Composition containing crystalline nanoscale apalutamide

Abstract

The present disclosure relates to a composition comprising nanoparticles of crystalline apalutamide and polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methylcellulose (HPMC). The present disclosure also relates to a method for preparing a composition.

Description

Technology Field

[0001] The present disclosure relates to a composition comprising crystalline nanoscale apalutamide and one or more polymers, and a method for preparing the same. Background Technology

[0002] Apalutamide, i.e., (4-[7-(6-cyano-5-trifluoromethylpyridine-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3,4]oct-5-yl]-2-fluoro-N-methylbenzamide, 1 Erleada, manufactured by Janssen Biotech as 60 mg and 240 mg oral tablets in the U.S. and EU for the treatment of patients with non-metastatic castration-resistant prostate cancer. ® It is being sold under the product name [Name].

[0003]

[0004] Apalutamide is substantially insoluble in aqueous media over a wide range of pH values. Furthermore, apalutamide is a non-hygroscopic crystalline solid that remains unionized within the physiological pH range. Erleada ® The tablet contains apalutamide as an amorphous solid dispersion (ASD) in hypromellose acetate succinate (HPMCAS).

[0005] ASD is susceptible to thermodynamic instability due to the high free energy associated with its amorphous state. Numerous factors, such as the inappropriate selection of formulation ingredients, thermal stress, environmental stresses like humidity, and manufacturing stress, contribute to the physical instability of ASD. To obtain stable ASD medicines, the appropriate selection of formulation ingredients, manufacturing processes, process parameters, and packaging components is considered essential. Furthermore, ASD dosages must contain a significant amount of polymer to increase the dosage volume.

[0006] Therefore, there is still a need for additional stable and bioavailable forms of apalutamide.

[0007] It was observed that when amorphous nanoscale apalutamide was brought into contact with an aqueous solution containing a specific polymer, crystalline nanoscale apalutamide was obtained.

[0008] Accordingly, the purpose of the present disclosure is,

[0009] - Nanoparticles of crystalline apalutamide, and

[0010] - Polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methylcellulose (HPMC)

[0011] The purpose is to provide a composition comprising

[0012] Another object of the present disclosure is to provide a method for producing nanoparticles of crystalline apalutamide, wherein the method comprises:

[0013] a) A step of providing solid amorphous nanoscale apalutamide;

[0014] b) A step of providing an aqueous solution comprising polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methylcellulose (HPMC);

[0015] c) A step of contacting solid amorphous nanoscale apalutamide with an aqueous solution containing PVPVA and / or HPMC to form a mixture in which the content of amorphous nanoscale apalutamide in the mixture is higher than the solubility of amorphous nanoscale apalutamide in the aqueous solution.

[0016] It includes, thereby obtaining a suspension containing nanoparticles of crystalline apalutamide.

[0017] Another object of the present disclosure is to provide a crystalline polymorph of 4-[7-(6-cyano-5-trifluoromethylpyridine-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3,4]oct-5-yl]-2-fluoro-N-methylbenzamide (apalutamide) characterized by a powder X-ray diffraction pattern having peaks at 25.1, 28.2, 30.4, and 33.0 ± 0.2 [°2θ].

[0018] Another objective of the present disclosure is,

[0019] - Nanoparticles of an effective amount of crystalline apalutamide,

[0020] - Polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methylcellulose (HPMC), and

[0021] - At least one pharmaceutically acceptable excipient or carrier

[0022] The purpose is to provide a pharmaceutical composition comprising

[0023] Another object of the present disclosure is 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 [°2θ], and at least one pharmaceutically acceptable excipient or carrier.

[0024] Another object of the present disclosure is for use as a medicine, particularly for use in the treatment of patients with non-metastatic castration-resistant prostate cancer,

[0025] - Nanoparticles of crystalline apalutamide and

[0026] - Polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methylcellulose (HPMC)

[0027] The purpose is to provide a pharmaceutical composition comprising

[0028] Another object of the present disclosure is 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 [°2θ] for use as a medicine, particularly for use in the treatment of patients with non-metastatic castration-resistant prostate cancer.

