HK40085488A

HK40085488A - Pharmaceutical formulations of abiraterone acetate and niraparib

Info

Publication number: HK40085488A
Application number: HK62023074407.5A
Authority: HK
Inventors: Thomas Ronald A QUINTEN; Urbain Alfons C DELAET; Philip Erna H HEYNS; Tatiana MARCOZZI; Johny BERTELS; Katrien LUYTEN; Kaustubh Ramesh TAMBWEKAR; Angela LOPEZ-GITLITZ; Paul J A HARTMAN KOK
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2020-05-08
Filing date: 2021-05-07
Publication date: 2023-08-04

Description

Pharmaceutical formulations of abiraterone acetate and nilapanib acetate

Technical Field

The present disclosure relates to combinations of anti-cancer drugs, methods of using the combinations to treat prostate cancer, and pharmaceutical formulations comprising the combinations.

Background

Prostate cancer is the most common non-cutaneous malignancy in men and is the second leading cause of death from cancer in men in the western world.

Prostate cancer results from uncontrolled growth of abnormal cells in the prostate. Once prostate cancer tumors develop, androgens (such as testosterone) promote prostate cancer growth. Localized prostate cancer can often be cured in its early stages by local therapy, including, for example, surgical removal of the prostate and radiation therapy. However, when local therapy fails to cure prostate cancer as in up to one-third of men, the disease progresses to incurable metastatic disease (i.e., disease in which the cancer has spread from one part of the body to another).

Current treatment options to improve survival and limit progression for men with metastatic castration resistant prostate cancer (mCRPC) include taxane-based chemotherapy, and androgen receptor targeting agents such as apaluramine (apanutamide)And enzalutamide (enzalutamide)

Platinum-based chemotherapy has been tested in multiple clinical studies in molecularly non-selective prostate cancer patients, but the results are limited and toxicity is significant.

More recently, abiraterone acetatePlus prednisone has been approved for the treatment of metastatic castration resistant prostate cancer.

Nilaparib (Niraparib) is an orally available highly selective poly (adenosine diphosphate [ ADP ] -ribose) polymerase (PARP) inhibitor that is active against PARP-1 and PARP-2 deoxyribonucleic acid (DNA) repair polymerases. Jones P, wilcoxen K, rowley M, toniatti C. Niraparib A Poly (ADP-rib) Polymerase (PARP) Inhibitor for the Treatment of turbines with defected Homologous reduction [ Nilaparib: poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of tumors with defective homologous recombination J Med Chem. [ journal of pharmaceutical chemistry ]2015 year 4, 23; 58 (8):3302-3314.

PARP is an enzyme responsible for the repair of single strand breaks in DNA (SSB) by a process called base excision repair. PARP inhibition results in the accumulation of unrepaired SSBs, which leads to the arrest and collapse of replication forks and thus to Double Strand Breaks (DSBs). Typically, DSBs are repaired by Homologous Recombination (HR). DSBs cause cell death if not repaired. When tumor cells with defects in DNA repair involving the HR pathway (e.g., breast cancer gene [ BRCA ] -l/2) are treated with PARP inhibitors, these tumor cells fail to repair DSB efficiently and accurately, resulting in synthetic lethal conditions. In men with metastatic castration resistant prostate cancer (mCRPC), tumors with aberrant DNA repair account for approximately 20% to 30% of sporadic cancers.

There is a need for treatment options for prostate cancer patients that do not initially respond to existing treatments or become refractory to these existing treatments. Importantly, there is an unmet need for treatment options for prostate cancer patients.

Disclosure of Invention

The present disclosure relates to a combination of abiraterone acetate and nilapanib acetate which can be administered to a mammal, particularly a human, suffering from an Androgen Receptor (AR) related disease or condition, particularly cancer, more particularly prostate cancer.

These pharmaceutical formulations are fixed dose combinations of abiraterone acetate and nilapanib.

It is an object of the present invention to provide a therapy for prostate cancer, including inter alia hormone sensitive prostate cancer, hormone naive high risk prostate cancer, castration resistant prostate cancer, metastatic castration resistant prostate cancer (mCRPC), metastatic castration sensitive prostate cancer (mCSPC), non-metastatic castration resistant prostate cancer (nmCRPC), biochemically recurrent (BCR) prostate cancer and Localized Prostate Cancer (LPC).

It is an object of the present invention to provide a free dose combination (FrDC) of abiraterone acetate and nilapanib tosylate monohydrate; or a Fixed Dose Combination (FDC) comprising abiraterone acetate and nilapanib tosylate monohydrate.

It is an object of the present invention to provide pharmaceutical formulations that support patient compliance, therapy compliance and therapy efficiency.

It is an object of the present invention to provide pharmaceutical formulations that reduce the tablet burden on patients, for example from six or four abiraterone acetate and nilapanib tosylate monohydrate tablets per day to three, or preferably two or one tablet per day.

It is an object of the present invention to provide Fixed Dose Combination (FDC) pharmaceutical formulations having comparable or improved stability or shelf life relative to separately formulated pharmaceutical dosage forms.

It is an object of the present invention to provide a fixed-dose combination pharmaceutical formulation that is bioequivalent to a pharmaceutical dosage form when administered as a separate dosage form.

It is an object of the present invention to provide fixed-dose combination pharmaceutical formulations having an immediate release profile for both abiraterone acetate and nilapanib.

It is an object of the present invention to provide fixed-dose combination pharmaceutical formulations with good content uniformity or uniform distribution of abiraterone acetate and nilapanib tosylate monohydrate. In some aspects, abiraterone acetate and nilapanib tosylate monohydrate are uniformly distributed within the intragranular phase. In some aspects, abiraterone acetate and nilapanib tosylate monohydrate are uniformly distributed within a dosage form (e.g., tablet). In some aspects, where abiraterone acetate and nilapanib tosylate monohydrate are prepared as separate particles, the corresponding particles are uniformly distributed in the particle blend. The abiraterone acetate and nilapanib tosylate monohydrate drug substances in the fixed dose combination of the invention have different particle sizes (d of 4-5 μm each) ₅₀ And d of about 50 μm ₅₀ ) Different bulk densities, and different contents (33% and 5% -10% (w/w), respectively). When these two drug substances are so blended, they tend to segregate, causing problems with respect to homogeneity in the blend and thus with respect to dose control in the individual tablets. Administering FDC in accurate and consistent amounts of the two drug substances is critical to ensure safety and efficacy.

Content uniformity may be affected by formulation manufacturing conditions such as inlet air temperature, spray rate, inlet air flow during granulation, and drying losses during granulation.

It is an object of the present invention to provide particles comprising abiraterone acetate and nilapanib tosylate monohydrate having good uniformity of the layered content.

It is an object of the present invention to provide particles comprising abiraterone acetate and nilapanib tosylate monohydrate having a desired particle size distribution, which may be in d ₁₀ 、d ₅₀ And/or d ₉₀ The value of (b) represents (c). If the granules are too small, this may cause problems during compression when preparing tablets. If the particles are too large, this may lead to differences in content uniformity and undesirable segregation, problems with compression during tableting, and problems with dissolution and bioavailability of the API.

It is an object of the present invention to provide an immediate release film-coating fixed-dose combination pharmaceutical formulation for oral administration whose ingredients do not cause such degradation of the API known to be susceptible to oxidative degradation, namely abiraterone acetate. The presence of organic or inorganic impurities and/or degradants and/or metabolites may, if exaggerated, have an impact on patient safety or efficacy of therapy.

It is an object of the present invention to provide fixed dose combination pharmaceutical formulations of abiraterone acetate and nilapanib tosylate monohydrate having comparable dissolution profiles relative to each other. This dissolution profile may support the use of a fixed dose combination, as both agents will be suitable for administration according to the same schedule. It is another object of the present invention to provide fixed-dose combination formulations having comparable or improved dissolution profiles for one or two, and preferably both, active ingredients when compared to one or both of the corresponding drugs formulated alone, for example in their current commercial formulations such as abiraterone acetate tablets and nilapanib tosylate monohydrate capsules. The dissolution profile may be affected by manufacturing conditions such as inlet air temperature, spray rate, inlet air flow during granulation, and tablet hardness.

It is an object of the present invention to provide fixed-dose combination pharmaceutical formulations having comparable or improved bioavailability for each drug when compared to drugs administered as separate formulations (e.g., in their current commercial formulations as abiraterone acetate tablets and nilapanib tosylate monohydrate capsules). It is another object of the invention to provide fixed-dose combination pharmaceutical formulations wherein the two active ingredients exhibit one or more comparable pharmacokinetic parameters (e.g. similar or improved T) relative to the individual formulations _max And/or t _1/2 Or C _max %). Reduced bioavailability relative to single agent administration, or bioavailability parameters that do not support the same dosing schedule for both agents, will result in low plasma levels and affect the efficacy of the therapy, and may require increased dosing frequency, number of doses, or both.

It is an object of the present invention to provide immediate release film-coated fixed-dose combination pharmaceutical formulations for oral administration comprising 500mg of abiraterone acetate and 50mg or 100mg of the free base nilapanib in the form of tosylate monohydrate.

It is an object of the present invention to provide immediate release film-coated fixed-dose combination pharmaceutical formulations for oral administration comprising 375mg of abiraterone acetate and 50mg or 100mg of the free base nilapanib in the form of tosylate monohydrate.

It is an object of the present invention to provide immediate release film-coating fixed-dose combination pharmaceutical formulations for oral administration comprising 250mg of abiraterone acetate and 50mg or 100mg of the free base nilapanib in the form of tosylate monohydrate.

It is an object of the present invention to provide fixed-dose combination pharmaceutical formulations having comparable or increased efficacy (e.g., due to increased bioavailability at the same dose) when compared to the drugs administered alone.

In view of the different physicochemical properties of abiraterone acetate (lipophilic and poorly bioavailable) and nilapanib tosylate monohydrate (hydrophilic and moderately to highly bioavailable), it is also an object of the present invention to provide the formulator with a technical solution when compounding the two drugs together.

The present disclosure relates to a method for treating prostate cancer in a male human patient, the method comprising administering to the patient an effective amount of a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as described herein, plus a glucocorticoid, such as prednisone, hydrocortisone, dexamethasone, prednisolone (including methylprednisolone).

The present disclosure relates to a method for treating mCRPC in a male human patient suffering from mCRPC, the method comprising administering to the patient an effective amount of a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as described herein, plus prednisone. In one aspect, the mCRPC treatment is a first line (L1) treatment of mCRPC. In one aspect, the patient has not been treated with abiraterone acetate plus prednisone for more than 5 months. In one aspect, the patient is positive for a Homologous Recombination Deficiency (HRD), or the patient is not positive for an HRD. In one aspect, the HRD status is detected by a single or double allelic alteration in one or more DNA repair genes including, but not limited to, BRCA1 (breast cancer gene 1), BRCA2 (breast cancer gene 2), ATM (ataxia-telangiectasia mutated) gene, FANCA (fanconi anemia complementation group a gene), PALB2 (BRCA 2 chaperone and localizer gene), CHEK2 (checkpoint kinase 2 gene), BRIP1 (BRCA 1 interacting protein C-terminal helicase 1 gene), HDAC2 (histone deacetylase 2) gene, or CDK12 (cyclin-dependent kinase 12) gene. In one aspect, the patient has received gonadotropin releasing hormone agonist (GnRHa) therapy or has undergone bilateral orchiectomy prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, gnRHa therapy continues during treatment with the pharmaceutical formulation plus prednisone if surgical castration is not performed.

