Composition comprising crystalline nanosized apalutamide

Abstract

The disclosure relates to a composition comprising nanoparticles of crystalline apalutamide and polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methyl cellulose (HPMC). The disclosure also relates to a method for producing the composition.

Description

[0001] Composition comprising crystalline nanosized apalutamide

[0002] FIELD

[0003] The present disclosure relates to compositions comprising crystalline nanosized apalutamide and one or more polymers, and to methods for producing the same.

[0004] BACKGROUND

[0005] Apalutamide, (4-[7-(6-cyano-5-trifluoromethyl pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methyl benzamide, 1) is marketed by Janssen Biotech under the trade name Erleada® as 60 mg and 240 mg oral tablet in the US and EU for the treatment of patients with non-metastatic castration-resistant prostate cancer.

[0006] Apalutamide is practically insoluble in aqueous media over a wide range of pH values. Further, it is non-hygroscopic, crystalline solid that remains unionized over the physiologic pH range. The Erleada® tablets include apalutamide as an amorphous solid dispersion (ASD) in hypromellose acetate succinate (HPMCAS).

[0007] ASDs are susceptible to thermodynamic instability due to the higher free energy associated with the amorphous state. Numerous factors such as the improper selection of formulation components, thermal stress, environmental stress such as humidity, and manufacturing stress contribute to the physical instability of ASD. The proper selection of formulation ingredients, manufacturing process, process parameters, and packaging components are deemed essential to obtain a stable ASD drug product. Furthermore, an ASD dose must include a significant amount of the polymer increasing the dose size.

[0008] Accordingly, there is still need for further stable bioavailable forms of apalutamide.

[0009] SUMMARY

[0010] It was observed that when amorphous nanosized apalutamide was contacted with aqueous solutions comprising certain polymers, nanosized apalutamide in crystalline form was obtained. Accordingly, it is an object of the present disclosure to provide a composition comprising

[0011] - nanoparticles of crystalline apalutamide, and

[0012] - polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methyl cellulose (HPMC).

[0013] It is also an object of the present disclosure to provide a method for producing nanoparticles of crystalline apalutamide, the method comprising the following steps a) providing solid amorphous nanosized apalutamide; b) providing an aqueous solution comprising polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methyl cellulose (HPMC); c) contacting the solid amorphous nanosized apalutamide and the aqueous solution comprising PVPVA and / or HPMC to form an admixture wherein content of the amorphous nanosized apalutamide in the admixture is higher than solubility of the amorphous nanosized apalutamide in the aqueous solution thereby obtaining a suspension comprising nanoparticles of crystalline apalutamide.

[0014] It is still an object of the present disclosure to provide a crystalline polymorph of 4- [7-(6-cyano-5-trifluoromethyl pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5- yl]-2-fluoro-N-methyl benzamide (apalutamide) characterized by a powder X-ray diffraction pattern having peaks at 25.1 , 28.2, 30.4, and 33.0 ± 0.2 [°20].

[0015] It is still an object of the present disclosure to provide a pharmaceutical composition comprising

[0016] - an effective amount of nanoparticles of crystalline apalutamide,

[0017] - polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methyl cellulose (HPMC), and

[0018] - at least one pharmaceutically acceptable excipient or carrier.

[0019] It is still an object of the present disclosure to provide a pharmaceutical composition comprising an effective amount of a crystalline polymorph of apalutamide characterized by a powder X-ray diffraction pattern having peaks at 25.1 , 28.2, 30.4, and 33.0 ± 0.2 [°20] and at least one pharmaceutically acceptable excipient or carrier. It is still an object of the present disclosure to provide a pharmaceutical composition comprising

[0020] - nanoparticles of crystalline apalutamide and

[0021] - polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methyl cellulose (HPMC) for use as a medicament, in particular for use in the treatment of patients with non- metastatic castration-resistant prostate cancer.

[0022] It is still an object of the present disclosure to provide a crystalline polymorph apalutamide characterized by a powder X-ray diffraction pattern having peaks at 25.1 , 28.2, 30.4, and 33.0 ± 0.2 [°20] for use as a medicament, in particular for use in the treatment of patients with non-metastatic castration-resistant prostate cancer.