[0029] Another objective of the present disclosure is,

[0030] - Nanoparticles of crystalline apalutamide, and

[0031] - Polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methylcellulose (HPMC)

[0032] The invention provides a pharmaceutical dosage form for oral administration comprising a composition containing [the following].

[0033] Another object of the present disclosure is 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 [°2θ].

[0034] Various exemplary and non-limiting embodiments of the present invention are described in the appended dependent claims.

[0035] Various exemplary and non-limiting embodiments and methods of operation of the present invention are best understood from the following description of specific exemplary embodiments, along with additional purposes and benefits.

[0036] The verbs "to comprise" and "to include" are used as open limitations that do not exclude or require the existence of features not described in this document. Features described in dependent claims are freely combined with one another unless otherwise explicitly stated. Additionally, it should be understood that throughout this document, the use of "a" or "an," i.e., the singular form, does not exclude the plural. Brief explanation of the drawing

[0037] Figure 1 A represents the XRD diffraction pattern of a composition obtained by contacting nanoscale amorphous apalutamide with 5 wt% aqueous HPMC containing 0.2 wt% SLS, where the apalutamide:HPMC ratio was 4:1 (w / w), and B Figure 1 shows the XRD diffraction pattern of a composition obtained by contacting nanoscale amorphous apalutamide with 25 wt% aqueous PVPVA, where the apalutamide:PVPVA ratio was 2:1 (w / w). The sample was dried for 24 hours prior to XRD measurement. Figure 2 shows the XRD diffraction pattern of amorphous nanoscale apalutamide. Figure 3a) shows the XRD diffraction pattern of apalutamide contacted with an aqueous solution of 5 wt% HPMC and 0.2 wt% SLS at room temperature for 24 hours; b) shows the XRD diffraction pattern of apalutamide contacted with an aqueous solution of 25 wt% PVPVA and 0.2 wt% SLS at room temperature for 24 hours; and c) shows the XRD diffraction pattern of apalutamide contacted with an aqueous solution of 25 wt% Poloxamer 407 and 0.2 wt% SLS at room temperature for 24 hours. The apalutamide:polymer ratio was 2:1 (w / w). The samples were dried for 24 hours prior to XRD measurement. Figure 4 Arepresents an SEM image of apalutamide contacted with an aqueous solution of 5 wt% HPMC and 0.2 wt% SLS for 24 hours at room temperature; B represents an SEM image of apalutamide contacted with an aqueous solution of 25 wt% PVPVA and 0.2 wt% SLS for 24 hours at room temperature; C Figure 1 shows an SEM image of apalutamide in contact with an aqueous solution of 25 wt% poloxamer 407 and 0.2 wt% SLS. The apalutamide:polymer ratio was 2:1 (w / w). The sample was dried for 24 hours prior to SEM measurement. FIG. 5a) shows the SGF-FaSSIF dissolution profile of a composition of nanoscale crystalline apalutamide and PVPVA (the apalutamide:PVPVA ratio was 2:1 (w / w), and the composition contained 0.2 wt% SLS); b) shows the SGF-FaSSIF dissolution profile of bulk apalutamide; and c) shows the ASD (Erleada) of apalutamide ® This shows the dissolution profile of SGF-FaSSIF. Specific details for implementing the invention

[0038] Specific examples in the description provided below should not be construed as limiting the scope and / or applicability of the appended claims. The list and group of examples in the description provided below are not exhaustive unless otherwise expressly stated.

[0039] As defined herein, nanoscale apalutamide consists of particles with a Dv90 of 1000 nm or less, that is, 90% of the volume fraction of nanoscale apalutamide consists of particles having a diameter of less than 1000 nm. The apalutamide particle size may be 10 nm to 1000 nm, for example, 10 nm to 200 nm, 200 nm to 500 nm, or 500 nm to 1000 nm. The size distribution can be adjusted as desired.

[0040] As defined herein, the suspension is apalutamide suspended in a liquid (whereas an aqueous solution containing PVPVA and / or HPMC).