The present disclosure relates to a method for treating mCSPC in a male human patient with mCSPC having an adverse germline or somatic Homologous Recombination Repair (HRR) gene mutant mCSPC, said method comprising administering to the patient an effective amount of a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate, as described herein, plus prednisone. In one aspect, the deleterious germline or somatic HRR gene mutation is in one or more genes including, but not limited to, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B (RAD 51 paralog B), and RAD54L (RAD 54-like). In one aspect, the patient has experienced ADT prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the ADT is a drug or surgical castration. In one aspect, said ADT is initiated within 6 months, preferably at least 14 days, prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the patient undergoes ADT during treatment with the pharmaceutical formulation plus prednisone. In one aspect, the patient has not undergone prior therapy with a new generation androgen signaling inhibitor therapy (e.g., abiraterone acetate, enzalutamide, apalutamide, dalutamide (daroluamide), nilutamide (nilutamide), flutamide (flutamide), bicalutamide (bicalutamide), etc.). In one aspect, the patient has received docetaxel (docetaxel) or cabazitaxel (cabazitaxel) prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the patient has received radiation or surgical intervention prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the patient has received abiraterone peracetic acid plus prednisone prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the patient has received abiraterone peracetic acid plus prednisone during the one month period prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the patient has received treatment for localized prostate cancer prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, said treatment for localized prostate cancer is completed at least 1 year prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the treatment for localized prostate cancer is ADT for up to 3 years, including radiation therapy, prostatectomy, lymph node dissection, or systemic therapy.

The present disclosure relates to a method for treating mCRPC in a male human patient with or without DNA repair gene deficiency (DRD) or HRD, and optionally with mCRPC with altered cyclin dependent kinase 12 (CDK 12) pathogenicity, comprising administering to the patient an effective amount of a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate, as described herein, plus prednisone. In one aspect, if no surgical castration is performed, the patient continues with GnRHa therapy during treatment with the pharmaceutical formulation plus prednisone. In one aspect, prior to treatment with the pharmaceutical formulation plus prednisone, the patient has been exposed to an antiandrogen selected from: nilutamide, flutamide, bicalutamide, enzalutamide, apalutamide, dalutamide, and abiraterone acetate. In one aspect, the antiandrogen is washed prior to treatment with the pharmaceutical formulation plus prednisone.

The present disclosure relates to a method for treating high risk and/or lymph node positive prostate cancer in a male human patient suffering from high risk and/or lymph node positive prostate cancer, said method comprising administering to the patient an effective amount of a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as described herein, plus prednisone and leuprolide acetate (leuprolelin) before, during and after radiotherapy. In one aspect, the radiotherapy is stereotactic volume radiotherapy (SBRT) or ultra-low fraction radiotherapy with a total dose of about 37.5 to 40 gray (Gy).

The present disclosure relates to a method for treating castration-onset prostate cancer (metastasis) -with or without metastasis prostatecancer) in a male human patient, said method comprising administering to the patient an effective amount of a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as described herein, plus prednisone. In one aspect, if no surgical castration is performed, the patient continues with GnRHa therapy during treatment with the pharmaceutical formulation plus prednisone.

The present disclosure relates to a method for treating biochemically recurrent prostate cancer in a male human patient suffering from biochemically recurrent prostate cancer, said method comprising administering to the patient an effective amount of a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate, as described herein, plus prednisone. In one aspect, the biochemical recurrent prostate cancer is detected by: i) Elevation of Prostate Specific Antigen (PSA) greater than or equal to 2.0ng/mL above nadir; or ii) Next Generation Imaging (NGI) including prostate specific membrane antigen positron emission tomography (PSMA-PET). In one aspect, the patient is HRD biomarker positive, high risk, and/or has oligometastatic disease. In one aspect, the positive HRD biomarker is one or more of, but not limited to: BRCA1, BRCA2, ATM, BRIP1, CDK12, CDK17, CHEK2, FANCA, HDAC2, PALB2, PPP2R2A, RAD51B, and RAD54L.

The present disclosure relates to a method for treating locally advanced prostate cancer in a male human patient suffering from locally advanced prostate cancer and being a candidate for primary radiotherapy, said method comprising administering to the patient an effective amount of a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as described herein, plus prednisone.

The present disclosure relates to a method for treating mCRPC in a male human patient suffering from mCRPC, optionally having received prior chemotherapy including docetaxel or cabazitaxel, the method comprising administering to the patient an effective amount of a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as described herein, plus prednisone.

The present disclosure relates to a method for treating nmCRPC in a male human patient suffering from nmCRPC, said method comprising administering to the patient an effective amount of a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as described herein, plus prednisone. In one aspect, the patient has a PSA doubling time equal to or less than 10 months and is HRD positive. In one aspect, the patient is HRD positive. In one aspect, the patient has a high risk BCR.

In the methods of treatment disclosed herein, the pharmaceutical formulation may be a free dose combination (FrDC) of abiraterone acetate and nilapanib tosylate monohydrate; or a Fixed Dose Combination (FDC) comprising abiraterone acetate and nilapanib tosylate monohydrate. In one aspect, the FrDC or FDC each independently comprises about 50mg equivalent of nilapanib and about 500mg of abiraterone acetate; about 100mg equivalent of nilapanib and about 500mg of abiraterone acetate; about 50mg equivalent of nilapanib and about 375mg of abiraterone acetate; about 100mg equivalent of nilapanib and about 375mg of abiraterone acetate; about 50mg equivalent of nilapanib and about 250mg of abiraterone acetate; about 100mg equivalent of nilapanib and about 250mg of abiraterone acetate; about 33mg equivalent of nilapanib and about 333mg of abiraterone acetate; or about 67mg equivalent of nilapanib and about 333mg of abiraterone acetate. In one aspect, the FrDC or FDC is an oral dosage form. In one aspect, the oral dosage form is a tablet, capsule, or sachet.

In the methods of treatment disclosed herein, the Fixed Dose Combination (FDC) comprising abiraterone acetate and nilapanib, preferably nilapanib tosylate monohydrate, is as defined throughout the disclosure.

The present disclosure relates to a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as a combined preparation for simultaneous, separate or sequential use with prednisone to treat prostate cancer, such as mCRPC, such as first line (L1) mCRPC, in a patient. In one aspect, the patient has not been treated with abiraterone acetate and prednisone for more than 5 months. In one aspect, the patient is positive for a Homologous Recombination Deficiency (HRD), or the patient is not positive for an HRD. In one aspect, the HRD status is detected by a single or double allele change in one or more DNA repair genes, including, but not limited to, BRCA1 (breast cancer gene 1), BRCA2 (breast cancer gene 2), ATM (ataxia-telangiectasia mutated) gene, FANCA (fanconi anemia complementation group a gene), PALB2 (BRCA 2 chaperone and localizer gene), CHEK2 (checkpoint kinase 2 gene), BRIP1 (BRCA 1 interactor C-terminal helicase 1 gene), HDAC2 (histone deacetylase 2) gene, or CDK12 (cyclin dependent kinase 12) gene. In one aspect, the patient has received gonadotropin releasing hormone agonist (GnRHa) therapy or has undergone bilateral orchiectomy prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, if no surgical castration is performed, the GnRHa therapy continues during treatment with the pharmaceutical formulation plus prednisone.

The present disclosure relates to a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as a combined preparation for simultaneous, separate or sequential use with prednisone for the treatment of mCSPC in patients suffering from deleterious germline or somatic Homologous Recombination Repair (HRR) gene mutant mCSPC. In one aspect, the deleterious germline or somatic HRR gene mutation is in one or more genes including, but not limited to, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B, and RAD54L. In one aspect, the patient has experienced ADT prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the ADT is a drug or surgical castration. In one aspect, said ADT is initiated within 6 months, preferably at least 14 days, prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the patient undergoes ADT during treatment with the pharmaceutical formulation plus prednisone. In one aspect, the patient has not undergone prior therapy with a new generation androgen signaling inhibitor therapy (e.g., abiraterone acetate, enzalutamide, apalutamide, dalutamide, nilutamide, flutamide, bicalutamide, etc.). In one aspect, the patient has received docetaxel or cabazitaxel prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the patient has received radiation or surgical intervention prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the patient has received abiraterone peracetic acid plus prednisone prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the patient has received abiraterone peracetic acid plus prednisone during the one month period prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the patient has received treatment for localized prostate cancer prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, said treatment for localized prostate cancer is completed at least 1 year prior to treatment with the pharmaceutical formulation plus prednisone. In one aspect, the treatment for localized prostate cancer is ADT for up to 3 years, including radiation therapy, prostatectomy, lymphadenectomy, or systemic therapy.

The present disclosure relates to a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as a combined preparation for simultaneous, separate or sequential use with prednisone to treat mCRPC in patients with mCRPC with or without DNA repair gene defects (DRD) or HRD, and optionally with cyclin dependent kinase 12 (CDK 12) pathogenicity alterations. In one aspect, if no surgical castration is performed, the patient continues with GnRHa therapy during treatment with the pharmaceutical formulation plus prednisone. In one aspect, prior to treatment with the pharmaceutical formulation plus prednisone, the patient has been exposed to an antiandrogen selected from: nilutamide, flutamide, bicalutamide, enzalutamide, apalutamide, dalutamide, and abiraterone acetate. In one aspect, the antiandrogen is washed prior to treatment with the pharmaceutical formulation plus prednisone.

The present disclosure relates to a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as a combined preparation for simultaneous, separate or sequential use with prednisone and leuprolide acetate before, during and after radiotherapy for the treatment of high risk and/or lymph node positive prostate cancer in patients with high risk and lymph node positive prostate cancer. In one aspect, the radiation therapy is stereotactic volume radiation therapy (SBRT) or ultra-low fraction radiation therapy with a total dose of about 37.5 to 40Gy.

The present disclosure relates to a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as a combined preparation for simultaneous, separate or sequential use with prednisone for the treatment of castration-first prostate cancer in patients with castration-first prostate cancer with or without metastasis. In one aspect, gnRHa therapy continues during treatment with the pharmaceutical formulation plus prednisone if surgical castration is not performed.

The present disclosure relates to a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as a combined preparation for simultaneous, separate or sequential use with prednisone for the treatment of biochemically recurrent prostate cancer in a patient suffering from biochemically recurrent prostate cancer. In one aspect, the biochemical recurrent prostate cancer is detected by: i) Elevation of Prostate Specific Antigen (PSA) greater than or equal to 2.0ng/mL above nadir; or ii) Next Generation Imaging (NGI) including prostate specific membrane antigen positron emission tomography (PSMA-PET). In one aspect, the patients are HRD biomarker positive, high risk, and/or have oligometastatic disease. In one aspect, the positive HRD biomarker is one or more of, but not limited to: BRCA1, BRCA2, ATM, BRIP1, CDK12, CDK17, CHEK2, FANCA, HDAC2, PALB2, PPP2R2A, RAD51B, and RAD54L.