[0023] It is also an object of the present disclosure to provide a pharmaceutical dosage form for oral administration comprising the composition comprising

[0024] - nanoparticles of crystalline apalutamide, and

[0025] - polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methyl cellulose (HPMC).

[0026] It is also an object of the present disclosure to provide a pharmaceutical dosage form for oral administration comprising a crystalline polymorph apalutamide characterized by a powder X-ray diffraction pattern having peaks at 25.1 , 28.2, 30.4, and 33.0 ± 0.2 [°20].

[0027] Several exemplifying and non-limiting embodiments of the invention are described in accompanied dependent claims.

[0028] Various exemplifying and non-limiting embodiments of the invention and methods of operation, together with additional objects and advantages thereof, are best understood from the following description of specific exemplifying embodiments.

[0029] The verbs “to comprise” and “to include” are used in this document as open limitations that neither exclude nor require the existence of also unrecited features. The features recited in dependent claims are mutually freely combinable unless otherwise explicitly stated. Furthermore, it is to be understood that the use of "a" or "an", i.e., a singular form, throughout this document does not exclude a plurality.

[0030] BRIEF DESCRIPTION OF FIGURES Figure 1 depicts A: the XRD diffractogram of a composition obtained by contacting nanosized amorphous and aqueous 5 wt.-% HPMC including 0.2 wt.-% SLS. Apalutamide : HPMC ratio was 4:1 (w / w), and B: the XRD diffractogram of a composition obtained by contacting nanosized amorphous apalutamide and aqueous 25 wt.-% PVPVA. Apalutamide : PVPVA ratio was 2:1 (w / w). The samples were dried for 24 h before XRD.

[0031] Figure 2 depicts the XRD diffractogram of amorphous nanosized apalutamide.

[0032] Figure 3 depicts the XRD diffractograms of apalutamide contacted with a) aqueous solution of 5 wt.-% HPMC and 0.2 wt.-% SLS; b) aqueous solution of 25 wt.-% PVPVA and 0.2 wt.-% SLS; c) aqueous solution of 25 wt.-% poloxamer 407 and 0.2 wt.-% SLS for 24 hours at room temperature. Apalutamide: polymer ratio was 2:1 (w / w). The samples were dried for 24 h before XRD.

[0033] Figure 4 depicts the SEM images of apalutamide contacted with A: aqueous solution of 5 wt.-% HPMC and 0.2 wt-% SLS for 24 hours at room temperature; B: aqueous solution of 25 wt.-% PVPVA and 0.2 wt.-% SLS for 24 hours at room temperature; C: aqueous solution of 25 % poloxamer 407 and 0.2 wt.-% SLS. Apalutamide: polymer ratio was 2:1 (w / w). The samples were dried for 24 h before SEM.

[0034] Figure 5 depicts SGF-FaSSIF dissolution profiles of a) composition of nanosized crystalline apalutamide and PVPVA. Apalutamide : PVPVA ratio was ratio was 2:1 (w / w) and the composition included 0.2 wt.-% SLS; b) bulk apalutamide; c) ASD of apalutamide (Erleada®).

[0035] DESCRIPTION

[0036] The specific examples provided in the description given below should not be construed as limiting the scope and / or the applicability of the appended claims. Lists and groups of examples provided in the description given below are not exhaustive unless otherwise explicitly stated.

[0037] As defined herein a nanosized apalutamide consists of particles which Dv90 is equal to or is less than 1000 nm, i.e., a nanosized apalutamide consist of particles which 90% of volume fraction has a diameter below 1000 nm. The apalutamide particle size may be between 10 nm and 1000 nm, for example between 10 nm and 200 nm, between 200 nm and 500 nm, or between 500 nm and 1000 nm. The size distribution can be tuned as desired.

[0038] As defined herein a suspension is apalutamide suspended in liquid (here the aqueous solution comprising PVPVA and / or HPMC).

[0039] As defined herein, an aqueous solution is water that contains one or more dissolved substances. The dissolved substances in an aqueous solution may be solids, liquids, or gases.

[0040] Unless expressly stated otherwise, the term "apalutamide”, refers to apalutamide, its non-salt form, its physiologically acceptable salts, co-crystals, polymorphs and / or solvates thereof.

[0041] According to one aspect the present disclosure concerns a composition comprising nanoparticles of crystalline apalutamide and PVPVA and / or HPMC.