[0041] As defined herein, an aqueous solution is water containing one or more dissolved substances. The dissolved substances in the aqueous solution may be solid, liquid, or gas.

[0042] Unless otherwise explicitly stated, the term “apalutamide” refers to apalutamide, its non-salt forms, its physiologically acceptable salts, co-crystals, polymorphs, and / or solvates.

[0043] According to one aspect, the present disclosure relates to nanoparticles of crystalline apalutamide and a composition comprising PVPVA and / or HPMC.

[0044] According to one embodiment, the composition comprises apalutamide and PVPVA, and the apalutamide:PVPVA ratio is 10:1 (w / w) to 1:10 (w / w), preferably 3:1 to 1:1 (w / w), such as 2:1 (w / w) or 1:1 (w / w).

[0045] According to another embodiment, the composition comprises apalutamide, PVPVA, and one or more surfactants. The surfactant is generally selected from the group consisting of sodium lauryl sulfate (SLS), Tween 80, Tween 20, sodium dioctyl sulfosuccinate (DOSS), and tocopersolan (TPGS), preferably SLS. The ratio of apalutamide to PVPVA in the composition is generally 10:1 (w / w) to 1:10 (w / w), preferably 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).

[0046] According to another embodiment, the composition comprises apalutamide and HPMC, and the apalutamide:HPMC ratio is 10:1 (w / w) to 1:10 (w / w), preferably 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).

[0047] According to another embodiment, the composition comprises apalutamide, HPMC, and one or more surfactants. The surfactant is generally selected from the group consisting of sodium lauryl sulfate (SLS), Tween 80, Tween 20, sodium dioctyl sulfosuccinate (DOSS), and tocopersolan (TPGS), preferably SLS. The apalutamide:HPMC ratio is generally 10:1 (w / w) to 1:10 (w / w), preferably 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).

[0048] According to a specific embodiment, the polymer is HPMC, and the nanoscale crystalline apalutamide of the composition has a powder X-ray diffraction pattern with peaks at 25.1, 28.3, 30.6, and 33.0 ± 0.2 [°2θ], preferably has a powder X-ray diffraction pattern with peaks at 18.6, 20.4, 21.5, 25.1, 28.3, 30.6, and 33.0 ± 0.2 [°2θ], more preferably is the same as the X-ray powder diffraction pattern shown in FIG. 1A.

[0049] According to another specific embodiment, the polymer is PVPVA, and the nanoscale crystalline apalutamide of the composition has a powder X-ray diffraction pattern with peaks at 25.0, 28.1, 30.3, and 32.9 ± 0.2 [°2θ], preferably has a powder X-ray diffraction pattern with peaks at 18.5, 20.3, 21.5, 25.0, 28.1, 30.3, and 32.9 ± 0.2 [°2θ], more preferably is the same as the X-ray powder diffraction pattern shown in FIG. 1B.

[0050] According to another aspect, the present disclosure relates to a method for producing nanoparticles of crystalline apalutamide, wherein the method comprises:

[0051] a) a step of providing solid amorphous nanoscale apalutamide, preferably as a dry powder;

[0052] b) a step of providing an aqueous solution containing PVPVA and / or HPMC;

[0053] c) a step of contacting solid amorphous nanoscale apalutamide with an aqueous solution containing PVPVA and / or HPMC to form a mixture in which the content of amorphous nanoscale apalutamide in the mixture is higher than the solubility of amorphous nanoscale apalutamide in the aqueous solution.

[0054] It includes, thereby obtaining a suspension containing nanoparticles of crystalline apalutamide.

[0055] During crystallization, the particle size growth of apalutamide is inhibited, and the resulting particles are maintained as nanoparticles. For example, if the average particle size of amorphous apalutamide is about 40 nm, the average particle size of apalutamide crystallized using the method of the present disclosure may be about 120 nm. Thus, even if the particle size of crystalline apalutamide is larger than that of amorphous apalutamide, the crystalline apalutamide of the present disclosure is still nano-sized, and the particle size at crystallization generally increases by 300% or less, preferably 100% or less, more preferably 50% or less, even more preferably 25% or less, and most preferably 10% or less.

