WO2003043630A1 - Composition pharmaceutique solide renfermant 4-cyano-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- m-toluidide, pvp, un anti-oestrogene et/ou un inhibiteur de l'aromatase - Google Patents

Composition pharmaceutique solide renfermant 4-cyano-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- m-toluidide, pvp, un anti-oestrogene et/ou un inhibiteur de l'aromatase Download PDF

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WO2003043630A1
WO2003043630A1 PCT/GB2002/005158 GB0205158W WO03043630A1 WO 2003043630 A1 WO2003043630 A1 WO 2003043630A1 GB 0205158 W GB0205158 W GB 0205158W WO 03043630 A1 WO03043630 A1 WO 03043630A1
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Prior art keywords
toluidide
cyano
trifluoro
hydroxy
methylpropiono
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PCT/GB2002/005158
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English (en)
Inventor
Nicola Frances Bateman
Julie Kay Cahill
Neill Hugh Carman
Ian Derek Cockshott
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Astrazeneca Uk Limited
Astrazeneca Ab
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Priority to AU2002339169A priority Critical patent/AU2002339169A1/en
Publication of WO2003043630A1 publication Critical patent/WO2003043630A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical formulation comprising 4'-cyano- ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in a
  • the pharmaceutical formulation further comprising an anti- oestrogen and/or aromatase inhibitor.
  • >50% of the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy- 0 2-methylpropiono-m-toluidide provided by such a formulation.
  • the invention relates to the use of PVP in solid dispersion with 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide, for increasing the bioavailability of the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropi ⁇ no-m-toluidide; for reducing inter-patient variability in plasma concentrations of s 4'-cyano- ⁇ ', ⁇ ', '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide; for enhancing the storage stability of the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpro
  • Bicalutamide a non-steroidal anti-androgen, is the racemate of 4'-cyano- ⁇ ', ⁇ ', ⁇ '- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide.
  • Bicalutamide is known by the AstraZeneca trade name CASODEX .
  • EP-100172 discloses
  • 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- ⁇ ', ⁇ ', ⁇ '-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.
  • the enantiomers reference is made to Tucker and Chesterton, J. Med. Chem. 31, pp 885-887 (1988).
  • the chemical synthesis of racemic 4'-cyano- ⁇ ', ', ⁇ '-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.
  • 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- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ', ⁇ '-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.
  • AUC area under the curve
  • Such increased bioavailability could be useful in enabling a reduction in the daily dose of 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide as a monotherapy (ie, not in combination with LHRH analogue therapy or surgical castration).
  • EP-0988863 deals with the issue of increasing the bioavailability of poorly soluble drugs in general. 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-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.
  • 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.
  • a pharmaceutical product or formulation comprising 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide) by increasing the therapeutic potential of 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide as discussed above.
  • the present invention also aims to provide a 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide formulation having enhanced storage stability.
  • 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- ⁇ ', ⁇ ', ⁇ '- 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.
  • >50% of the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '- 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- ⁇ ', ⁇ ', ⁇ '-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.
  • FIG. 1 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- ⁇ ', ⁇ ', ⁇ '- 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- ⁇ ', ⁇ ', ⁇ '- 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- ⁇
  • 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.
  • Fig. 1 Dissolution of bicalutamide (ie, racemic 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide) from various solid dispersion formulations (50mg bicalutamide in 900ml of media).
  • bicalutamide ie, racemic 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide
  • Fig. 2 Dissolution of bicalutamide from solid dispersion formulations (50mg bicalutamide in 900ml of media) with or without SDS.
  • Fig. 3 Dissolution of bicalutamide and optically pure R-4'-cyano- ⁇ ', ⁇ '-trifluoro-3- (4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide from solid dispersion formulations (50mg 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in 900ml of media, 1:3 drug : PVP ratio).
  • the inventors chose to investigate solid dispersion formulations as a possible means of fulfilling at least one of the aims stated above.
  • the inventors sought to increase the therapeutic potential by achieving one or both of an increase in the bioavailability of 4'-cyano- ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide and a decrease in inter- patient variability in plasma concentrations of 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- 0 fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-/n-toluidide can be increased by formulating 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide in a solid dispersion specifically with PVP.
  • 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.
  • the present invention uses PVP having a K-value ⁇ 90.
  • the PVP has a K-value range ⁇ 60, or ⁇ 30, but >15, >17 or >25.
  • the K-value is selected from 25, 17, 15 and 12.
  • the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)-2- hydroxy-2-methylpropiono- -toluidide is in a solid dispersion with at least one PVP polymer.
  • PVP polymer a mixture of two or more PVP polymers differing in K-values can be used.
  • 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- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide in a solid dispersion comprising PVP, and optionally, wherein >50% of the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is provided in the form of the R-enantiomer.
  • the dose comprises an upper limit of 1000, 500, 450, 400, 300, 200, 150, 125, 100, 75, 50mg 25mg or lOmg of 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide.
  • the dose comprises 450mg of 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide.
  • 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.
  • the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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.
  • one or more fillers will be present in an amount of 1 to 70% by weight of the formulation or dose.
  • one or more binders will be present in an amount of 2 to 40% by weight of the formulation or dose.
  • 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.
  • a particular excipient may act as both a binder and a filler, or as a binder, a filler and a disintegrant.
  • the combined amount of filler, binder and disintegrant comprises, for example, 1 to 90% by weight of the formulation or dose.
  • 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.
  • 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.
  • 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
  • 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.
  • At least some of the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3- (4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide may be present in amorphous form in the solid dispersion with the PVP.
  • At least 25% of the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-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.
  • 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- ⁇ ', ⁇ ', ⁇ '-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.
  • 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).
  • PSA prostate specific antigen
  • 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.
  • >50%, >60%, >70%, >80%, >85%, >90%, >95%, >98% or >99% or thereabout of the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is provided in the form of the R-enantiomer.
  • 100% or substantially 100% of the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide is provided in the form of the R-enantiomer.
  • substantially 100% we mean that the 4'- cyano- ⁇ ', ⁇ ', ⁇ '-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.