The present disclosure relates to a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as a combined preparation for simultaneous, separate or sequential use with prednisone for the treatment of locally advanced prostate cancer in patients with locally advanced prostate cancer and who are candidates for primary radiotherapy.

The present disclosure relates to a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as a combined preparation for simultaneous, separate or sequential use with prednisone to treat mCRPC in patients with mCRPC, optionally having received prior chemotherapy including docetaxel or cabazitaxel.

The present disclosure relates to a pharmaceutical formulation comprising abiraterone acetate and nilapanib tosylate monohydrate as a combined preparation for simultaneous, separate or sequential use with prednisone to treat nmCRPC in patients with nmCRPC. In one aspect, the patients have a PSA doubling time equal to or less than 10 months and are HRD positive. In one aspect, the patients are HRD positive. In one aspect, these patients have a high risk of BCR.

The pharmaceutical formulation for use disclosed herein may be a free dose combination (FrDC) of abiraterone acetate and nilapanib; or a Fixed Dose Combination (FDC) comprising abiraterone acetate and nilapanib. The pharmaceutical formulation for use disclosed herein may be FrDC of abiraterone acetate and nilapanib tosylate monohydrate; or FDC comprising abiraterone acetate and nilapanib tosylate monohydrate. In one aspect, the FrDC or FDC each independently comprises about 50mg of nilapanib equivalent (equivalent to nilapanib free base) and about 500mg of abiraterone acetate; about 100mg nilapanib equivalent and about 500mg abiraterone acetate; about 50mg of nilapanib equivalent and about 375mg of abiraterone acetate; about 100mg nilapanib equivalent and about 375mg abiraterone acetate; about 50mg of nilapanib equivalent and about 250mg of abiraterone acetate; about 100mg of nilapanib equivalent and about 250mg of abiraterone acetate; about 33mg of nilapanib equivalent and about 333mg of abiraterone acetate; or about 67mg of nilapanib equivalent and about 333mg of abiraterone acetate. In one aspect, the FrDC or FDC is an oral dosage form. In one aspect, the oral dosage form is a tablet, capsule, or sachet.

The Fixed Dose Combination (FDC) comprising abiraterone acetate and nilapanib tosylate monohydrate (or nilapanib) is as defined throughout this disclosure.

The disclosure relates to a particulate composition comprising abiraterone acetate, nilapanib, and a pharmaceutically acceptable carrier. The present disclosure relates to a pharmaceutical formulation, such as an oral dosage form, comprising the particulate composition.

In one aspect, the particles consist essentially of abiraterone acetate, nilapanib, and a pharmaceutically acceptable carrier. In one aspect, the particles have a particle size distribution with a d of about 200 to about 500 μm, or about 231 to about 396 μm ₅₀ (ii) a Has a d of about 50 to about 250 μm, or about 93 to about 192 μm ₁₀ (ii) a And/or has a d of about 500 to about 900 μm, or about 616 to about 723 μm ₉₀ 。

In one aspect, a first portion of the particles consists essentially of abiraterone acetate and a pharmaceutically acceptable carrier; and a second portion of the particles consists essentially of nilapanib and a pharmaceutically acceptable carrier.

In one aspect, nilapanib is in the form of a salt of tosylate monohydrate, sulfate, benzene sulfate, fumarate, succinate, camphorate, mandelate, camphorsulfonate, lauryl sulfate, or a mixture of tosylate monohydrate and lauryl sulfate. In one aspect, the nilapanib tosylate monohydrate is in crystalline form. In one aspect, the abiraterone acetate is in crystalline form. In one aspect, the present disclosure relates to a pharmaceutical formulation comprising nilapanib lauryl sulfate and a pharmaceutically acceptable carrier. In one aspect, the present disclosure relates to a pharmaceutical formulation comprising a mixture of nilapanib tosylate monohydrate and nilapanib lauryl sulfate, and a pharmaceutically acceptable carrier.

In one aspect, the pharmaceutically acceptable carrier of the particulate composition comprises a wetting agent, a diluent, a disintegrant, an optional glidant, an optional lubricant, and an optional binder. In one aspect, the diluent is lactose, and the lactose also serves as a binder. In one aspect, the disintegrant is crospovidone.

The disclosure further relates to a pharmaceutical formulation, e.g., an oral dosage form, comprising the particulate composition described herein. In one aspect, the formulation or oral dosage form comprises about 50mg of nilapanib equivalent and about 500mg of abiraterone acetate; about 100mg nilapanib equivalent and about 500mg abiraterone acetate; about 50mg nilapanib equivalent and about 375mg abiraterone acetate; about 100mg nilapanib equivalent and about 375mg abiraterone acetate; about 50mg nilapanib equivalent and about 250mg abiraterone acetate; about 100mg of nilapanib equivalent and about 250mg of abiraterone acetate; about 33mg of nilapanib equivalent and about 333mg of abiraterone acetate; or about 67mg of nilapanib equivalent and about 333mg of abiraterone acetate.

In one aspect, the oral dosage form is a tablet, wherein the pharmaceutically acceptable carrier comprises a wetting agent, diluent, disintegrant, glidant, lubricant, optional binder, and optional coating material. In one aspect, the wetting agent is Sodium Lauryl Sulfate (SLS) and is present in the dosage form in a percentage of from about 3% to 6% (w/w). In one aspect, the humectant is SLS and is present in the final dosage forms in a ratio to abiraterone acetate of: about 0.05. In one aspect, SLS is present in both the intragranular phase and the extragranular phase of the tablet. In one aspect, the disintegrant is crospovidone and is present in both the intragranular phase and the extragranular phase of the tablet. In one aspect, the diluent of the extra-granular phase is silicified microcrystalline cellulose. In one aspect, the tablet has a hardness of 250 to 350N. In one aspect, the tablet has a stratified content uniformity of from 75% to 125%, or from 90% to 110%. In one aspect, the tablet has a blend homogeneity with a relative standard deviation of up to 3%.

In one aspect, the tablet comprises about 500mg of abiraterone acetate and about 50mg of nilapanib equivalent; and wherein when measured by USP paddle method at 75rpm in 900mL of an aqueous solution comprising 0.05mM sodium phosphate buffer and 0.25% (w/v) sodium lauryl sulfate at a pH of 4.5 and a temperature of 37.0 ℃ ± 0.5 ℃, (i) greater than 40%, or about 50% of the abiraterone acetate dissolved after 5 minutes, (ii) greater than 75%, or about 80% or 81% of the abiraterone acetate dissolved after 10 minutes, (iii) greater than 85%, or about 89% or 90% of the abiraterone acetate dissolved after 15 minutes, (iv) greater than 87%, or about 92% of the abiraterone acetate dissolved after 20 minutes, (v) greater than 90%, or about 95% of the abiraterone acetate dissolved after 30 minutes, (vii) greater than 91%, or about 96% of the abiraterone acetate dissolved after 45 minutes, (vii) greater than 92%, or about 97% of the abiraterone acetate dissolved after 60 minutes, (vi) greater than 93%, or about 98% of the abiraterone acetate dissolved after 60 minutes, (vii) greater than 93% of the abiraterone acetate dissolved after 90, or about 98 minutes.

In one aspect, the tablet comprises about 500mg of abiraterone acetate and about 100mg of nilapanib equivalent; and wherein when measured by USP paddle method at 75rpm in 900mL of an aqueous solution comprising 0.05mM sodium phosphate buffer and 0.25% (w/v) sodium lauryl sulfate at a pH of 4.5 and a temperature of 37.0 ℃ ± 0.5 ℃, (i) greater than 36%, or about 41% of the abiraterone acetate dissolved after 5 minutes, (ii) greater than 67%, or about 72% of the abiraterone acetate dissolved after 10 minutes, (iii) greater than 76%, or about 81% of the abiraterone acetate dissolved after 15 minutes, (iv) greater than 81%, or about 86% of the abiraterone acetate dissolved after 20 minutes, (v) greater than 85% or 86%, or about 90% or 91% of the abiraterone acetate dissolved after 30 minutes, (vii) greater than 90%, or about 95% of the abiraterone acetate dissolved after 45 minutes, (vii) greater than 90% or 91%, or about 95% of the abiraterone acetate dissolved after 60 minutes, (vii) greater than 90% or about 99% of the abiraterone acetate dissolved after 60 minutes, (vi) greater than 90%, or about 99% of the abiraterone acetate dissolved after 45 minutes, (vii) dissolved after 90% of the abiraterone acetate dissolved after 90% or about 99 minutes.

In one aspect, the tablet comprises about 500mg of abiraterone acetate and about 50mg of nilapanib equivalent; and wherein when measured by the USP paddle method at 75rpm in 900mL of an aqueous solution comprising 0.05mM sodium phosphate buffer and 0.25% (w/v) sodium lauryl sulfate at a temperature of pH 4.5 and 37.0 ℃ ± 0.5 ℃, (i) greater than 30% or 35%, or about 39% or 40% of the nilapanib dissolves after 5 minutes, (ii) greater than 79% or 80%, or about 84% or 85% of the nilapanib dissolves after 10 minutes, (iii) greater than 90%, or about 95% of the nilapanib dissolves after 15 minutes, (iv) greater than 92%, or about 97% of the nilapanib dissolves after 20 minutes, (v) greater than 93%, or about 98% of the nilapanib dissolves after 30 minutes, (vii) greater than 93%, or about 98% of the nilapanib dissolves after 45 minutes, (vii) greater than 93%, or about 98% of the nilapanib dissolves after 60 minutes, (vi) greater than 93%, or about 98% of the nilapanib dissolves after 90 minutes, (vii) after 93%, or about 98% of the nilapanib dissolves after 60 minutes.

In one aspect, the tablet comprises about 500mg of abiraterone acetate and about 100mg of nilapanib equivalent; and wherein when measured by USP paddle method at 75rpm in 900mL of an aqueous solution comprising 0.05mM sodium phosphate buffer and 0.25% (w/v) sodium lauryl sulfate at a pH of 4.5 and 37.0 ℃ ± 0.5 ℃, (i) greater than 23%, or about 28% of the nilapanib is dissolved after 5 minutes, (ii) greater than 64%, or about 69% of the nilapanib is dissolved after 10 minutes, (iii) greater than 80% or 81%, or about 85% or 86% of the nilapanib is dissolved after 15 minutes, (iv) greater than 87%, or about 92% of the nilapanib is dissolved after 20 minutes, (v) greater than 90%, or about 95% of the nilapanib is dissolved after 30 minutes, (vi) greater than 91%, or about 96% of the nilapanib is dissolved after 45 minutes, (vii) greater than 92%, or about 97% of the nilapanib is dissolved after 60 minutes, (ii) greater than 92%, or about 97% of the nilapanib is dissolved after 120 minutes, (vii) greater than 92%, or about 97% of the nilapanib is dissolved after 45 minutes.