[0056] The content of amorphous nanoscale apalutamide in the mixture must be higher than its solubility in an aqueous solution containing PVPVA or HPMC to form a suspension, for example, at least 10 times higher, preferably at least 50 times higher, more preferably at least 100 times higher, and even more preferably at least 500 times higher. Accordingly, the amount of amorphous apalutamide required for the method depends on its solubility in an aqueous solution containing PVPVA and / or HPMC. Solubility can be measured by any method known in the art.

[0057] Generally, contact is performed at 15-40°C, preferably at 20-40°C, for example at 30°C.

[0058] According to a preferred embodiment, contact involves mixing the suspension. Mixing is preferably performed for at least 10 hours, more preferably for 16 hours, and even more preferably for at least 24 hours. A relatively long mixing time is preferred to achieve complete wetting and good dispersion. Mixing may be performed, for example, by shaking, stirring, or using a spatula. Mixing and wetting may be facilitated by sonication. However, high-intensity ultrasound is not required.

[0059] If mixing is omitted, contact is preferably performed for at least 24 hours.

[0060] The apalutamide:polymer ratio is generally 10:1 to 1:10, more preferably 5:1 to 1:5, most preferably 3:1 to 1:1, e.g. 2:1 or 1:1, where the amount of apalutamide is calculated as mg / mL of the suspension and the amount of polymer is calculated as weight-% of the suspension. For example, 25 mg / mL of amorphous nanoscale apalutamide with an API:PVPVA and / or HPMC ratio of 1:1 produces the desired crystals within 24 hours at 20°C.

[0061] Excessively high polymer content can lead to slow crystal formation. The optimal polymer content varies depending on the polymer.

[0062] According to one embodiment, the copolymer is PVPVA. The content of PVPVA in the aqueous solution is generally 0.2-50 wt%, e.g. 0.2-40 wt%, preferably 10 wt% to 45 wt%.

[0063] According to another embodiment, the polymer is HPMC. The content of HPMC in the aqueous solution is generally 0.2-5 weight%.

[0064] 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, sodium dioctyl sulfosuccinate (DOSS), and tocopersolane (TPGS). The total content of one or more surfactants in the aqueous solution is preferably 0.0025 to 1.5 weight percent. A specific surfactant is SLS. The surfactant improves wetting efficiency.

[0065] According to one embodiment, the suspension is dried to provide a solid product comprising crystalline nanoscale apalutamide and PVPVA and / or HPMC. Drying may be performed using methods known in the art. Exemplary drying methods include heating, evaporation, vacuum drying, the use of a fluidized bed dryer, and freeze-drying. A specific drying method is evaporation. For example, grinding the solid product using a mortar and pestle produces a powder prepared for purification. Grinding does not affect the particle size.

[0066] According to another embodiment, the method comprises removing the polymer from the suspension by, for example, filtering with a hydrophilic filter or centrifuging and then discarding the supernatant along with the PVPVA and / or HPMC solution. Subsequently, the material may be washed, for example, by washing with water and repeating the filtration or centrifugation step. This may be repeated as many times as necessary.

[0067] Another aspect of the present disclosure relates to a process for manufacturing a pharmaceutical dosage form, wherein the process is,

[0068] - A step of granulating, preferably wet granulating, a composition comprising crystallized nanoscale apalutamide obtained by the process of the present disclosure together with one or more pharmaceutical excipients; and

[0069] - It includes a step of compressing the granules.

[0070] The method of the present disclosure enables the production of pharmaceutical compositions and oral administration forms containing a relatively high dose of apalutamide. Thus, swallowable tablets can be produced, i.e., tablets with a total weight of about 1000 mg or less but still having a high drug content. Additionally, the tablet size can be reduced because less polymer is required compared to the corresponding ASD formulation.

[0071] According to another aspect, the present disclosure is,

[0072] - Nanoparticles of an effective amount of crystalline apalutamide,

[0073] - PVPVA and / or HPMC, and

[0074] - At least one pharmaceutically acceptable excipient or carrier

[0075] This relates to a pharmaceutical composition comprising

[0076] The present disclosure also relates to a pharmaceutical composition comprising nanoparticles of crystalline apalutamide and polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methylcellulose (HPMC) for use as a medicine, particularly for use in the treatment of patients with non-metastatic castration-resistant prostate cancer.