[0042] According to one embodiment the composition comprises apalutamide and PVPVA, wherein ratio apalutamide: PVPVA is from 10:1 (w / w) to 1 :10 (w / w), preferably from 3:1 to 1 :1 (w / w), such as 2:1 (w / w) or 1 :1 (w / w).

[0043] According to another embodiment the composition comprises apalutamide, PVPVA, and one or more surfactants. The surfactants are typically selected from a group consisting of sodium lauryl sulfate (SLS) Tween 80, Tween 20, dioctyl sulfosuccinate sodium salt (DOSS), and tocofersolan (TPGS), preferably SLS. The ratio apalutamide: PVPVA ratio of the composition is typically from 10:1 (w / w) to 1 :10 (w / w), preferably from 5:1 to 1 :1 (w / w), such as 4:1 (w / w), 3:1 (w / w), 2:1 (w / w), or 1 :1 (w / w).

[0044] According to another embodiment the composition comprises apalutamide and HPMC, wherein ratio apalutamide: HPMC is from 10:1 (w / w) to 1 :10 (w / w), preferably from 5:1 to 1 :1 (w / w), such as 4:1 (w / w), 3:1 (w / w), 2:1 (w / w), or 1 :1 (w / w).

[0045] According to still another embodiment the composition comprises apalutamide, HPMC, and one or more surfactants. The surfactants are typically selected from a group consisting of sodium lauryl sulfate (SLS) Tween 80, Tween 20, dioctyl sulfosuccinate sodium salt (DOSS), and tocofersolan (TPGS), preferably SLS. The ratio apalutamide: HPMC is typically from 10:1 (w / w) to 1 :10 (w / w), preferably from 5:1 to 1 :1 (w / w), such as 4:1 (w / w), 3:1 (w / w), 2:1 (w / w), or 1 :1 (w / w). According to a particular embodiment the polymer is HPMC, and the nanosized crystalline apalutamide of the composition has powder X-ray diffraction pattern having peaks at 25.1 , 28.3, 30.6, and 33.0 ± 0.2 [°20], preferably 18.6, 20.4, 21.5, 25.1 , 28.3, 30.6, and 33.0 ± 0.2 [°20], more preferably the same as the X-ray powder diffraction pattern shown in Fig 1A.

[0046] According to another particular embodiment the polymer is PVPVA, and the nanosized crystalline apalutamide of the composition has powder X-ray diffraction pattern having peaks at 25.0, 28.1 , 30.3, and 32.9 ± 0.2 [°20], preferably 18.5, 20.3, 21 .5, 25.0, 28.1 , 30.3, and 32.9 ± 0.2 [°20], more preferably the same as the X-ray powder diffraction pattern shown in Fig 1 B.

[0047] According to another aspect the present disclosure concerns a method for producing nanoparticles of crystalline apalutamide, the method comprises a) providing solid amorphous nanosized apalutamide, preferably as dry powder; b) providing an aqueous solution comprising PVPVA and / or HPMC; c) contacting the solid amorphous nanosized apalutamide and the aqueous solution comprising PVPVA and / or HPMC to form an admixture wherein content of the amorphous nanosized apalutamide in the admixture is higher than solubility of the amorphous nanosized apalutamide in the aqueous solution, thereby obtaining a suspension comprising nanoparticles of crystalline apalutamide.

[0048] Particle size growth of apalutamide is inhibited during crystallization, and the resulting particles remain nanoparticles. For example, if the average particle size of an amorphous apalutamide is ca. 40 nm average particle size of the apalutamide crystallized using the method of the present disclosure may be ca. 120 nm. Accordingly, although the particle size of the crystalline apalutamide would be larger than particle size of amorphous apalutamide, the crystalline apalutamide of the present disclosure is still nanosized and the particle size does not typically grow more than 300%, preferably not more than 100%, more preferably not more than 50%, still even more preferably not more than 25%, most preferably not more than 10% larger upon crystallization.

[0049] The content of the amorphous nanosized apalutamide in the admixture must be higher, such as at least 10 times higher, preferably at least 50 times, more preferably at least 100 times higher, even more preferably at least 500 times higher than its solubility in the aqueous solution comprising PVPVA or HPMC to form a suspension. Accordingly, the amount of the amorphous apalutamide needed for the method is dependent on its solubility to the aqueous solution comprising PVPVA and / or HPMC. The solubility can be measured by any method known in the art.