  • the predominance of the R-enantiomer in the present invention provides for a 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)- 2-hydroxy-2-methylpropiono-m-toluidide formulation with good storage stability and an enhanced therapeutic potential.
  • the present invention provides a pharmaceutical product for administration to a patient, the formulation comprising 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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).
  • an anti-oestrogen eg, tamoxifen or a pharmaceutically acceptable salt or solvate thereof, eg, tamoxifen citrate.
  • PVP polymers can be used.
  • 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- ⁇ ' , ⁇ ', ⁇ '- 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.
  • a side effect selected from gynaecomastia, breast tenderness, 10 hot flushes, impotence, reduction in libido, nausea, vomiting, fatigue and diarrhoea.
  • the side effect is one or both of gynaecomastia and breast tenderness.
  • Tamoxifen an anti-oestrogen
  • AstraZeneca trade name an anti-oestrogen
  • Tamoxifen is the trans isomer of l-(p-beta-dimethylaminoethoxyphenyl)-
  • the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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,
  • the invention also provides a pharmaceutical product for mucosal administration to a patient, the formulation comprising 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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.
  • >50% of the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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.
  • a side effect selected from gynaecomastia, breast tenderness, hot flushes, impotence, reduction in libido, nausea, vomiting, fatigue and diarrhoea.
  • the side effect is one or both of gynaecomastia and breast tenderness.
  • Anastrozole an aromatase inhibitor
  • AstraZeneca trade name an aromatase inhibitor
  • 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:-
  • Exemestane an aromatase inhibitor
  • AROMASIN an aromatase inhibitor
  • Exemestane 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.
  • the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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
  • the invention also provides a pharmaceutical dose of 10 to 600 mg, or 25 to 600mg, of 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-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.
  • 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- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide or a pharmaceutically acceptable salt or solvate thereof.
  • 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.
  • the dose is 150 mg of 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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).
  • the anti -oestrogen eg, tamoxifen citrate
  • the invention provides a pharmaceutical dose of 25 to 600 mg of 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-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.
  • 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- ⁇ ', ⁇ ', ⁇ '- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide or a pharmaceutically acceptable salt or solvate thereof.
  • 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.
  • the dose is 150 mg of 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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 aromatase inhibitor eg, anastrozole
  • the anti-oestrogen/aromatase inhibitor and the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide are preferably administered daily.
  • Another possible regime would be dosing of the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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.
  • the pharmaceutical product may include administration instructions.
  • the 4'- cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '- trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide).
  • FIG. 1 Further aspects of the invention relate to the use in the manufacture of a pharmaceutical product of an anti -oestrogen and 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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
  • reducing the risk of prostate cancer includes reducing the risk of re-occurrence of prostate cancer, the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide being in solid dispersion with PVP.
  • treating we mean reducing the severity of a side effect or eliminating a side effect already being experienced by a patient.
  • preventing the side effect(s) we mean suppressing increase in the incidence or severity of a side effect.
  • the invention relates to the use in the manufacture of a pharmaceutical product of an anti-oestrogen and 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methyl
  • the invention relates to the use in the manufacture of a pharmaceutical product of an aromatase inhibitor and 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)- 2-hydroxy-2-methylpropiono-m-toluidide in the patient; or
  • reducing the risk of prostate cancer includes reducing the risk of re-occurrence of prostate cancer, the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- - toluidide being in solid dispersion with an PVP.
  • the invention relates to the use in the manufacture of a pharmaceutical product of an aromatase inhibitor and 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophen
  • 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.
  • the anti-oestrogen/aromatase inhibitor is provided in the solid dispersion, along with the 4 ' -cyano- ⁇ ', ⁇ ', ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m- toluidide prior to spray drying (or other method described above for removing the solvent).
  • the solid dispersion of the polymer and the 4'-cyano- ⁇ ', ⁇ ', ⁇ '- 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.
  • >50% of the 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-/7 ⁇ -toluidide is provided in the form of the R-enantiomer.
  • racemate of 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide is used.
  • a method for preparing a pharmaceutical formulation comprising 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide with reduced inter-patient variability in plasma concentrations of 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono-m-toluidide and/or increased bioavailability of 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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
  • the antioestrogen is tamoxifen, in a further embodiment, greater than 50% of the 4 ' -cyano- ⁇ ' , ⁇ ' , ⁇ '-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- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)- 2-hydroxy-2-methylpropiono-/n-toluidide is in amorphous form.
  • 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.
  • a form suitable for oral administration is used, for example as tablets or capsules.
  • 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.
  • inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
  • granulating and disintegrating agents such as croscarmellose sodium, sodium starch glycollate,corn starch or alginic 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.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil such as peanut oil, liquid paraffin or olive oil.
  • the inventors prepared a formulation of a solid dispersion of bicalutamide (racemic 4'-cyano- ⁇ ', ⁇ ', ⁇ '-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.
  • 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.
  • Figure 1 shows the results of in vitro dissolution tests performed on the various solid dispersions.
  • 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.
  • a solid dispersion was made that had a 1:3 ratio by weight of R-4'-cyano- ⁇ ', ⁇ ', ⁇ '- 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.
  • SDS sodium dodecyl sulphate
  • 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- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide) : PVP K-25 polymer.
  • bicalutamide ie, racemic R-4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- -toluidide
  • Figure 3 shows a comparison of cumulative % 4'-cyano- ⁇ ', ⁇ ', ⁇ '-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono- -toluidide released v. time for the two formulations and for a conventional 50mg bicalutamide tablet formulation.
  • 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.
  • 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).
  • provision of the drug (4'-cyano- ⁇ ', ⁇ ', ⁇ '-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).
  • 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.
  • XRD X-ray diffraction
  • 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.