[0077] According to another aspect, the present disclosure relates to 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 [°2θ], preferably having a powder X-ray diffraction pattern having peaks at 18.5, 20.4, 21.5, 25.1, 28.2, 30.4, and 33.0 ± 0.2 [°2θ]. According to a preferred embodiment, the crystalline polymorph consists of particles in which Dn90 is 1000 nm or less.

[0078] According to another aspect, the present disclosure relates to a pharmaceutical composition comprising an effective amount of apalutamide crystalline polymorph having a powder X-ray diffraction pattern having peaks at 25.1, 28.2, 30.4, and 33.0 ± 0.2 [°2θ], preferably having a powder X-ray diffraction pattern having peaks at 18.5, 20.4, 21.5, 25.1, 28.2, 30.4, and 33.0 ± 0.2 [°2θ], and at least one pharmaceutically acceptable excipient or carrier.

[0079] The present disclosure also relates to a pharmaceutical composition comprising a 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 [°2θ], preferably having peaks at 18.5, 20.4, 21.5, 25.1, 28.2, 30.4, and 33.0 ± 0.2 [°2θ], and at least one pharmaceutically acceptable excipient or carrier, for use as a medicine, particularly for use in the treatment of patients with non-metastatic castration-resistant prostate cancer.

[0080] The present disclosure also,

[0081] - Nanoparticles of crystalline apalutamide and

[0082] - Polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methylcellulose (HPMC)

[0083] This relates to a pharmaceutical dosage form for oral administration comprising a composition containing [a specific composition].

[0084] The pharmaceutical dosage form generally has a total weight of 1,000 mg or less, preferably 950 mg or less, more preferably 900 mg or less, even more preferably 850 mg or less, even more preferably 800 mg or less, even more preferably 750 mg or less, most preferably 700 mg or less, particularly 650 mg or less. Preferably, the pharmaceutical dosage form contains apalutamide in doses 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, expressed in each case as the weight equivalent of the non-salt form of apalutamide. The pharmaceutical dosage form may be tablets and granules.

[0085] The present disclosure also relates to a pharmaceutical dosage form for oral administration comprising a polymorph of crystalline 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 [°2θ], preferably having a powder X-ray diffraction pattern having peaks at 18.6, 20.4, 21.5, 25.1, 26.3, 28.2, 30.4, and 32.0 ± 0.2 [°2θ]. The pharmaceutical dosage form according to claim 26 generally has a total weight of 1000 mg or less, preferably 950 mg or less, more preferably 900 mg or less, even more preferably 850 mg or less, even more preferably 800 mg or less, even more preferably 750 mg or less, most preferably 700 mg or less, particularly 650 mg or less. Preferably, the pharmaceutical dosage form contains apalutamide in 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, expressed in each case as a weight equivalent of the non-salt form of apalutamide. The pharmaceutical dosage forms may be tablets and granules.

[0086] Materials and Methods

[0087] Amorphous nanoscale apalutamide was prepared from bulk crystalline apalutamide purchased from Habotech using the process disclosed in US 10,098,842. The XRD diffraction pattern of the amorphous nanoscale apalutamide is shown in Fig. 2.

[0088] SEM images were taken using a Zeiss Sigma 300 VP SEM instrument. The sample was dispersed in water and filtered through a 0.1 μm filter. The filter was dried, transferred to an SEM sample holder, and coated with a 5 nm thick platinum layer.

[0089] XRPD measurements were performed using a Malvern PANalytical Empyrean X-ray diffractometer equipped with a Cu Kα (1.54 Å) source, a MultiCore optical system, and a solid-state PIXcel3D detector. Samples were attached to aluminum or polycrystalline silicon sample holders using Kapton tape. Dried slurries were measured under Kapton tape without additional sample preparation; the suspension was filtered and dried, after which a filter was attached using double-sided tape. Samples were measured in reflection geometry on a rotary measurement stage. The measurement range was 5–40 (°2θ). The step size and time per step values ​​varied according to the obtained counts per second.

