissolution Test The test was performed following the protocol above. Figure 4 shows a comparison of cumulative % 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide released v. time for the two formulations with a 1:1 ratio. Again, both solid dispersion formulations displayed enhanced drug release compared to the conventional formulation. Note, however, that at the 1:1 ratio the formulation according to the present invention displayed a release profile that was enhanced when compared with the bicalutamide solid dispersion. Indeed, the formulation according to the invention achieved 100% of drug in solution and supersaturation was maintained over the 60 minute test (ie, no drug precipitation was observed). Thus, provision of the drug (4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)- 2-hydroxy-2-methylpropiono-m-toluidide) in the R-enantiomer form according to the invention, particularly where 100% of the drug is in the R-form, provides an additional dissolution advantage. Provision of the R-enantiomer generally gives a higher percentage dissolution (eg, determined as % drug dissolved after 60 minutes in the in vitro dissolution test described above) than another solid dispersion that is identical but for the provision of a significantly higher proportion of the drug in the S-form (but where the total proportion of drug : PVP remains the same). The advantage is most evident as one increases the total proportion of drug : PVP in the formulation (eg, for proportions of 1:0.25 to 1:<3). Thus, for a 1 : 1 drug:PVP ratio, one finds a higher percentage dissolution of drug after 60 minutes in the in vitro dissolution test with a solid dispersion comprising 100% of the R-enantiomer as compared to a solid dispersion containing the racemate. The advantage is also expected to be achieved with other formulations of the invention wherein > 50% of the drug is provided in the R-form. Enhancement of storage stability provided by the R-enantiomer

Solid dispersion formulations were prepared as in part B(i) above (ie, having a 1:3 ratio of drug : PVP).

The storage stability of the formulations was assessed using X-ray diffraction (XRD) as follows. The formulations were placed in sealed glass amber vials and stored at the following conditions, 4°C, 25°C/60%RH, 50°C and 40°C/75%RH (RH, relative humidity) for three months. After three months the samples were removed and analysed by XRD (X-ray diffraction) to determine the presence or absence of crystallinity. The results are presented in the following table.

X = no crystallinity = crystallinity

As the results show, no crystallinity was detected after 3 months when the formulation according to the invention was stored under any of the conditions, indicating the superior stability of the formulation. With the bicalutamide (R/S-) formulation, however, the formulation was less stable under all of the experimental conditions, as indicated by the presence of crystallinity. The presence of crystallinity in the R/S sample corresponded with a reduction in the dissolution performance of the formulation when tested after 3 months of storage under all conditions.

Claims

CLAIMS:

1. A pharmaceutical product for administration to a patient, the product comprising 4'- cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide, or a pharmaceutically acceptable salt or solvate thereof, in a solid dispersion comprising PVP, the product further comprising an anti-oestrogen and/or an aromatase inhibitor.

2. A pharmaceutical product for administration to a patient, the product comprising 4' cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide, or a pharmaceutically acceptable salt or solvate thereof, in a solid dispersion comprising PVP, the product further comprising an anti -oestrogen

3. The pharmaceutical product according to claim 1 or 2, wherein the anti -oestrogen is in solid dispersion with the PVP.

4. The pharmaceutical product according to claim 1,2 or 3, wherein the anti -oestrogen is tamoxifen or a pharmaceutically acceptable salt or solvate thereof.

5. The pharmaceutical product according to any preceding claim, wherein the 4'-cyano α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide and anti -oestrogen are provided in a ratio of 25 to 350 : 0.5 to 100 respectively.

6. A pharmaceutical product for administration to a patient, the product comprising 4' cyano-α', α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide, or a pharmaceutically acceptable salt or solvate thereof, in a solid dispersion comprising PVP, the product further comprising an aromatase inhibitor.

7. The pharmaceutical product according to claim 1 or 6, wherein the aromatase inhibitor is in solid dispersion with the PVP.

8. The pharmaceutical product according to claim 6 or 7, wherein the aromatase inhibitor is selected from anastrazole, letrozole and exemestane or a pharmaceutically acceptable salt or solvate thereof.

9. The pharmaceutical product according to any one of claims 1, 6, 7 or 8, wherein the 4' 5 cyano-α', α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- - toluidide and aromatase inhibitor are provided in a ratio of 25 to 350 : 0.005 to 100 respectively.