In one aspect, the tablet dosage forms are bioequivalent to a free dose combination of abiraterone acetate and nilapanib when administered orally on an equivalent dose basis (e.g., wherein one or more pharmacokinetic parameters are within 20% or within 10% or within 5% of the corresponding values after administration with the free dose combination or single agent).

In one aspect, the oral dosage form is a capsule or sachet, optionally further comprising a diluent.

In one aspect, the oral dosage form is Fixed Dose Combination (FDC).

The disclosure also relates to a pharmaceutical formulation or oral dosage form as described herein for use in treating prostate cancer in a patient. Similarly, the disclosure also relates to a method of treating prostate cancer in a patient, said method comprising administering said pharmaceutical formulation or oral dosage form to the patient.

<xnotran> , , , , , , , , , , , , , , , (CRPC), CRPC (nmCRPC), CRPC, CRPC, CRPC, CRPC, CRPC (mCRPC), DNA (DRD) HRD mCRPC, DRD HRD mCRPC, DRD HRD mCRPC, DRD HRD / mCRPC, mCRPC, ( , , ) CRPC, ( , , ) CRPC, CRPC, mCRPC, CRPC, mCRPC, CRPC, CRPC, ( , , ) CRPC, ( , , ) CRPC, </xnotran> CRPC with visceral metastasis and progression, castration Sensitive Prostate Cancer (CSPC), non-metastatic CSPC (nmCSPC), localized CSPC, locally advanced CSPC, regional CSPC, advanced CSPC, metastatic CSPC (mCSPC), chemotherapy-naive CSPC, chemotherapy-naive mCSPC, hormone Sensitive Prostate Cancer (HSPC), hormone-dependent prostate cancer, androgen-sensitive prostate cancer, biochemically relapsed HSPC, metastatic HSPC (mhpc), hormone-resistant prostate cancer (HRPC), non-metastatic HRPC (nmHRPC), localized HRPC, local advanced HRPC, regional HRPC, advanced HRPC, metastatic HRPC (mHRPC), recurrent prostate cancer, prostate cancer with persistent or relapsed Prostate Specific Antigen (PSA) following prostate resection, with or without distant metastasis, radiation-resistant prostate cancer, and any combination thereof. In one aspect, the patient has first-line (L1) mCRPC and is positive for DRD or HRD. In one aspect, the patient has an adverse germline or somatic Homologous Recombination Repair (HRR) gene mutant mCSPC. In one aspect, the patient has mCRPC or CRPC with visceral metastasis with or without DNA repair gene deficiency (DRD), and optionally with a cyclin dependent kinase 12 (CDK 12) pathogenicity alteration. In one aspect, the patient has a high risk localized prostate cancer.

In one aspect, the patient is in a risk group selected from: very low, moderately favorable, moderately unfavorable, high, very high, and regional. In one aspect, the medical use or method of treatment comprises administering about 666 to about 1500 mg/day abiraterone acetate; administering about 999 to about 1500 mg/day of abiraterone acetate; administering about 666 mg/day abiraterone acetate; or about 1000 mg/day of abiraterone acetate. In one aspect, the medical use or method of treatment comprises administering about 33 to about 300 mg/day of nilapanib; administering about 100 to about 200 mg/day of nilapanib equivalent; administering about 66 mg/day of nilapanib equivalent; administering about 100 mg/day of nilapanib equivalent; administering about 134 mg/day of nilapanib equivalent; or about 200 mg/day equivalent of nilapanib. In one aspect, the medical use or method of treatment comprises administering 1, 2, or 3 oral dosage forms per day. In one aspect, the medical use or method of treatment comprises administering the one or more oral dosage forms once a day (q.d.) or twice a day (b.i.d.); preferably at least 1 hour before a meal or at least two hours after a meal, once a day. In one aspect, the medical use or method of treatment comprises administering prednisone alone in an amount of from about 1 to about 60 mg/day; about 5 to about 15 mg/day of prednisone; about 9 to about 11 mg/day of prednisone; about 10 mg/day prednisone; about 5 mg/day prednisone; or about 5 mg/day of prednisone.

The present disclosure also relates to a method for preparing certain particulate compositions disclosed herein, comprising the steps of:

(a) Preparing a binder solution comprising a wetting agent;

(b) Blending the binder solution of step (a) with abiraterone acetate, nilapanib, and a diluent, optionally in the presence of a disintegrant;

(c) Wet granulating the blend obtained from step (b);

(d) Drying the product obtained from step (c).

In one aspect, the binder solution comprises a binder, the wetting agent, and a solvent. In one aspect, the inlet air temperature during the wet granulation of step (c) is from 25 ℃ to 65 ℃. In one aspect, the spray rate during the wet granulation of step (c) is from 190 to 300g/min. In one aspect, the inlet air flow rate during the wet granulation of step (c) is from 800 to 1300m ³ /h。

(a) Blending abiraterone acetate, nilapanib, a wetting agent, and a diluent, optionally in the presence of a disintegrant and a lubricant;

(b) Dry granulating the blend obtained from step (a);

(c) Grinding the dry granulated product obtained from step (b);

(d) Optionally blending the product obtained from step (c) with a wetting agent, diluent, disintegrant, and glidant.

a) Blending nilapanib with a diluent, optionally in the presence of a disintegrant, a glidant, and a lubricant;

b) Dry granulating the blend obtained from step (a);

c) Grinding the dry granulated blend obtained from step (b);

d) Preparing a binder solution comprising a wetting agent;

e) Blending the binder solution of step (d) with abiraterone acetate and a diluent, optionally in the presence of a disintegrant;

f) Wet granulating the blend obtained from step (e);

g) Drying the product obtained from step (f);

h) Blending the granulate blends obtained from steps (c) and (g), optionally in the presence of a wetting agent, diluent, disintegrant, lubricant, and glidant;

wherein steps d) to g) can be carried out before, or in parallel with, steps a) to c).

In one aspect, the obtained particulate composition is further compressed into tablets, optionally with a lubricant. In one aspect, the method further comprises preparing a coating suspension and coating the tablet with said suspension.

In one aspect, the obtained particulate composition is further dosed into capsules or sachets, optionally with a diluent.

Drawings

FIG. 1: a flow chart for the manufacturing process and in-process control of wet co-pelletization of abiraterone acetate and nilapanib tosylate monohydrate.

FIG. 2: a flow chart for the manufacturing process and in-process control of a tablet for coating comprising abiraterone acetate and nilapanib tosylate monohydrate.

FIG. 3: flow chart for the manufacturing process of dry co-granulating abiraterone acetate and nilapanib tosylate monohydrate and compressing into tablets.

FIG. 4 is a schematic view of: a manufacturing process and in-process control flow diagram for dry granulation of nilapanib tosylate monohydrate and blending with particles of abiraterone acetate (the latter prepared by wet granulation).

FIG. 5A: in vitro dissolution profile of abiraterone acetate from: i) A combination of single agents as 1 capsule of 100-mg equivalent nilapanib (in the form of tosylate monohydrate) and 2 tablets of 250-mg abiraterone acetate; ii) FDC tablets having the composition of Table 2 (50-mg equivalent nilapanib (in its tosylate monohydrate form), and 500-mg abiraterone acetate); and iii) FDC tablets having the composition of Table 4 (100-mg equivalent Nilaparib (in its tosylate monohydrate form), and 500-mg abiraterone acetate).

FIG. 5B: in vitro dissolution profiles of nilapanib from: i) A combination of single agents as 1 capsule of 100-mg equivalent nilapanib (in its tosylate monohydrate form), and 2 tablets of 250-mg abiraterone acetate; ii) FDC tablets having the composition of Table 2 (50-mg equivalent nilapanib (in its tosylate monohydrate form), and 500-mg abiraterone acetate); and iii) FDC tablets having the composition of Table 4 (100-mg equivalent Nilaparib (in its tosylate monohydrate form), and 500-mg abiraterone acetate).

FIG. 6: loss On Drying (LOD) profiles for pellets having the compositions of table 1 and table 3.

FIG. 7: sieve analysis of the pellets of table 1.

FIG. 8: sieve analysis of the pellets in table 3.

Detailed Description

The present invention may be understood more readily by reference to the following detailed description taken in conjunction with the accompanying examples which form a part of this disclosure. It is to be understood that this invention is not limited to the specific products, methods, conditions or parameters described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed invention.

The entire disclosure of each patent, patent application, and publication cited or described in this document is hereby incorporated by reference.

Definition of

As used above and throughout this disclosure, the following terms and abbreviations, unless otherwise indicated, shall be understood to have the following meanings.

In this disclosure, the singular forms "a" and "an" and "the" include plural referents unless the context clearly dictates otherwise, and reference to a given numerical value includes at least that value. Thus, for example, reference to "an ingredient" is a reference to one or more of such ingredients, equivalents of such ingredients known to those skilled in the art, and so forth. Further, when it is stated that an element "may be" X, Y or Z, such usage is not intended to exclude other choices of the element in all cases.

When values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. As used herein, "about X" (where X is a numerical value) preferably means the stated value ± 10%, inclusive. For example, the phrase "about 8" refers to a value of 7.2 to 8.8, inclusive; as another example, the phrase "about 8%" refers to a value of 7.2% to 8.8, inclusive. Where present, all ranges are inclusive and combinable. For example, when a range of "1 to 5" is recited, the recited range should be understood to include ranges of "1 to 4", "1 to 3", "1-2 and 4-5", "1-3 and 5", and the like. Further, when a list of alternatives is affirmatively provided, such list may also include embodiments in which any of the alternatives may be excluded. For example, when a range of "1 to 5" is described, such description may support a case in which any one of 1, 2, 3, 4, or 5 is excluded; thus, recitation of "1 to 5" may support "1 and 3-5, except 2", or only "no 2 included therein".

The term "immediate release" when used in the context of a dosage form (such as a pharmaceutical formulation, free dose combination, fixed dose combination, granule, tablet, capsule, etc.) refers to the rapid disintegration and dissolution of the dosage form to release the active pharmaceutical ingredient contained therein. Immediate release dosage forms dissolve or disintegrate in the stomach within a short period of time and provide rapid dissolution and absorption of the active pharmaceutical ingredient, which may result in rapid onset of action.

As used herein, and unless otherwise defined, the terms "treat", "treating" and "treatment" include eradicating, removing, altering, managing or controlling a tumor or primary, regional or metastatic cancer cells or tissue, particularly prostate cancer cells or tissue, and minimizing or delaying the spread of a cancer, particularly prostate cancer. Minimizing or delaying the spread of the cancer includes inhibiting the progression of the cancer, reducing the rate of progression of the cancer, or stopping the rate of progression of the cancer.

As used herein, and unless otherwise defined, the phrase "therapeutically effective amount" or "effective amount" means an amount of a therapeutic agent that is effective for treating prostate cancer.

As used herein, and unless otherwise defined, the phrase "safe to treat" means an amount of a therapeutic agent that is safe for treating prostate cancer.

The term "pharmaceutically acceptable" means that it is generally safe, non-toxic and not biologically or otherwise undesirable, and includes that it is acceptable for human pharmaceutical use as well as veterinary use.