[0050] Typically, the contacting is at 15-40 °C, preferably at 20-40 °C, such as at 30 °C.

[0051] According to a preferable embodiment the contacting comprises mixing the suspension. The mixing is performed preferably for at least 10 h, more preferably for 16 h still more preferably for at least 24 h. Relatively long mixing time is preferable to achieve complete wetting and good dispersion. The mixing can be done e.g. by shaking, stirring, or using a spatula. The mixing and wetting can be facilitated by ultrasonication. However, high-intensity ultrasound is not needed.

[0052] If the mixing is omitted, the contacting is performed preferably for at least 24 h.

[0053] Apalutamide : polymer ratio is typically from 10:1 to 1 :10, more preferably from 5:1 to 1 :5, most preferably from 3:1 to 1 :1 , such as 2:1 or 1 :1 wherein amount of apalutamide is calculated as mg / mL of the suspension and amount of the polymer is calculated as weight-% of the suspension. For example, 25 mg / mL of amorphous nanosized apalutamide with 1 :1 API : PVPVA and / or HPMC ratio produces desired crystals in 24 h at 20 °C.

[0054] Too high polymer content may lead to slow crystal formation. The optimal polymer content is dependent on the polymer.

[0055] According to one embodiment the copolymer is PVPVA. Content of PVPVA in the aqueous solution is typically 0.2-50 % by weight, such as 0.2 - 40% by weight, preferably from 10 wt.-% to 45 wt.-%.

[0056] According to another embodiment the polymer is HPMC. Content of HPMC in the aqueous solution is typically 0.2-5 % by weight.

[0057] According to one embodiment the aqueous solution comprises one or more surfactants. Exemplary surfactants suitable for the method are sodium lauryl sulfate (SLS) Tween 80, Tween 20, dioctyl sulfosuccinate sodium salt (DOSS), and tocofersolan (TPGS). The overall content of the one or more surfactants in the aqueous solution is preferably 0.0025-1 .5% by weight. A particular surfactant is SLS. The surfactants enhance the wetting efficiency.

[0058] According to one embodiment the suspension is dried to give a solid product comprising crystalline nanosized apalutamide and PVPVA and / or HPMC. The drying can be done by using methods known in the art. Exemplary drying methods comprise heating, evaporating, vacuum drying, using a fluidized bed dryer, and freeze drying. A particular drying is evaporating. Crushing of the solid product using e.g. a mortar produces a powder ready for tableting. The crushing has no effect on the particle size.

[0059] According to another embodiment the method includes removing the polymer from the suspension e.g., by filtering with hydrophilic filter or centrifuging and subsequently discarding the supernatant with PVPVA and / or HPMC solution. After this the material can be washed e.g., with water and repeating the filtering or centrifugation step. This can be repeated as many times as needed.

[0060] Another aspect of the present disclosure relates to a process for the preparation of pharmaceutical dosage form, the process comprising

[0061] - granulating, preferably wet-granulating, the composition comprising crystallized nanosized apalutamide obtained by the process of the present disclosure with one or more pharmaceutical excipients; and

[0062] - compressing the granulate.

[0063] The method of the present disclosure allows manufacture of pharmaceutical compositions and oral dosage forms containing a comparatively high dose of the apalutamide. Accordingly, tablets that can be swallowed, i.e., tablets which have a total weight of not more than about 1000 mg but still a high drug load can be produced. Also, the tablet size can be reduced since less polymer is needed than in the corresponding ASD formulations.

[0064] According to still another aspect the present disclosure concerns a pharmaceutical composition comprising

[0065] - an effective nanoparticles of crystalline apalutamide,

[0066] - PVPVA and / or HPMC, and

[0067] - at least one pharmaceutically acceptable excipient or carrier. The disclosure also concerns a pharmaceutical composition comprising nanoparticles of crystalline apalutamide and polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methyl cellulose (HPMC) for use as a medicament, in particular in the treatment of patients with non-metastatic castration-resistant prostate cancer.

[0068] According to still another aspect the present disclosure concerns a novel polymorph of crystalline apalutamide having a powder X-ray diffraction pattern having peaks at 25.1 , 28.2, 30.4, and 33.0 ± 0.2 [°20], preferably at 18.5, 20.4, 21.5, 25.1 , 28.2,

[0069] 30.4, and 33.0 ± 0.2 [°20]. According to a preferable embodiment the crystalline polymorph consisting of particles which Dn90 is equal to or is less than 1000 nm.