[0090] Dissolution research

[0091] Solubility characteristics were measured using a Pion Rainbow R2D instrument (Pion Inc UK Ltd, Forest Row, UK) in biphasic mode starting for 15 minutes in simulated gastric juice (SGF) (0.025 M HCl pH 1.6). Subsequently, 10 mL of FaSSIF concentrated medium was added to the contents of the SGF to convert the pH to FaSSIF medium pH 6.5. The temperature was set to 37°C and the stirring speed to 150 rpm. Apalutamide concentration was continuously monitored using a fiber optic UV-Vis probe. UV-Vis spectra were collected at 30-second intervals using a Pion Rainbow Dynamic equipped with a 5 mm tip. Apalutamide concentration was calculated based on a standard curve using second-order derivative data transformation (5 mg / mL stock solution of each apalutamide in ethanol) in the 293–320 nm range.

[0092] Calculation of apalutamide and polymer content

[0093] The content of apalutamide (APA) and polymer in the suspension was calculated as shown in Table 1.

[0094] Table 1.

[0095]

[0096] crystallization

[0097] Amorphous nanoscale apalutamide was added to an aqueous polymer solution as a dry powder. The resulting mixture was blended with a metal spatula and left at room temperature for 18–24 hours. The resulting suspension was analyzed after 18–24 hours. SEM and XRD samples were prepared as described above.

[0098] Crystallization confirmation

[0099] The confirmation of crystallization of amorphous apalutamide nanoparticles from aqueous suspensions containing PVPVA or HPMC was evaluated as a function of time. Accordingly, XRD measurements were performed on the suspensions at different time points. Crystallization was defined as reaching a thermodynamic maximum when the peak height no longer increased over time.

[0100] Manufacturing of solid materials

[0101] The suspension containing nanoscale apalutamide prepared as disclosed above was dried overnight in a vacuum desiccator. The solid material was ground to produce a powder. The powder containing nanoscale apalutamide was used in a dissolution test. The results are shown in Table 2.

[0102] Table 2.

[0103]

[0104]

[0105] a: mg of APA per g of polymer solution, b: Weight basis; c : Bulk = Same as API before conversion to amorphous nanoparticles; d : Determined by visual inspection of SEM images; 5 = nanocrystals, 1 = large crystals; e : Apalutamide / polymer ratio (w / w); f Loading percentage (weight%).

[0106] Refining

[0107] The formulation was prepared using a wet granulation technique. An apalutamide content of 20% w / w was used, and tablet compression parameters (e.g., die cavity height, compression force, ejection force, stroke / min) were kept constant to investigate the effect of excipients on tablet characteristics.

[0108] Compressed tablets were manufactured by the following process steps:

[0109] 1. Wet blending

[0110] 2. Wet granulation

[0111] 3. Drying

[0112] 4. Grinding and sieving

[0113] 5. Hwaltaek

[0114] 6. Compression

[0115] 7. Dust Removal and Storage

[0116] Characterization of the new form of Apalutamid

[0117] Solid materials containing apalutamide and PVPVA or HPMC were characterized by XRD. The diffraction pattern after background subtraction is shown in Fig. 1. The main peak positions were extracted using the simulation protocol of HighScore software. Peak parameters are presented in Tables 3 and 4. The XRD pattern shows 13 reflections, which do not match polymorphic forms known in patent literature to date. This makes it possible to conclude that the specific 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. 1B).

[0118] Table 3. Composition containing apalutamide and HPMC.

[0119]

[0120] Table 4. Composition comprising apalutamide and PVPVA.

[0121]

[0122] Results and Discussion

[0123] Figures 3 and 4 show XRD diffraction and SEM images of amorphous nanoscale apalutamide evaporated after contact with an aqueous polymer in the presence of SLS for 24 hours at 25°C. In each case, the apalutamide:polymer ratio was 2:1 (w / w). As can be seen in the figures, apalutamide formed desired nanoscale crystals when crystallization was performed in the presence of aqueous PVPVA and HPMC. The obtained polymorph is not disclosed in the art. On the other hand, when amorphous nanoscale apalutamide was crystallized from a suspension containing poloxamer, large crystals of apalutamide (morph B) were produced.