The terms "formulation" and "composition" are used interchangeably in this disclosure. Both "formulation" and "composition" mean that at least two or more components are combined as a fixed-dose combination or as a free-dose combination. Thus, the term "pharmaceutical formulation" refers to both fixed dose combinations and free dose combinations. The two or more components herein encompass at least 1) abiraterone acetate; and 2) nilapanib and any pharmaceutically acceptable salt, solvate and hydrate forms thereof, such as nilapanib tosylate monohydrate. The additional component is typically an excipient.

As used herein, a "fixed dose combination" (FDC) is a formulation or composition that includes two or more active ingredients combined in a single dosage form. Herein, the two active ingredients are 1) abiraterone acetate; and 2) nilapanib and any pharmaceutically acceptable salt, solvate and hydrate forms thereof, such as nilapanib tosylate monohydrate.

In contrast, "free dose combination" (FrDC) is a formulation or composition comprising two or more active ingredients combined in separate dosage forms. Herein, the two active ingredients are 1) abiraterone acetate; and 2) nilapanib and any pharmaceutically acceptable salt, solvate and hydrate forms thereof, such as nilapanib tosylate monohydrate.

The terms "excipient" and "carrier" are used interchangeably in this disclosure. The european pharmacopoeia (ph.eur.) defines an excipient as "any component other than one or more active substances present in a pharmaceutical product or used in the manufacture of such a product". The intended function of an excipient is to serve as a carrier (excipient or matrix (basis)) or component of one or more active substances, and in so doing, contribute to product attributes such as stability, biomedical profile, appearance and patient acceptability and to the ease with which a product can be manufactured. Typically, more than one excipient is used in the formulation of a pharmaceutical product. The terms vehicle and matrix are further defined in the same pharmacopoeia: the "vehicle is a carrier (consisting of one or more excipients) for the active substance(s) in the liquid formulation" and the "matrix is a carrier (consisting of one or more excipients) for the active substance(s) in the semi-solid and solid formulations".

A "granule", "granulate" or "granulated particle" is defined herein as a particle formed by granulation, containing one or more Active Pharmaceutical Ingredients (APIs) and at least one pharmaceutically acceptable carrier. The particulate compositions according to the present disclosure comprise two APIs and at least one pharmaceutically acceptable carrier. One part of the particulate composition, i.e. the first part of the particles, may consist essentially of one API and at least one pharmaceutically acceptable carrier, and another part of the particulate composition, i.e. the second part of the particles, may consist essentially of another API and at least one pharmaceutically acceptable carrier. In another aspect, each and all portions of the particle composition, i.e., each and all particles, comprise both APIs and at least one pharmaceutically acceptable carrier.

Abiraterone acetate

Abiraterone acetate is a compound having the formula:

and are prodrugs of abiraterone, which are potent and selective orally active inhibitors of the key enzyme in testosterone synthesis (17 α -hydroxylase-C17, 20-lyase), also known as steroid 17 α -monooxygenase inhibitors or human cytochrome P45017 α. Inhibition of testosterone synthesis in patients with prostate cancer with abiraterone acetate has been demonstrated. This compound is disclosed in WO93/20097 (A1). In some aspects, abiraterone acetate is used herein in crystalline form.

Abiraterone acetate plus prednisone is approved for use in metastatic castration resistant prostate cancer (mCRPC) and metastatic hormone sensitive prostate cancer (mhpc). Abiraterone acetate tablets are currently on the market as 250 or 500mg oral tablets.

Nilaparib

Nilapanib or 2- [4- [ (3S) -piperidin-3-yl ] phenyl ] -2H-indazole-7-carboxamide is an orally available highly selective poly (adenosine diphosphate [ ADP ] -ribose) polymerase (PARP) inhibitor that is active against PARP-1 and PARP-2 deoxyribonucleic acid (DNA) repair polymerases. The preparation of nilapanib is described in U.S. patent nos. 8,071,623 and 8,436,185, both of which are incorporated herein by reference.

The currently marketed capsule formulation (ZEJULA) contains 159.4mg of nilapanib tosylate monohydrate (equivalent/eq.) to 100mg of nilapanib free base) as active ingredient. Inactive ingredients in the capsule fill include magnesium stearate and lactose monohydrate.

As used herein, the term "nilapanib" means any of the free base compounds (2- [4- [ (3S) -piperidin-3-yl ] phenyl ] -2H-indazole-7-carboxamide), salt forms (including pharmaceutically acceptable salts) of 2- [4- [ (3S) -piperidin-3-yl ] phenyl ] -2H-indazole-7-carboxamide (e.g., 4-methylbenzenesulfonic acid; 2- [4- [ (3S) -piperidin-3-yl ] phenyl ] -2H-indazole-7-carboxamide), and/or solvated (including hydrated forms) thereof (e.g., 2- [4- [ (3S) -piperidin-3-yl ] phenyl ] -2H-indazole-7-carboxamide tosylate monohydrate). Such forms may be referred to individually as "nilapanib free base", "nilapanib tosylate" and "nilapanib tosylate monohydrate", respectively. Unless otherwise indicated, the term "nilapanib" includes all crystals, polymorphs, pseudopolymorphs, hydrates, monohydrate, anhydrous forms, solvates, salt forms, and combinations thereof (if applicable) of the compound 2- [4- [ (3S) -piperidin-3-yl ] phenyl ] -2H-indazole-7-carboxamide. Examples of salts include, but are not limited to, tosylate or 4-methylbenzenesulfonate, sulfate, benzene sulfate, fumarate, succinate, camphorate, mandelate, camphorsulfonate, and lauryl sulfate. In a particular aspect, the term "nilapanib" refers to nilapanib tosylate monohydrate.

The term "nilapanib" also encompasses amorphous and crystalline polymorphs of this compound, as well as hydrates, non-solvates, and solvates thereof. Examples of polymorphs are described in WO 2018/183354 A1, which is incorporated herein by reference. Crystalline form I of 2- [4- [ (3S) -piperidin-3-yl ] phenyl ] -2H-indazole-7-carboxamide tosylate monohydrate characterized by at least one X-ray diffraction pattern reflection of 2 Θ values selected from the group consisting of: 9.5 + -0.2, 12.4 + -0.2, 13.2 + -0.2, 17.4 + -0.2, 18.4 + -0.2, 21.0 + -0.2, 24.9 + -0.2, 25.6 + -0.2, 26.0 + -0.2, and 26.9 + -0.2. A crystalline form II of a non-stoichiometric hydrate of 2- [4- [ (3S) -piperidin-3-yl ] phenyl ] -2H-indazole-7-carboxamide tosylate salt is characterized by at least one X-ray diffraction pattern reflection of 2 Θ values selected from the group consisting of: 9.7 + -0.3, 12.8 + -0.3, 17.9 + -0.3, 19.7 + -0.3, and 21.8 + -0.3. A crystalline form III of 2- [4- [ (3S) -piperidin-3-yl ] phenyl ] -2H-indazole-7-carboxamide tosylate anhydrous form characterized by at least one X-ray diffraction pattern reflection of 2 Θ values selected from the group consisting of: 17.8 + -0.2, 19.0 + -0.2, or 22.8 + -0.2. Crystalline form I is preferred. Further examples of polymorphs are described in WO 2020/072797 A1, which is hereby incorporated by reference.

The term "nilapanib equivalent (or nilapanib equivalent)" refers to the dosage amount of the free base of nilapanib.

Preparation of dosage forms

Dosage forms of the present disclosure may be prepared according to the schemes of figures 1 and 2. A binder solution comprising purified water, a binder (e.g., hypromellose), and a wetting agent (e.g., sodium lauryl sulfate) is prepared by mixing with a mixer/blender. Abiraterone acetate, nilapanib tosylate monohydrate, diluent (e.g., lactose monohydrate), and disintegrant (e.g., crospovidone) are screened, blended (blend No. 1), and added to the binder solution. Wet granulation was performed, including warming, spraying, and drying. The moisture content and particle size distribution were measured to meet quality requirements. Subsequently, a mixture of diluent (e.g. silicified microcrystalline cellulose), disintegrant (e.g. crospovidone), wetting agent (e.g. sodium lauryl sulfate), and glidant (e.g. colloidal anhydrous silicon dioxide) is sieved and blended with the previously obtained granular material (blend No. 2). Lubricant (e.g., magnesium stearate) is screened and added to blend No. 2, which is finally blended (blend No. 3), compressed into tablets, and packaged. During compression, the appearance, weight, hardness, thickness, friability, and disintegration of the tablets were measured to meet quality requirements.

Subsequently, a powder comprising purified water and a coating (e.g., a powder comprising purified water and a coating) is preparedAMB II, e.g.AMB II 88a220039 yellow). The previously obtained tablets comprising abiraterone acetate and nilapanib tosylate monohydrate were film coated with the coating suspension. The appearance of the obtained coated tablets was measured to meet the quality requirements. The tablets are then packaged in, for example, blister packs or bottles.

In another aspect, a dosage form of the present disclosure can be prepared as depicted in fig. 3 and 2. Abiraterone acetate and nilapanib tosylate monohydrate were co-granulated with suitable excipients by fluid bed granulation or by roller compaction granulation. The granular material is then compressed into a single layer tablet.

In yet another aspectThe dosage forms of the present disclosure may be prepared as depicted in fig. 4 and fig. 2. Nilapanib tosylate monohydrate, diluents (e.g., lactose monohydrate and microcrystalline cellulose), binders (e.g., povidone K30), disintegrants (e.g., crospovidone), glidants (e.g., colloidal anhydrous silicon dioxide), and lubricants (e.g., magnesium stearate) are screened, blended, co-milled, re-blended, and dry granulated (dry granulation composition No. 1). Abiraterone acetate, a diluent (e.g. lactose monohydrate), and a disintegrant (e.g. croscarmellose sodium) are mixed and optionally sieved. A binder solution comprising a binder (e.g., hypromellose), a wetting agent (e.g., sodium lauryl sulfate), and purified water is prepared and added to a mixture of abiraterone acetate, a diluent, and a disintegrant. Abiraterone acetate granules were then formed by fluid bed granulation and subsequently dried (wet granules composition No. 2). Wet granulation composition No. 2, diluent (e.g., silicified microcrystalline cellulose), disintegrant (e.g., crospovidone), wetting agent (e.g., sodium lauryl sulfate), and glidant (colloidal anhydrous silicon dioxide) are added to dry granulation composition No. 1, and the resulting mixture is sieved and blended. A lubricant (e.g., magnesium stearate) is added to the previous blend, and the resulting mixture is further sieved, blended, compressed into tablets, and packaged. During compression, the properties of the tablets (including appearance, weight, hardness, thickness, friability, and disintegration) were measured to meet quality requirements. Subsequently, a powder comprising purified water and a coating (e.g., a powder comprising purified water and a coating) is preparedAMB II, e.g.AMB II 88a220039 yellow). The previously obtained tablets comprising abiraterone acetate and nilapanib tosylate monohydrate were film coated with the coating suspension. The appearance of the obtained coated tablets was measured to meet the quality requirements. The tablets are then packaged in, for example, blister packs or bottles.