[0070] According to still another aspect the present disclosure concerns a pharmaceutical composition comprising an effective amount of the crystalline polymorph of apalutamide having a powder X-ray diffraction pattern having peaks at 25.1 , 28.2,

[0071] 30.4, and 33.0 ± 0.2 [°20], preferably at 18.5, 20.4, 21 .5, 25.1 , 28.2, 30.4, and 33.0 ± 0.2 [°20] and at least one pharmaceutically acceptable excipient or carrier.

[0072] The disclosure also concerns a pharmaceutical composition comprising crystalline polymorph of apalutamide having a powder X-ray diffraction pattern having peaks at 25.1 , 28.2, 30.4, and 33.0 ± 0.2 [°20], preferably at 18.5, 20.4, 21 .5, 25.1 , 28.2,

[0073] 30.4, and 33.0 ± 0.2 [°20] and at least one pharmaceutically acceptable excipient or carrier for use as a medicament, in particular in the treatment of patients with non- metastatic castration-resistant prostate cancer.

[0074] The disclosure also concerns a pharmaceutical dosage form for oral administration comprising a composition comprising

[0075] - nanoparticles of crystalline apalutamide and

[0076] - polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methyl cellulose (HPMC).

[0077] The pharmaceutical dosage form has typically a total weight not more than 1000 mg, preferably not more than 950 mg, more preferably not more than 900 mg, still more preferably not more than 850 mg, yet more preferably not more than 800 mg, even more preferably not more than 750 mg, most preferably not more than 700 mg, and in particular not more than 650 mg. Preferably, the pharmaceutical dosage form contains the apalutamide at a dose within the range of 30±15 mg, or 40±20 mg, or 60±30 mg, or 80±40 mg, or 120±60 mg, or 150±75 mg, or 160±80 mg, or 200±80 mg, or 240±120 mg, or 300±150 mg, or 360±180 mg, in each case expressed as weight equivalent of the non-salt form of apalutamide. The pharmaceutical dosage form may be a tablet and a granulate.

[0078] The disclosure also concerns a pharmaceutical dosage form for oral administration comprising crystalline polymorph of apalutamide having a powder X-ray diffraction pattern having peaks at 25.1 , 26.31 , 25.1 , 26.3, 28.2, 30.4, and 32.0 ± 0.2 [°20], preferably at 18.6, 20.4, 21.5, 25.1 , 26.3, 28.2, 30.4, and 32.0 ± 0.2 [°20]. The pharmaceutical dosage form according to claim 26 has typically a total weight not more than 1000 mg, preferably not more than 950 mg, more preferably not more than 900 mg, still more preferably not more than 850 mg, yet more preferably not more than 800 mg, even more preferably not more than 750 mg, most preferably not more than 700 mg, and in particular not more than 650 mg. Preferably, the pharmaceutical dosage form contains the apalutamide at a dose within the range of 30±15 mg, or 40±20 mg, or 60±30 mg, or 80±40 mg, or 120±60 mg, or 150±75 mg, or 160±80 mg, or 200±80 mg, or 240±120 mg, or 300±150 mg, or 360±180 mg, in each case expressed as weight equivalent of the non-salt form of apalutamide. The pharmaceutical dosage form may be a tablet and a granulate.

[0079] Materials and methods

[0080] The amorphous nanosized apalutamide was prepared from bulk crystalline apalutamide purchased from Habotech using the process disclosed in US 10,098,842. XRD diffractogram of amorphous nanosized apalutamide is shown in figure 2.

[0081] SEM images were captured using the Zeiss Sigma 300 VP SEM instruments. Samples were dispersed into water and filtered with 0.1 pm filter. Filters were dried, transferred to SEM sample holders, and coated with a 5 nm thick layer of platinum.

[0082] XRPD measurements were carried out using the Malvern PANalytical Empyrean X- ray diffractometer equipped with a Cu Ka (1.54 A) source, MultiCore optics and a solid-state PIXcel3D detector. By using Kapton tape the samples were attached onto aluminum or polycrystalline silicon sample holders. Dried slurries were measured without further sample preparation under Kapton tape and suspensions were filtered, dried, and filters were attached with double sided tape. The samples were measured in the reflection geometry in a spinning measurement stage. The measurement range was 5 - 40 (°20). The step size and time per step values were varied depending on the counts per second obtained.