10. The pharmaceutical product according to any preceding claim, wherein >50% of the 4' 10 cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- - toluidide is provided in the form of the R-enantiomer.

11. The pharmaceutical product according to claim 10, wherein about >50%, >60%, >70%, >80%, >85%, >90%, >95%, >98% or >99%, or substantially 100% of the 4'-cyano-α',α',α'-

15 trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is provided in the form of the R-enantiomer.

12. The pharmaceutical product according ot any preceding claim, wherein the PVP has a K value <90.

20

13. The pharmaceutical product of claim 12, wherein the 4'-cyano-α',α',α'-trifluoro-3-(4 fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-/n-toluidide is in solid dispersion with PVP K-25.

25 14. The pharmaceutical product according to any preceding claim, wherein the weight ratio of 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide : PVP is from 1:0.25 to 1:10.

15. The pharmaceutical product according to claim 14, wherein the ratio of 4'-cyano

30 α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide: PVP by weight is 1:>3 to 1:10.

16. The pharmaceutical product of any preceding claim, wherein the solid dispersion comprises a wetting agent.

17. The pharmaceutical product of claim 14, wherein the ratio of 4'-cyano-α',α',α'-trifluoro 3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide: PVP by weight is 1:0.25 to 1:<3 and the solid dispersion includes a wetting agent.

18. A pharmaceutical dose of 10 to 600 mg of 4'-cyano-α',α',α'-trifluoro-3-(4 fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide administrable to a patient for treating and/or reducing the risk of prostate cancer in the patient, wherein the dose comprises 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide, or a pharmaceutically acceptable salt or solvate thereof, in a solid dispersion comprising PVP, the dose further comprising an anti -oestrogen.

19. The dose of claim 17, wherein the anti-oestrogen is as defined in claim 3 or 4.

20. The dose of claim 18 or 19, wherein the anti -oestrogen is provided in an amount of 0.5 to 200 mg.

21. A pharmaceutical dose of 10 to 600 mg of 4'-cyano-α',α',α'-trifluoro-3-(4 fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide administrable to a patient for treating and/or reducing the risk of prostate cancer in the patient, wherein the dose comprises 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide, or a pharmaceutically acceptable salt or solvate thereof, in a solid dispersion comprising PVP, the dose further comprising an aromatase inhibitor.

22. The dose of claim 21, wherein the aromatase inhibitor is as defined in claim 7 or 8.

23. The dose of claim 21 or 22, wherein the aromatase inhibitor is provided in an amount of 0.005 to 200 mg.

24. The dose of any one of claims 18 to 23, wherein >50% of the 4'-cyano-α',α',α'-trifluoro 3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide is provided in the form of the R-enantiomer.

25. The dose according to claim 24, wherein about >50%, >60%, >70%, >80%, >85%, >90%, s >95%, >98% or >99%, or substantially 100% of the 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is provided in the form of the R-enantiomer.

26. The dose of any one of claims 18 to 25, wherein the PVP is as defined in claim 12 or 13. 0

27. The dose of any one of claims 18 to 26, wherein the weight ratio of 4'-cyano-α',α',α' trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide : PVP is from 1:0.25 to 1:10.

s 28. The dose according to claim 27, wherein the weight ratio of 4'-cyano-α',α',α'-trifluoro-3 (4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide: PVP by weight is 1:>3 to 1:10.

29. The dose of any one of claims 18 to 27, wherein the solid dispersion comprises a wetting 0 agent.

30. The dose according to claim 27, wherein the weight ratio of 4'-cyano-α',α',α'-trifluoro-3 (4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide: PVP by weight is 1:0.25 to 1:<3 and the solid dispersion includes a wetting agent. 5

31. Use in the manufacture of a pharmaceutical product of an anti-oestrogen and 4'-cyano α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide or a pharmaceutically acceptable salt or solvate thereof, for simultaneous or sequential administration to a patient, for increasing the bioavailability of 4'-cyano-α',α',α'-trifluoro-3- 0 (4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in the patient and treating and/or preventing at least one side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, the 4'-cyano-α',α',α'-trifluoro-3- (4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide being in solid dispersion with PVP.