Granulating

Granulation is a process in which powdered particles are enlarged to form granular agglomerates. Further efficiently processing the granules formed from the particles of the mixture of one or more Active Pharmaceutical Ingredients (API) and excipients into solid dosage forms, such as tablets and capsules; or multiparticulates such as pellets, beads, or spheroids, for example, to be filled into capsules or packaged as a spray formulation.

Abiraterone acetate and nilapanib may be co-granulated. Alternatively, particles of each of 1) abiraterone acetate and 2) nilapanib may be prepared separately and thereafter mixed or blended and further processed.

Co-granulation is actually achieved by: the two drugs are brought into contact with each other and with one or more excipients, such as a binder solution, and the entire mixture is granulated. Alternatively, each drug is contacted with one or more excipients, thereby creating separate mixtures, and then each mixture is brought together and placed in contact with the binder solution.

Abiraterone acetate and nilapanib acetate may be dry granulated or wet granulated and then further processed, such as tableting or encapsulation.

In one aspect, abiraterone acetate and nilapanib may be co-granulated by wet granulation and further processed. In one aspect, abiraterone acetate and nilapanib may be co-granulated by dry granulation and further processed. In one aspect, abiraterone acetate is wet granulated and nilapanib is dry granulated and the resulting granules are blended and further processed. In one aspect, abiraterone acetate is dry granulated and nilapanib is wet granulated and the resulting granules are blended and further processed.

Wet granulation

As used herein, the term "wet granulation" refers to The general process of using a granulation liquid during granulation to subsequently form granules, such as Remington: the Science and Practice of Pharmacy [ ramington: pharmaceutical science and practice ], 20 th edition (2000), chapter 45, which is hereby incorporated by reference.

Wet granulation generally comprises the following steps: mixing; wetting and kneading, i.e. wet massing; granulating; drying; and sieved. These steps are discussed in more detail below.

The wet granulation process begins by forming a powder blend of one or more therapeutic compounds and at least one pharmaceutically acceptable excipient by: the ingredients are mixed (i.e., brought into close proximity) in a suitable container, such as a pharmaceutical granulation apparatus, to form a mixture. Examples of pharmaceutical granulation equipment include, but are not limited to, a combination of a shear granulator (e.g., hobart, collette, beken) and an oscillating granulator; high speed mixer/granulator (e.g., diosna, fielder, collette-Gral); and fluid bed granulators (e.g., aeromatic, glatt) with subsequent screening equipment. Excipients that may be used in initial admixture with the therapeutic compound include, for example, binders, fillers, disintegrants, diluents, wetting agents, and any combination of the foregoing.

The next step is to wet agglomerate the powder blend by: the granulation liquid is added while stirring or kneading the powder blend until the powder blend is wetted with the granulation liquid to form a wet mass. For example, 10% -30% (w/w) of the granulation liquid is added to the powder blend. Alternatively, 10-25% (w/w), for example 20-25%, of a granulation liquid may be added to the powder blend. The granulation liquid is, for example, pharmaceutically acceptable and volatile. Examples of suitable granulation liquids include, but are not limited to, water, organic solvents (e.g., methanol, ethanol, isopropanol, acetone), alone or in combination. Examples of the combined granulation liquids collectively include water, ethanol, and isopropanol.

Alternatively, the wet granulation process may begin with the one or more therapeutic compounds as a powder by itself. In the wet agglomeration process, the granulation liquid introduced into the powder is a solvent containing dissolved excipients (e.g., binders). Regardless of how the wet agglomeration occurs, the pharmaceutical composition containing the therapeutic compound and at least one pharmaceutically acceptable excipient is wetted by the granulation liquid. In one example, water is used as the granulation liquid.

The wet mass is optionally sieved to form wet or moist granules. The wet mass may be sieved, for example through a mesh, such as a 5, 4, 3, 2 or 1mm screen, preferably from 1 to 2mm screen. One of ordinary skill in the art can select an appropriate size screen to form the most appropriate pellet size.

Alternatively, a pulverizing mill may be used instead of the screen or the sieve. Examples of pulverizing mills include, but are not limited to, stokes oscillators, colton rotary granulators, fitzpatrick pulverizing mills, stokes tornado mills.

Further alternatively, a high speed mixer equipped with e.g. chopper blades may be used instead of a screen or a pulverizer mill. This allows, for example, the wet-massing, granulating, and grinding to be combined into a single step.

Other wet granulation methods that may be employed include high shear granulation and twin screw granulation. High shear granulation involves adding a binder solution to a powder (which is often a mixture of one or more APIs and one or more excipients) and granulating the resulting mixture with blending tools and a chopper. The powder agglomerates into larger particles, which are held together by a binder. Twin-screw pelletization can be accomplished using commercially available twin-screw extruders such as those manufactured by Leistritz extrusion tech GmbH (NANO 16), seimer Fisher Scientific (Pharma 16 TSG). ConsiGma from Gea pharmaceutical Systems, inc. (GEA Pharma Systems) ^TM The system is a complete continuous package that includes some or all of blending, twin screw granulation, drying (semi-continuous), grinding, and tableting.

For example, the wet granulate is subsequently dried. For example, the wet pellets may be collected on a tray and transferred to a dry box. Alternatively, the moist granulates can be placed in a drying cabinet with a circulating air flow and thermostatic heating control. Yet another option is to dry the wet granulate in a fluid bed dryer. In this example, the wet pellets are suspended and agitated in a stream of warm air so that the wet pellets remain in motion. For example, the temperature may be from about room temperature to about 90 ℃, e.g., 70 ℃. The wet granulate is dried to a loss on drying ("LOD") value preferably less than or equal to about 3% or 2%, for example less than 2.6%, less than 2%, for example 1% -2%, by weight of the composition. Drying may be performed within the pharmaceutical granulation apparatus or outside the pharmaceutical granulation apparatus.

The granules comprising abiraterone acetate and nilapanib tosylate monohydrate prepared by wet granulation of the present invention achieve an improved LOD of between 1% and 2%. If the LOD is to be too low, the granules may later develop compaction problems during tableting. If too high, the particles may have stability problems.

After drying, the granulate may be further sieved, i.e. dry sieved, alone or in combination with at least one excipient. This typically results in a more uniform particle size of the granulate, thereby preparing the granulate for further processing into a solid oral dosage form. The dried particles can be screened at a fixed rotational speed (rpm) using standard equipment such as Quadro comil to produce a material having the desired particle size and free of agglomerates. The rotation speed may be from 5 to 15rpm, preferably from 8 to 10rpm.

In one way of preparation by wet granulation, e.g. by fluid bed granulation, the binder solution is produced by: the binder, wetting agent, and purified water are dissolved until a clear solution is obtained. The therapeutic compound, optionally mixed with diluents and disintegrants, is transferred to a suitable wet granulation apparatus and the resulting material is warmed while being fluidized. The binder solution was sprayed completely onto the material using wet granulation techniques. The resulting granulate is dried after spraying while being fluidized. The dried powder is collected and packaged in a bag (e.g., an aluminum bag).

In another manner of preparation, one may be usedOr more therapeutic compounds, are wet granulated in a fluid bed granulator (such as, for example, GEA Sirocco 300 or Niro Aeromatic D600) to obtain pharmaceutical granulates. The inlet air temperature of the fluidized bed may vary from 25 ℃ to 80 ℃ or from 25 ℃ to 70 ℃, preferably from 25 ℃ to 65 ℃; the outlet air temperature may vary from 25 ℃ to 50 ℃, from 20 ℃ to 50 ℃, or from 25 ℃ to 80 ℃; the inlet air flow rate may be from 500 to 2200m ³ H, from 2000 to 3000m ³ H, from 800 to 1300m ³ H, or from 500 to 4500m ³ In the range of/h; the solution flow rate or spray rate may range from 170 to 4200g/min, from 190 to 300g/min, from 400 to 900g/min, or from 0.200 to 2kg/min depending on the batch size and equipment capacity; the atomization gas pressure may be in the range of from 2-6 bar, from 3 to 4 bar, or from 1.00 to 5.00 bar. In one example, abiraterone acetate and nilapanib or nilapanib tosylate monohydrate can be wet granulated with a binder solution comprising a solvent (e.g., like water), a binder (e.g., like a polymer, such as hypromellose), and a wetting agent (e.g., like sodium lauryl sulfate). In one example, abiraterone acetate may be mixed with a suitable diluent (such as lactose monohydrate, for example) and a suitable disintegrant (such as crospovidone, for example) prior to granulation with the binder solution.

Dry granulation

The term "dry granulation" means a process of blending one or more therapeutic compounds with at least one excipient. The blend is then compressed, or compacted, to form a compressed material or "compact". This material is then broken up into dry granular particles by crushing, milling or cutting. Optionally, the particles may be further processed, such as further mixed with additional excipients. The crushing, grinding or cutting process includes an operation to reduce the size of the compacted material, such as by grinding or by other operations known to those skilled in the art.

"compactates" are compacted materials formed by processing the one or more therapeutic compounds and optional excipients via impact compaction or via roller compaction.

To prepare the blend, the components were weighed and placed into a blending container. Blending is carried out using suitable mixing equipment for a period of time to produce a homogeneous blend. Optionally, the blend is passed through a mesh screen to de-agglomerate the blend. The screened blend may be returned to the blending vessel and blended for an additional period of time. The lubricant may then be added and the blend mixed for an additional period of time. The blend is then compressed, or compacted, to form a compact. The blend may be subjected to a pre-compression step prior to compression, such as on a rotary tablet press. Compressing the blend to form the pellets can be accomplished by techniques known in the art, including slugging, wherein the blend is introduced into a die comprising one or more punch faces mounted on a press, such as a tablet press, and pressure is applied to the blend by movement of the one or more punch faces in the die. Dry granulation may also be performed by a roller compactor. Roller presses typically incorporate two or more rollers adjacent and parallel to each other with a fixed or adjustable gap between the rollers. A hopper or other feeding device deposits the blend between moving rollers that act to compact the blend into a compacted material. Roller presses are typically equipped with dividers that cut or otherwise divide the compacted material formed from the roller press into ribbons. One example of a roll press is a TF micro-roll press (Carrier Corporation, vector Corporation, marion, IA, freund).

The compact is then typically broken up into particles by suitable mechanical means, such as by crushing, milling or cutting. For example, the particles may be formed from the compact by grinding. Milling involves subjecting the granules to shear forces so that the desired particle size of the granulation is achieved. The grinding step can range from a brute force process that significantly reduces particle size to a non-brute force process that does not significantly reduce particle size, but rather is used only to deblock or break up larger sized pieces.

In the pharmaceutical industry, grinding is often used to reduce the particle size of solid materials. Many types of mills are available, including pin mills, hammer mills, and jet mills. One of the most common types of mills is the hammer mill. Hammermills utilize a high speed rotor with multiple fixed or oscillating hammers attached. The hammer may be attached such that the blade face or hammer face contacts the material. When the material is fed into the mill, it impacts the rotating hammer and breaks into smaller particles. The screen is positioned below the hammer, allowing smaller particles to pass through the openings in the screen. The larger particles remain in the mill and continue to be broken up by the hammers until the particles are fine enough to flow through the screen. The material may optionally be sieved. In screening, the material is passed through a mesh screen or series of mesh screens to achieve the desired particle size.