[0083] Dissolution studies

[0084] The dissolution properties were measured with a Pion Rainbow R2D instrument (Pion Inc UK Ltd, Forest Row, UK) in biphasic mode starting in Simulated gastric media (SGF) (0.025 M HCI pH 1 .6) for 15 min. Thereafter, the content of the SGF was converted to FaSSIF medium pH 6.5 by addition of 10 mL of FaSSIF concentrate media. The temperature was set to 37°C and stirring rate to 150 rpm. Apalutamide concentrations were continuously monitored with a fiber optical UV-Vis probe. UV-Vis spectra were collected in 30-sec intervals using the Pion Rainbow Dynamic with 5 mm tips. The apalutamide concentration was calculated based on a standard curve using 2nd derivative data transformation (stock solution 5 mg / mL in ethanol of respective apalutamide) at a range of 293-320 nm.

[0085] Calculation of contents of apalutamide and the polymers

[0086] Calculation of contents of apalutamide (APA) and polymers in the suspension was done as shown in table 1 .

[0087] Table 1 .

[0088] Crystallization

[0089] Amorphous nanosized apalutamide was added as dry powder to aqueous polymer solutions. The admixtures formed were blended with a metal spatula and allowed to stand at room temperature for 18-24 h. The suspension formed was analyzed after 18-24 h. SEM and XRD samples were prepared as described above.

[0090] Determination of crystallization

[0091] Determination of crystallization of amorphous apalutamide nanoparticles from aqueous suspensions comprising PVPVA or HPMC was evaluated as a function of time. Accordingly, XRD measurement was done for suspension in different time points. Crystallization has reached its thermodynamic maximum when the peak heights do not increase anymore in time.

[0092] Preparation of solid materials Suspension comprising nanosized apalutamide prepared as disclosed above were dried in a vacuum desiccator overnight. The solid materials were grounded to produce powders. The powders comprising nanosized apalutamide were used in the dissolution tests. Results are shown in table 2.

[0093] Table 2. a: mg APA in g of polymer solution, b: by weight; c: bulk = same as the API before conversion to amorphous nanoparticles; d: determined from SEM images by visual inspection 5 = nanocrystals, 1 = large crystals; e: apalutamide / polymer ratio (w / w); f. loading degree (wt.-%). Tableting

[0094] Formulations were manufactured by using the wet granulation technique.

[0095] Apalutamide loading of 20% w / w was used and tablet compression parameters (e.g., die cavity height, compression force, ejection force, strokes / min) were kept constant to investigate the impact of excipients on the tablet properties.

[0096] Compressed tablets were manufactured by a process comprising the following steps:

[0097] 1 . Wet blending

[0098] 2. Wet granulating

[0099] 3. Drying

[0100] 4. Grinding and sieving

[0101] 5. Lubricating

[0102] 6. Compressing

[0103] 7. Dedusting and storing

[0104] Characterization of the new form of apalutamide

[0105] Solid material including apalutamide and PVPVA or HPMC were characterized by XRD. Diffractograms after background subtraction are shown in figure 1 . Main peak positions were extracted via a simulation protocol in HighScore software. Peak parameters are presented in table 3 and 4. The XRD patterns, indicated by 13 reflections do not match to the polymorphic forms known in the patent literature up to date. This allows to conclude, that the particular molecular arrangement found in the formulated API based system represents a novel structural entity of nanocrystalline apalutamide, stabilized by HPMC (Fig 1A) or PVPVA (Fig 1 B).

[0106] Table 3. Composition comprising apalutamide and HPMC. Table 4. Composition comprising apalutamide and PVPVA

[0107] Results and Discussion

[0108] Figures 3 and 4 show XRD diffractograms and SEM images of amorphous nanosized apalutamide contacted with aqueous polymers in the presence of SLS for 24 h at 25 °C followed by evaporation. In each case the apalutamide : polymer ratio was 2:1 (w / w). As seen from the figures, apalutamide formed desired nanosized crystals when the crystallization was performed in the presence of aqueous PVPVA and HPMC. The polymorph obtained is not disclosed in the art. Crystallization of amorphous nanosized apalutamide from a suspension comprising poloxamer, in turn, produced large crystals of apalutamide (form B).