32. Use in the manufacture of a pharmaceutical product of an anti-oestrogen and 4'-cyano α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide or a

5 pharmaceutically acceptable salt or solvate thereof, for simultaneous or sequential administration to patients, for reducing inter-patient variability in plasma concentrations of 4'- cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide in the patient and treating and/or preventing at least one side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, the 4'-

10 cyano-α', α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- - toluidide being in solid dispersion with PVP.

33. Use in the manufacture of a pharmaceutical product of an anti-oestrogen and 4'-cyano α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide or a is pharmaceutically acceptable salt or solvate thereof, for simultaneous or sequential administration to a patient, for treating and/or reducing the risk of prostate cancer in the patient and treating and/or preventing at least one side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, the 4'-cyano-α',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide being in solid

20 dispersion with PVP.

34. The use according to claim 31, 32 or 33, wherein the anti -oestrogen is tamoxifen or a pharmaceutically acceptable salt or solvate thereof.

25 35. The use according to claim 31, 32, 33 or 34, wherein the 4'-cyano-α',α',α'-trifluoro-3-(4 fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide and anti -oestrogen are provided in a ratio of 25 to 350 : 0.5 to 100 respectively.

36. Use in the manufacture of a pharmaceutical product of an aromatase inhibitor and 4' 30 cyano-α', α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide or a pharmaceutically acceptable salt or solvate thereof, for simultaneous or sequential administration to a patient, for increasing the bioavailability of 4'-cyano-α',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-7κ-toluidide in the patient and treating and/or preventing at least one side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, the 4'-cyano-α',α',α'-trifluoro-3- (4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-w-toluidide being in solid dispersion with PVP.

5

37. Use in the manufacture of a pharmaceutical product of an aromatase inhibitor and 4' cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide or a pharmaceutically acceptable salt or solvate thereof, for simultaneous or sequential administration to patients, for reducing inter-patient variability in plasma lo concentrations of 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono- -toluidide in the patient and treating and/or preventing at least one side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, the 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono- -toluidide being in solid dispersion with PVP. is

38. Use in the manufacture of a pharmaceutical product of an aromatase inhibitor and 4' cyano-α', α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide or a pharmaceutically acceptable salt or solvate thereof, for simultaneous or sequential administration to a patient, for treating and/or reducing the risk of prostate cancer

20 in the patient and treating and/or preventing at least one side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence and reduction in libido, the 4'- cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- - toluidide being in solid dispersion with PVP.

2₅

39. The use according to any one of claims 36 to 38, wherein the aromatase inhibitor is selected from anastrazole, letrozole and exemestane or a pharmaceutically acceptable salt or solvate thereof.

40. The use according to any one of claims 36 to 39, wherein the 4'-cyano-α',α',α'-trifluoro 30 3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide and aromatase inhibitor are provided in a ratio of 25 to 350 : 0.005 to 100 respectively.

41. A pharmaceutical product comprising 4'-cyano-α',α',α'-trifluoro-3-(4 fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide, or a pharmaceutically acceptable salt or solvate thereof, in a solid dispersion comprising PVP, the product further comprising tamoxifen.

42. A pharmaceutical product according to claim 41, wherein about >50%, >60%, >70%, >80%, >85%, >90%, >95%, >98% or >99%, or substantially 100% of the 4'-cyano-α',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide is provided in the form of the R-enantiomer.

43. A method for treating prostate cancer and/or reducing the risk of prostate cancer in a patient comprising administering to a patient in need thereof of a pharmaceutical formulation comprising 4'-cyano-α',α', α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide in solid dispersion with PVP, the product further comprising an anti -oestrogen and/or an aromatase inhibitor.

44. A method for treating prostate cancer and/or reducing the risk of prostate cancer in a patient comprising administering to a patient in need thereof of a pharmaceutical dose of 5 to 1000 mg of 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide, wherein the dose comprises 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in a solid dispersion comprising PNP, the product further comprising an anti-oestrogen and/or an aromatase inhibitor.

45. The method according to claim 41 or 42, wherein about >50%, >60%, >70%, >80%, >85%, >90%, >95%, >98% or >99%, or substantially 100% of the 4'-cyano-α',α',α'- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide is provided in the form of the R-enantiomer.

46. The product, dose, use, or method according to any of the preceding claims wherein, at least 30%, 40%, 50%, 75%, 90%, 95% or 99% of the 4'-cyano-α',α',α'-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is in amorphous form.