Excipient

Formulations (including granules and finished dosage forms such as tablets) of the present disclosure may contain one or more conventional excipients (pharmaceutically acceptable carriers) such as disintegrants, diluents, binders, buffers, lubricants, glidants, thickeners, sweeteners, flavoring agents, and coloring agents. Some excipients may serve multiple purposes. In one aspect, formulations of the present disclosure include a disintegrant, a diluent or filler, a lubricant, and a glidant. In one aspect, formulations of the present disclosure include a disintegrant, diluent or filler, a lubricant, a glidant, a wetting agent, and a binder. In one aspect, formulations of the present disclosure include a disintegrant, diluent or filler, a lubricant, a glidant, a wetting agent, and a binder, wherein the wetting agent or a portion thereof, and the binder are present in granules of abiraterone acetate and nilapanib. In one aspect, formulations of the present disclosure include a disintegrant, diluent or filler, a lubricant, a glidant, a wetting agent, and a binder, wherein the wetting agent or a portion thereof, the binder, and the disintegrant or a portion thereof are present in the granules of abiraterone acetate and nilapanib. In one aspect, formulations of the present disclosure include a disintegrant, diluent or filler, a lubricant, a glidant, a wetting agent, and a binder, wherein the wetting agent or a portion thereof, the binder, the diluent, and the disintegrant or a portion thereof are present in the granules of abiraterone acetate and nilapanib. In one aspect, formulations of the present disclosure include a disintegrant, diluent or filler, a lubricant, a glidant, and a wetting agent, wherein the wetting agent or a portion thereof is present in the granules of abiraterone acetate and nilapanib.

In one aspect, a formulation of the present disclosure comprises an intragranular phase and an extragranular phase.

In one aspect, the intragranular phase comprises an API, a diluent or filler, a disintegrant, a wetting agent, and a binder. In one aspect, the intragranular phase comprises an API, a diluent or filler, a disintegrant, a wetting agent, a glidant, and a binder.

In one aspect, the extragranular phase comprises a diluent or filler, a disintegrant, a wetting agent, a glidant, and a lubricant.

In one aspect, the intragranular phase and extragranular phase comprise a disintegrant, such as crospovidone. The presence of a disintegrant in both the intragranular and extragranular phases improves the disintegration of the tablet and granules, thereby increasing the dissolution rate of the API in vivo, and ultimately increasing the bioavailability of the API.

Suitable wetting agents may be selected from anionic, cationic or nonionic surfactants (surface-active agents or surfactants). Suitable anionic surfactants include those containing carboxylate, sulfonate, and sulfate ions, such as Sodium Lauryl Sulfate (SLS), sodium laurate, sodium dialkyl sulfosuccinates (particularly sodium bis- (2-ethylhexyl) sulfosuccinate), sodium stearate, potassium stearate, sodium oleate, and the like. Suitable cationic surfactants include those containing long chain cations such as benzalkonium chloride, bis-2-hydroxyethyl oleylamine, and the like. Suitable nonionic surfactants include polyoxyethylene sorbitan fatty acid esters; fatty alcohols such as lauryl alcohol, cetyl alcohol, and stearyl alcohol; glycerides, such as naturally occurring monoglycerides, diglycerides, and triglycerides; fatty acid esters of fatty alcohols and other alcohols such as propylene glycol, polyethylene glycol, sorbitan, sucrose, and cholesterol. In one aspect, the wetting agent is sodium lauryl sulfate.

The amount of wetting agent in a tablet or pharmaceutical formulation according to the present disclosure may conveniently be in the range from about 0.5% to about 8% (w/w), and preferably in the range from about 1% to 7% (w/w), or from about 2% to 6% (w/w), or from about 3% to 6% (w/w). In one aspect, the wetting agent is sodium lauryl sulfate and is present in the final dosage form in the following percentages: about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.85%, about 3.9%, about 4.00%, about 4.07%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, or about 5.9% by weight.

In one aspect, the wetting agent is sodium lauryl sulfate and is present in the granular composition in the following ratios by weight to abiraterone acetate: about 0.005.

In one aspect, the wetting agent is sodium lauryl sulfate and is present in the final dosage form in the following ratio by weight to abiraterone acetate: about 0.05.

Suitable disintegrants are those having a large coefficient of expansion. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starch; clay; cellulose; an alginate; gluing; hydrophilic, insoluble or poorly water soluble cross-linked polymers such as crospovidone (cross-linked polyvinylpyrrolidone, commercially available, for example, as Kollidon CL-F and Polyplasdone XL-10) and croscarmellose sodium (croscarmellose sodium). The disintegrant may be present in the tablet or pharmaceutical formulation in the following amounts: from about 1% to about 20% (w/w), preferably from about 2% to about 10% (w/w), in particular from about 3% to 9%, or from about 5% to 9% (w/w).

Less preferred in the formulations disclosed herein for the particulate compositions of the present invention and oral dosage forms comprising these particulate compositions are excipients that dissociate into ions, with the exception of sodium lauryl sulfate (wetting agent) and magnesium stearate (lubricant). In particular embodiments, the disintegrant is a non-ionic disintegrant, such as crospovidone.

A variety of materials may be used as diluents or fillers. Examples are lactose monohydrate, anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g. microcrystalline cellulose (Avicel) ^TM ) Silicified microcrystalline cellulose), dibasic calcium phosphate dihydrate or anhydrous, and others known in the art, and mixtures thereof (e.g., a spray-dried mixture of lactose monohydrate (75%) and microcrystalline cellulose (25%), as isCommercially available). Preferred are microcrystalline cellulose, silicified microcrystalline cellulose, or lactose monohydrate. Lactose monohydrate is generally characterized as a diluent or filler, but it also has binding properties that are particularly useful for granulation of the intragranular phase. The amount of diluent or filler in a tablet or pharmaceutical formulation according to the present disclosure may conveniently range from about 20% to about 70% (w/w), and preferably from about 20% to about 60% (w/w), or from about 25% to about 35% (w/w), or from about 25% to about 30% (w/w). Preferably, a diluent silicified microcrystalline cellulose is used in the particulate external phase. Preferably, the tablet FDC comprises an extragranular phase comprising from about 25% to about 30% (w/w) silicified MCC HD 90. This content of silicified MCC HD90 provides the best compression profile of the tablets, reducing their friability and abrasiveness.

Examples of pharmaceutically acceptable binders include, but are not limited to, starch; fibers and derivatives thereof, such as microcrystalline cellulose (e.g., AVICEL PH from FMC (philiadelphia, PA), hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methyl fiber (e.g., METHOCEL from Dow Chemical corp.) (Midland, michigan)); sucrose; dextrose; corn syrup; a polysaccharide; and gelatin. The binder may be present, for example, in an amount from about 0.5% to about 5%, e.g., 0.5% to 3%, by weight of the formulation. Preferably, the binder is a low viscosity grade of hypromellose, such as HPMC 2910 15mpa.s.

Lubricants and glidants may be used in the manufacture of certain dosage forms and will generally be utilized when producing tablets. Examples of lubricants and glidants are hydrogenated vegetable oils such as hydrogenated cottonseed oil, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, mixtures thereof, and others known in the art. Lubricants of interest are magnesium stearate, and mixtures of magnesium stearate with colloidal anhydrous silicon dioxide. A preferred lubricant is magnesium stearate. A preferred glidant is colloidal anhydrous silicon dioxide. Glidants generally constitute from 0.2% to 5.0%, particularly from 0.25% to 1.5%, more particularly from 0.3% to 1.0% (w/w) of the total weight of the composition, particularly of the total tablet weight. Lubricants (such as magnesium stearate) typically comprise 0.2% to 5.0%, particularly 0.5% to 2.5%, more particularly 0.5% to 2.0%, for example about 1.0%, about 1.25%, or about 1.5% (w/w) of the total tablet weight.

Final pharmaceutical formulation

The granules may be formulated with excipients into oral dosage forms, solid oral dosage forms, tablets, pills, lozenges, caplets, hard or soft capsules, sachets, troches, aqueous or oily suspensions, dispersible powders or granules, granulates.

Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose monohydrate, silicified microcrystalline cellulose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as crospovidone, microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia; lubricants, such as magnesium stearate, stearic acid or talc; and glidants, such as colloidal anhydrous silicon dioxide.

To make, for example, tablets, the granules are combined or blended with at least one excipient (e.g., lubricant) to form a mixture. Blending can be accomplished using any conventional pharmaceutical equipment (e.g., a V-blender).

Furthermore, any additional excipients used may be sieved separately from the particles as described in the aforementioned dry sieving step or simultaneously with the sieving of these particles. One of ordinary skill in the art will appreciate the desired particle size of each component necessary to formulate a particular pharmaceutical composition.

The blended mixture may be, for example, subsequently compacted into tablets (e.g., by using a tablet press) or encapsulated into capsules. The tablet hardness is preferably in the range of 250 to 350N. The solid oral dosage form may be subjected to further conventional processing, such as stamping, embossing or coating, as known to those of ordinary skill in the art.

The tablets may be uncoated or they may be coated by known techniques. The tablets of the present disclosure may be further film coated, for example, to improve taste, to provide ease of swallowing and an elegant appearance. Many suitable polymeric film coating materials are known in the art. In one aspect, the film coating material isAMB II 88A170010 beige,AMB II 88A210027 green,AMB II 88A620004 yellow,AMB II 88A220039 yellow,QX 321A220006 yellow, orII 32F220009. The film coating material is typically mixed with purified water (ph. Eur) to form a coating suspension. Preferred coating suspensions are those in which the film coating material isAMB II 88A170010 beige,AMB II 88A210027 Green, andAMB II 88a620004 yellow, since the resulting coated tablets showed no scratches. Other suitable film-forming polymers may also be used herein, including hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC) (especially HPMC 2910 5mpa.s), and acrylate-methacrylate copolymers. Preferred film coating materials are water permeable film coating materials such as, for example, HPMC coating Opadry II 32F220009. In addition to the film forming polymer, the film coating may further comprise a plasticizer (e.g., propylene glycol) and optionally a pigment (e.g., titanium dioxide). The film coating suspension may also contain talc as an anti-adherent. In tablets according to the present disclosure, the film coating preferably comprises about 5% (w/w) or less by weight of the total tablet weight.

In order to facilitate swallowing of the formulation by mammals, it is advantageous to shape the formulations, in particular the tablets, appropriately. A film coating on the tablet may further help it be easily swallowed. In one aspect of the present disclosure, the tablet may be a rectangular tablet, in particular a rectangular tablet having a length ≦ 19 mm.

Other excipients such as colorants and pigments may also be added to the formulations of the present disclosure. Colorants and pigments include titanium dioxide and dyes suitable for food products. Colorants are optional ingredients in the formulations of the present disclosure, but when used, the colorants can be present in the following amounts: from about 1% to about 6% by weight based on the total tablet weight, for example from about 2% to about 5%, from about 3% to about 4%, or up to 3.5% by weight based on the total tablet weight.