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Abstract

L'invention concerne une formulation pharmaceutique comprenant le médicament 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophénylsulphonyl)-2-hydroxy-2-méthylpropiono-m-toluidide dans une dispersion solide avec PVP, la formulation comprenant également un anti-oestrogène (par exemple du citrate de tamoxifène) et/ou un inhibiteur de l'aromatase (par exemple, de l'anastrozole). L'invention concerne également une dose pharmaceutique du médicament et un anti-oestrogène/inhibiteur de l'aromatase selon ladite formulation. Celle-ci présente un caractère avantageux en ce qu'elle permet de traiter et/ou de prévenir au moins un effet secondaire sélectionné parmi la gynécomastie, la tension mammaire, des bouffées de chaleur, l'impotence et la diminution de la libido, tout en augmentant la biodisponibilité du médicament; ainsi que de réduire la variabilité entre patients des teneurs en plasma du 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophénylsulphonyl)-2-hydroxy-2-méthylpropiono-m-toluidide; et d'améliorer la stabilité de stockage du médicament; et/ou de traiter et/ou de réduire le risque de cancer de la prostate chez un patient.
PCT/GB2002/005158 2001-11-16 2002-11-14 Composition pharmaceutique solide renfermant 4-cyano-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- m-toluidide, pvp, un anti-oestrogene et/ou un inhibiteur de l'aromatase WO2003043630A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004100944A1 (fr) * 2003-05-14 2004-11-25 Synthon B.V. Formes et compositions de bicalutamide, et leurs procedes
EP2087883A1 (fr) * 2004-03-10 2009-08-12 Bayer Schering Pharma Aktiengesellschaft Solutions solides supersaturées stabilisées de médicaments stéroides
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
CN104146974A (zh) * 2014-08-14 2014-11-19 杭州华东医药集团新药研究院有限公司 一种含来曲唑的组合物及其制备方法
US20170165243A1 (en) * 2004-08-27 2017-06-15 Bayer Healthcare, Llc Pharmaceutical compositions for the treatment of hyper-proliferative disorders
US10189957B2 (en) 2007-01-26 2019-01-29 Isp Investments Llc Formulation process method to produce spray dried products
US10532028B2 (en) * 2005-07-28 2020-01-14 Isp Investments Llc Method to improve characteristics of spray dried powders and granulated materials, and the products thereby produced