[0109] Figure 5 shows SGF-FaSSIF dissolution profiles of compositions comprising nanocrystalline apalutamide and PVPVA included 0.2 wt.-% SLS (apalutamide: polymer ratio 2:1 , w / w) prepared according to the method of the present disclosure and commercial Erleada® tablet i.e. an amorphous solid dispersion comprising apalutamide and HPMCAS. Also, SGF-FaSSIF dissolution profile of bulk apalutamide is disclosed. As seen from the figure dissolution of the composition of the present disclosure is significantly less pH sensitive than that of the amorphous solid dispersion.

[0110] Areas under curve (AUC; 0-60 min) of dry powdered apalutamides of the present disclosure resuspended in 1 % PVPVA suspension vehicle, bulk apalutamide, and Erleada® tablets resuspended in water are collected in table 5. Table 5

[0111] As seen from the table, the apalutamide compositions of the present disclosure have higher AUC than the commercial amorphous solid dispersion. Compositions comprising nanocrystalline apalutamide and PVPVA or HPMC prepared according to the present disclosure were stable under accelerated conditions (40 °C / 75% RH) up to tested 30 days as verified by HPLC and XRD analysis.

[0112] In contrast to amorphous solid dispersion of apalutamide the nanosized crystalline apalutamide of the present does not need to be supersaturated by the polymer for stabilization. Accordingly, the amount of the polymer and / or copolymer in the dose can be reduced compared to a corresponding dose including apalutamide in amorphous form. Furthermore, the method of the present disclosure has an advantage that it does not include organic solvents which may not be completely removable by practical manufacturing techniques. Also, subjecting apalutamide to significant mechanical force for breaking apalutamide particles into smaller ones can be avoided.

Claims

What is claimed is1 . A composition comprising- nanoparticles of crystalline apalutamide and- polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methyl cellulose (HPMC).

2. The composition according to claim 1 wherein the composition comprises one or more surfactants preferably selected from the group consisting of sodium lauryl sulfate (SLS) Tween 80, Tween 20, dioctyl sulfosuccinate sodium salt (DOSS), and tocofersolan (TPGS), more preferably SLS.

3. The composition according to claim 1 or 2 wherein the composition comprises PVPVA and wherein the ratio apalutamide : PVPVA is from 10:1 (w / w) to 1 :10 (w / w), preferably from 5:1 (w / w) to 1 :1 (w / w), such as 4:1 (w / w), 3:1 (w / w), 2:1 (w / w), or 1 :1 (w / w).

4. The composition according to any one of claims 1 to 3 wherein the composition comprises HPMC and wherein the ratio apalutamide : HPMC is from 10:1 (w / w) to 1 :10 (w / w), preferably from 5:1 (w / w) to 1 :1 (w / w), such as 4:1 (w / w), 3:1 (w / w), 2:1 (w / w), or 1 :1 (w / w).

5. The composition according to any one of claims 1 to 4 wherein the polymer is HPMC and the crystalline apalutamide of the composition is a polymorph characterized by a powder X-ray diffraction pattern having peaks at 25.1 , 28.3, 30.6, and 33.0 ± 0.2 [°20], preferably at 18.6, 20.4, 21 .5, 25.1 , 28.3, 30.6, and 33.0, more preferably the same as the X-ray powder diffraction pattern shown in Fig 1A.

6. The composition according to any one of claims 1 to 4 wherein the polymer is PVPVA and the crystalline apalutamide of the composition is a polymorph characterized by a powder X-ray diffraction pattern having peaks at 25.0, 28.1 , 30.4, and 32.9 ± 0.2 [°20], preferably 18.5, 20.3, 21.5, 25.0, 28.11 , 30.3, and 32.9 ± 0.2 [°20], more preferably the same as the X-ray powder diffraction pattern shown in Fig 1 B.

7. A method for producing nanoparticles of crystalline apalutamide, the method comprising the steps of: a) providing solid amorphous nanosized apalutamide;b) providing an aqueous solution comprising polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methyl cellulose (HPMC); and c) contacting the solid amorphous nanosized apalutamide and the aqueous solution to form an admixture wherein content of the amorphous nanosized apalutamide in the admixture is higher than solubility of the amorphous nanosized apalutamide in the aqueous solution, thereby obtaining a suspension comprising nanoparticles of crystalline apalutamide.