[0124] FIG. 5 shows a composition comprising nanocrystalline apalutamide containing 0.2 wt% SLS prepared according to the method of the present disclosure and PVPVA (apalutamide:polymer ratio 2:1, w / w) and commercial Erleada ® The SGF-FaSSIF solubility profile of a purified amorphous solid dispersion comprising apalutamide and HPMCAS is shown. Additionally, the SGF-FaSSIF solubility profile of bulk apalutamide is also disclosed. As can be seen in the figure, the solubility of the composition of the present disclosure exhibits significantly lower pH sensitivity compared to the solubility of the amorphous solid dispersion.

[0125] Dry powdered apalutamide of the present disclosure resuspended in a 1% PVPVA suspension vehicle, bulk apalutamide, and Erleada resuspended in water ® The area under the curve (AUC; 0-60 min) of the tablets is collected in Table 5.

[0126] Table 5

[0127]

[0128] As can be seen in the table, the apalutamide composition of the present disclosure has a higher AUC than commercial amorphous solid dispersions.

[0129] A composition comprising nanocrystalline apalutamide and PVPVA or HPMC prepared according to the present disclosure was stable for up to 30 days under accelerated conditions (40°C / 75% RH), as verified by HPLC and XRD analysis.

[0130] Unlike amorphous solid dispersions of apalutamide, the nanoscale crystalline apalutamide of the present disclosure does not need to be supersaturated by a polymer for stabilization. Therefore, the amount of polymer and / or copolymer in the dose can be reduced compared to a corresponding dose containing apalutamide in its amorphous form. Additionally, the method of the present disclosure has the advantage of not including organic solvents that may not be completely removed by practical manufacturing techniques. Furthermore, it is possible to avoid applying significant mechanical force to the apalutamide to grind the apalutamide particles into smaller ones.