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994027610A1 (fr) * 1993-05-28 1994-12-08 Schering Aktiengesellschaft Agents contenant un compose a action anti-androgene ainsi qu'un compose a action competitive antagoniste de la progesterone
EP1027886A2 (fr) * 1999-02-10 2000-08-16 Pfizer Products Inc. Dispersions pharmaceutiques solides
WO2001049294A1 (fr) * 1999-12-30 2001-07-12 Pharmacia Italia S.P.A. Produit pour le traitement de la gynecomastie
WO2001089515A1 (fr) * 2000-05-23 2001-11-29 Astrazeneca Ab Association pharmaceutique de bicalutamide et de tamoxifene destinee a produire un effet anti-androgenique et anti-oestrogenique
WO2002067893A2 (fr) * 2001-02-27 2002-09-06 Astrazeneca Ab Preparation pharmaceutique
WO2002080902A1 (fr) * 2001-04-02 2002-10-17 Astrazeneca Ab Composition pharmaceutique solide contenant 4-cyano-trifluoro-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methylpropiono-m-toluidiure et pvp

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994027610A1 (fr) * 1993-05-28 1994-12-08 Schering Aktiengesellschaft Agents contenant un compose a action anti-androgene ainsi qu'un compose a action competitive antagoniste de la progesterone
EP1027886A2 (fr) * 1999-02-10 2000-08-16 Pfizer Products Inc. Dispersions pharmaceutiques solides
WO2001049294A1 (fr) * 1999-12-30 2001-07-12 Pharmacia Italia S.P.A. Produit pour le traitement de la gynecomastie
WO2001089515A1 (fr) * 2000-05-23 2001-11-29 Astrazeneca Ab Association pharmaceutique de bicalutamide et de tamoxifene destinee a produire un effet anti-androgenique et anti-oestrogenique
WO2002067893A2 (fr) * 2001-02-27 2002-09-06 Astrazeneca Ab Preparation pharmaceutique
WO2002080902A1 (fr) * 2001-04-02 2002-10-17 Astrazeneca Ab Composition pharmaceutique solide contenant 4-cyano-trifluoro-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methylpropiono-m-toluidiure et pvp

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MCLEOD DAVID G ET AL: "Gynecomastia in patients with prostate cancer: A review of treatment options.", UROLOGY, vol. 56, no. 5, November 2000 (2000-11-01), pages 713 - 720, XP001146105, ISSN: 0090-4295 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004100944A1 (fr) * 2003-05-14 2004-11-25 Synthon B.V. Formes et compositions de bicalutamide, et leurs procedes
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
EP2087883A1 (fr) * 2004-03-10 2009-08-12 Bayer Schering Pharma Aktiengesellschaft Solutions solides supersaturées stabilisées de médicaments stéroides
US8715735B2 (en) 2004-03-10 2014-05-06 Bayer Intellectual Property Gmbh Stabilised supersaturated solids of lipophilic drugs
US20170165243A1 (en) * 2004-08-27 2017-06-15 Bayer Healthcare, Llc Pharmaceutical compositions for the treatment of hyper-proliferative disorders
US10532028B2 (en) * 2005-07-28 2020-01-14 Isp Investments Llc Method to improve characteristics of spray dried powders and granulated materials, and the products thereby produced
US10189957B2 (en) 2007-01-26 2019-01-29 Isp Investments Llc Formulation process method to produce spray dried products
CN104146974A (zh) * 2014-08-14 2014-11-19 杭州华东医药集团新药研究院有限公司 一种含来曲唑的组合物及其制备方法

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