8. The method according to claim 7 wherein content of the amorphous nanosized apalutamide in the admixture is at least 10 times higher, preferably at least 50 times higher, more preferably at least 100 times higher, even more preferably at least 500 times higher than solubility of the amorphous nanosized API in the solution comprising the one or more polymers and / or copolymers.

9. The method according to claim 7 or 8 wherein the aqueous solution comprises one or more surfactants and wherein content of the one or more surfactants in the aqueous solution is 0.0025-1 .5% by weight.

10. The method according to any one of claims 7 to 9 wherein the aqueous solution comprises 0.2-50 wt.-% PVPVA, preferably 10-25 wt.-% PVPVA.

11. The method according to any one of claims 7 to 10 wherein the aqueous solution comprises 0.2-5 wt.-% HPMC.

12. The method according to any one of claims 7 to 11 wherein particle size of the crystalline apalutamide is not more than 300%, preferably not more than 100%, even more preferably not more than 50%, still even more preferably not more than 25%, most preferably not more than 10% larger than the particle size of the nanosized amorphous apalutamide.

13. The method according to any one of claims 7 to 12 wherein the contacting comprises mixing the suspension.

14. The method according to any one of claims 7 to 13 wherein the contacting comprises subjecting the suspension to ultrasound.

15. The method according to claim any one of claims 7 to 14 wherein the contacting is at least for 10 h, preferably at least for 16 h, more preferably at least for 24 h.

16. The method according to any one of claims 7 to 15 comprising drying the suspension thereby producing a solid comprising nanosized apalutamide in crystalline form and PVPVA and / or HPMC.

17. The method according to claim 16 comprising crushing the solid thereby producing a powder comprising nanosized apalutamide in crystalline form and PVPVA and / or HPMC.

18. A pharmaceutical composition comprising the composition according to any one of claims 1 to 6 including an effective amount of apalutamide and at least one pharmaceutically acceptable excipient or carrier.

19. The composition according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 18 for use as a medicament.

20. The composition according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 18 for use in the treatment of patients with non- metastatic castration-resistant prostate cancer.

21. A crystalline polymorph of 4-[7-(6-cyano-5-trifluoromethyl pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methyl benzamide(apalutamide) characterized by a powder X-ray diffraction pattern having peaks at 25.1 , 28.2, 30.4, and 33.0 ± 0.2 [°20], preferably at 18.5, 20.4, 21.5, 25.1 , 28.2, 30.4, and 33.0 ± 0.2 [°20].

22. The crystalline polymorph according to claim 21 consisting of particles which Dv90 is equal to or is less than 1000 nm.

23. A pharmaceutical composition comprising an effective amount of the crystalline polymorph of apalutamide according to claim 21 or 22 and at least one pharmaceutically acceptable excipient or carrier.

24. The crystalline polymorph according to claim 21 or 22 or the pharmaceutical composition according to claim 23 for use as a medicament.

25. The crystalline polymorph according to claim 21 or 22 or the pharmaceutical composition according to claim 23 for use in the treatment of patients with non- metastatic castration-resistant prostate cancer.

26. A pharmaceutical dosage form for oral administration comprising the composition according to any of claims 1 to 6 or the crystalline polymorph according to claim 21 or 22.

27. The pharmaceutical dosage form according to claim 26 which has a total weight of not more than 1000 mg, preferably not more than 950 mg, more preferably not more than 900 mg, still more preferably not more than 850 mg, yet more preferably not more than 800 mg, even more preferably not more than 750 mg, most preferably not more than 700 mg, and in particular not more than 650 mg.

28. The pharmaceutical dosage form according to 27, which contains the apalutamide at a dose within the range of 30±15 mg, or 40±20 mg, or 60±30 mg, or 80±40 mg, or 120±60 mg, or 150±75 mg, or 160±80 mg, or 200±80 mg, or 240±120 mg, or 300±150 mg, or 360±180 mg, in each case expressed as weight equivalent of the non-salt form of apalutamide.

29. The pharmaceutical dosage form according to any one of claims 26 to 28 wherein the form is selected from a tablet and a granulate.

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