Claims

Claim 1 - A composition comprising nanoparticles of crystalline apalutamide and - polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methylcellulose (HPMC). Claim 2 A composition according to claim 1, wherein the composition comprises one or more surfactants, said surfactants preferably selected from the group consisting of sodium lauryl sulfate (SLS), Tween 80, Tween 20, sodium dioctyl sulfosuccinate (DOSS), and tocopersolan (TPGS), and more preferably SLS. Claim 3 A composition according to claim 1 or 2, wherein the composition comprises PVPVA, and the apalutamide:PVPVA ratio is 10:1 (w / w) to 1:10 (w / w), preferably 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). Claim 4 A composition according to any one of claims 1 to 3, wherein the composition comprises HPMC, and the apalutamide:HPMC ratio is 10:1 (w / w) to 1:10 (w / w), preferably 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). Claim 5 A 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 [°2θ], preferably a powder X-ray diffraction pattern having peaks at 18.6, 20.4, 21.5, 25.1, 28.3, 30.6, and 33.0, more preferably the same diffraction pattern as the X-ray powder diffraction pattern shown in FIG. 1A. Claim 6 A 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 [°2θ], preferably a powder X-ray diffraction pattern having peaks at 18.5, 20.3, 21.5, 25.0, 28.11, 30.3, and 32.9 ± 0.2 [°2θ], more preferably the same diffraction pattern as the X-ray powder diffraction pattern shown in FIG. 1B. Claim 7 A method for preparing nanoparticles of crystalline apalutamide, the method comprising: a) providing a solid amorphous nanoscale apalutamide; b) providing an aqueous solution comprising polyvinylpyrrolidone / vinyl acetate (PVPVA) and / or hydroxypropyl methylcellulose (HPMC); and c) contacting the solid amorphous nanoscale apalutamide with the aqueous solution to form the mixture in which the content of the amorphous nanoscale apalutamide in the mixture is higher than the solubility of the amorphous nanoscale apalutamide in the aqueous solution, thereby obtaining a suspension comprising nanoparticles of crystalline apalutamide. Claim 8 In claim 7, the content of amorphous nanoscale apalutamide in the mixture is at least 10 times higher than the solubility of amorphous nanoscale API in a solution containing one or more polymers and / or copolymers, preferably at least 50 times higher, more preferably at least 100 times higher, and even more preferably at least 500 times higher, method. Claim 9 A method according to claim 7 or 8, wherein the aqueous solution comprises one or more surfactants, and the content of the one or more surfactants in the aqueous solution is 0.0025-1.5 weight%. Claim 10 A method according to any one of claims 7 to 9, wherein the aqueous solution comprises 0.2-50 weight% of PVPVA, preferably 10-25 weight% of PVPVA. Claim 11 A method according to any one of claims 7 to 10, wherein the aqueous solution comprises 0.2 to 5 weight% of HPMC. Claim 12 A method according to any one of claims 7 to 11, wherein the particle size of the crystalline apalutamide is 300% or less, preferably 100% or less, more preferably 50% or less, even more preferably 25% or less, and most preferably 10% or less larger than the particle size of the nano-sized amorphous apalutamide. Claim 13 A method according to any one of paragraphs 7 through 12, wherein the contact comprises mixing the suspension. Claim 14 A method according to any one of claims 7 to 13, wherein the contact comprises applying ultrasound to a suspension. Claim 15 A method according to any one of claims 7 to 14, wherein contact is performed for at least 10 hours, preferably for at least 16 hours, more preferably for at least 24 hours. Claim 16 A method comprising the step of drying a suspension to produce a solid comprising nanoscale apalutamide and PVPVA and / or HPMC in a crystalline form, in any one of claims 7 to 15. Claim 17 A method according to claim 16, comprising the step of grinding a solid to produce a powder comprising nano-sized apalutamide in a crystalline form and PVPVA and / or HPMC. Claim 18 A pharmaceutical composition according to any one of claims 1 to 6 comprising an effective amount of apalutamide and at least one pharmaceutically acceptable excipient or carrier. Claim 19 A composition according to any one of paragraphs 1 to 6 or a pharmaceutical composition according to paragraph 18 for use as a medicine. Claim 20 A composition according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 18 for use in the treatment of patients with non-metastatic castration-resistant prostate cancer. Claim 21 A crystalline polymorph of 4-[7-(6-cyano-5-trifluoromethylpyridine-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (apalutamide), characterized by a powder X-ray diffraction pattern having peaks at 25.1, 28.2, 30.4, and 33.0 ± 0.2 [°2θ], preferably at 18.5, 20.4, 21.5, 25.1, 28.2, 30.4, and 33.0 ± 0.2 [°2θ]. Claim 22 In claim 21, a crystalline polymorph composed of particles with a Dv90 of 1000 nm or less. Claim 23 A pharmaceutical composition comprising an effective amount of a polymorph of crystalline apalutamide according to claim 21 or 22 and at least one pharmaceutically acceptable excipient or carrier. Claim 24 A crystalline polymorph according to paragraph 21 or 22 or a pharmaceutical composition according to paragraph 23 for use as a medicine. Claim 25 A crystalline polymorph according to claim 21 or 22 or a pharmaceutical composition according to claim 23 for use in the treatment of patients with non-metastatic castration-resistant prostate cancer. Claim 26 A pharmaceutical dosage form for oral administration comprising a composition according to any one of claims 1 to 6 or a crystalline polymorph according to claim 21 or 22. Claim 27 A pharmaceutical dosage form according to claim 26, wherein the total weight is 1000 mg or less, preferably 950 mg or less, more preferably 900 mg or less, even more preferably 850 mg or less, even more preferably 800 mg or less, even more preferably 750 mg or less, most preferably 700 mg or less, and particularly 650 mg or less. Claim 28 A pharmaceutical dosage form according to claim 27 containing apalutamide in doses 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, expressed in weight equivalents of the non-salt form of apalutamide in each case. Claim 29 In any one of paragraphs 26 to 28, the pharmaceutical dosage form is selected from tablets and granules.

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