Flavoring agents are optional in the formulation and may be selected from synthetic flavoring oils and flavoring aromatics or natural oils, extracts from plant leaves, flowers, fruits, and the like, and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oil, bay oil, anise oil, eucalyptus oil, or thyme oil. Also useful as flavoring agents are vanilla, citrus oil (including lemon, orange, grape, lime and grapefruit), and fruit essence (including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and the like), the amount of flavoring agent may depend on a number of factors, including the desired organoleptic effect. Typically, the flavoring agent will be present in an amount from about 0% to about 3% (w/w).

Formulations for oral use may also be presented as hard gelatin or HPMC capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier or oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain particles of the therapeutic compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide (e.g. lecithin), or a condensation product of an alkylene oxide with fatty acids (e.g. polyoxyethylene stearate), or a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g. heptadecaethyleneoxycetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (such as polyoxyethylene sorbitol monooleate), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g. polyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives (e.g., ethyl or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by: suspending particles of the therapeutic compound in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil; or mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients (e.g., sweetening, flavoring, and coloring agents) may also be present. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

In the first instance, by the present disclosure, pharmaceutical formulations (such as tablets and capsules) for oral administration are contemplated, but the pharmaceutical formulations of the present disclosure may also be used for rectal administration. Preferred formulations are those suitable for oral administration shaped as tablets, for example. They may be produced by conventional tableting techniques with conventional ingredients or excipients (pharmaceutically acceptable carriers) and with a conventional tableting press.

Therapeutic methods and medical uses

The method, or medical use, of the pharmaceutical formulation for treating prostate cancer comprises, consists of, and/or consists essentially of: administering to a patient in need thereof a therapeutically effective amount of the PARP inhibitor nilapanib, a therapeutically effective amount of the CYP17 inhibitor abiraterone acetate, and optionally a therapeutically effective amount of another drug such as a glucocorticoid (e.g., prednisone).

The method, or medical use, of the pharmaceutical formulation for treating prostate cancer comprises, consists of, and/or consists essentially of: administering to a patient in need thereof a free dose combination (FrDC) or a Fixed Dose Combination (FDC) of nilapanib and abiraterone acetate. The method, or medical use, of the pharmaceutical formulation for treating prostate cancer comprises, consists of and/or consists essentially of: the aforementioned free-dose combination or fixed-dose combination, plus a glucocorticoid (e.g., prednisone), is administered to a patient in need thereof.

The methods of treatment and medical uses disclosed herein comprise administering to a patient in need thereof an oral dosage form as defined in the present disclosure comprising a particulate composition comprising abiraterone acetate, nilapanib, and a pharmaceutically acceptable carrier. These oral dosage forms and granular compositions constitute FDC.

Also disclosed are dosage regimens for the oral dosage forms disclosed herein, comprising, consisting of, and/or consisting essentially of: FDC of nilapanib and abiraterone acetate, and optionally a glucocorticoid (e.g., prednisone), are administered in a total amount that is therapeutically effective to treat prostate cancer in a human patient.

The present disclosure also discloses kits comprising, consisting of, and/or consisting essentially of: a free-dose combination or a fixed-dose combination comprising nilapanib and abiraterone acetate, and printed instructions for administering the free-dose combination or fixed-dose combination to a human patient suffering from prostate cancer.

The kit may comprise, consist of, and/or consist essentially of: a free-or fixed-dose combination comprising nilapanib and abiraterone acetate, a separate composition comprising a glucocorticoid (e.g., prednisone); and printed instructions for administering the free-dose combination or fixed-dose combination to a human patient suffering from prostate cancer.

Where reference is made specifically to "prednisone" in the present disclosure, one of ordinary skill will recognize that prednisone may be substituted with a different glucocorticoid, such as prednisolone, hydrocortisone, methylprednisolone, or dexamethasone. One skilled in the art would know how to exchange prednisone with these other drugs and adjust their dosage if needed.

Specific suitable glucocorticoids include, but are not limited to: (1) Dexamethasone (e.g., dicarbazone (Decadron), oral; dicarbazone-LA injection, etc.), (2) prednisolone (e.g.,prednisolone acetatePrednisolone sodium phosphatePrednisolone tert-butyl acetate (Etc.), (3) prednisone (prednisone, etc.), (ii) and (iii) in combination with other agents to reduce or eliminate blood pressureEtc.), or (4) methylprednisolone (e.g.,) And combinations thereof. See, e.g., the Pharmacological Basis of Therapeutics of The Pharmacological Basis of Goodman and Gilman]10 th edition 2001.

The formulations described herein may be used in methods of treating prostate cancer patients with a negative biomarker status. The formulations described herein may be used in methods of treating prostate cancer patients with positive biomarker status.

The formulations described herein may be used in methods of treating prostate cancer patients with a Homologous Recombination Deficiency (HRD) positive biomarker status. HRD is also known as Homologous Recombination Repair (HRR) defect and can be caused by DNA repair gene defects (DRD). The HRD or HRR defect positive status can be detected by: evaluation of somatic or germline changes, or evaluation of loss of whole genome heterozygosity (LOH), or homozygous deleterious changes in DNA repair genes. HRD or HRR defect positive status is also a synonym for PARP biomarker positive status.

The positive biomarker status may be an HRD positive status. The negative biomarker status may be an HRD negative status. HRD status can be assessed by plasma (analytical biosciences, inc.) or tissue (Foundation Medicine, inc.) based assays, particularly by detecting circulating plasma DNA or circulating tumor cells. HRD positive status may be defined as having a single or double allelic alteration in one or more DNA repair genes including, but not limited to, BRCA1 (breast cancer gene 1), BRCA2 (breast cancer gene 2), ATM (ataxia telangiectasia mutated) gene, FANCA (FANCA anemia complementation group a gene), PALB2 (BRCA 2 chaperone and localizer gene), CHEK2 (checkpoint kinase 2 gene), BRIP1 (BRCA 1 interacting protein C-terminal helicase 1 gene), HDAC2 (histone deacetylase 2) gene, CDK12 (cyclin-dependent kinase 12) gene, RAD51B (RAD 51 paralogue B) gene, RAD54L (RAD 54-like) gene, CDK17 (cyclin-dependent kinase 17) gene, or PPP2R2A (protein phosphatase 2 regulatory subunit B α) gene.

Gene expression profiling and protein biomarkers can also be used in risk stratification of patients with prostate cancer to guide treatment decisions. Commercially available tests include(Mailiya Genetics, myriad Genetics, salt Lake City, utah);prostate cancer assay (genome Jiankanggong)Department (Genomic Health), redwood City, calif.; proMark ^TM Protein biomarker test/ProMark ^TM Risk score (Metamark Genetics, cambridge, MA);CDx (basic medicine, cambrix, massachusetts);liquid CDx (basic medicine, cambrix, massachusetts); carris Molecular Intelligence (Caris Molecular Intelligence) (Caris Life Sciences, german, irving, TX); guardant360 (quaden Health inc., reed wood city, california);(Ambry Genetics, inc., allo Viewjo, calif.); color hereditary cancer test (Color Genomics, burlingame, california); panels of prostate cancer from veittia (Invitae) (San Francisco, ca)); prostate gene (kakon (GeneHealth), cambridge, UK); mailiya deGenetic cancer test (Mailiyade genetics, utah salt lake City) andprostate cancer testing (decoding Biosciences (GenomeDx Biosciences), san Diego, california), the latter based on the expression pattern of 22RNA markers in biopsy or radical prostatectomy samples.Andis a tissue-based gene expression test.

The formulations described herein may be used in methods of treating prostate cancer patients with biochemical relapse (BCR) or Biochemical Failure (BF). BCR or BF can be defined by elevation of Prostate Specific Antigen (PSA) in the absence of disease signs on imaging. For patients who have received primary radiation therapy, BCR is currently defined as an increase in PSA greater than or equal to 2.0ng/mL above nadir ("Phoenix (Phoenix) criteria"). For patients who have undergone primary surgery, BCR is currently defined as a confirmed increase in PSA greater than or equal to 2.0ng/mL above nadir.

New Generation Imaging (NGI) such as prostate specific membrane antigen positron emission tomography (PSMA-PET) can be used to detect lesions that are not visible on routine imaging or are below the phoenix threshold (i.e., PSA elevation <2.0 ng/mL). For example, NGI may classify some patients with localized prostate cancer, BCR, nmCRPC, or nmHRPC as having metastatic prostate cancer.

The formulations described herein may be used in methods of treating prostate cancer patients who have BCR or BF and are HRD biomarker positive and/or high risk. The positive HRD biomarker may be at least one of: BRCA1, BRCA2, ATM, BRIP1, CDK12, CDK17, CHEK2, FANCA, HDAC2, PALB2, PPP2R2A, RAD51B, and RAD54L.

The formulations described herein may be used in methods of treating BCR or BF, oligometastatic disease, or localized prostate cancer in a patient, which can be detected by conventional imaging.

The formulations described herein may be used in methods of treating BCR or BF, oligometastatic disease, or localized prostate cancer in a patient that can be detected by NGI.

The formulations described herein may be used in methods of treating patients with locally advanced prostate cancer that are candidates for primary radiation therapy.

The formulations described herein may be used in methods of treating cancer patients, particularly CRPC patients, who have a circulating tumor cell test that is negative for androgen receptor splice variant 7 (AR-V7). The formulations described herein may be used in methods of treating cancer patients, particularly CRPC patients, who have a circulating tumor cell test positive for androgen receptor splice variant 7 (AR-V7).

The formulations described herein may be used in methods of treating prostate cancer in patients with detectable Circulating Tumor Cells (CTCs), circulating DNA, or plasma DNA depletion. The formulations described herein may be used in methods of treating metastatic prostate cancer in patients with detectable CTC and/or measurable and unmeasurable bone disease or disorder. CTC clearance in patients with metastatic prostate cancer can be established when ≧ 5 cells/7.5 mL of blood are detected at baseline, <5 cells/7.5 mL of blood are detected at nadir, as further confirmed by a second continuum of values obtained after 4 weeks or more.

A free-dose combination or a fixed-dose combination of abiraterone acetate and nilapanib, and optionally a separate composition comprising a glucocorticoid (e.g., prednisone), can be administered to a subject, patient, mammal, particularly a human, suffering from prostate cancer, primary peritoneal cancer, breast cancer, or ovarian cancer. In one aspect, a human afflicted with breast cancer or ovarian cancer is a biomarker positive patient.

The prostate cancer may be metastatic prostate cancer, advanced prostate cancer, regional prostate cancer, locally advanced prostate cancer, localized prostate cancer, non-metastatic advanced prostate cancer, non-metastatic regional prostate cancer, non-metastatic locally advanced prostate cancer, non-metastatic localized prostate cancer, hormone-naive prostate cancer, chemotherapy-naive prostate cancer, castration-naive cancer with or without metastasis, radiation-naive prostate cancer, castration-resistant prostate cancer (CRPC), CRPC with DRD, non-metastatic CRPC (nmCRPC), nmCRPC of patients with PSA doubling time equal to or less than 10 months and that are HRD positive (or biomarker-enriched), nmCRPC of patients with DRD or HRD, nmCRPC of patients without DRD, nmCRPC of patients with HRD nmCRPC in patients with high risk BCR (e.g., DRD + population), nmCRPC in patients monitored with New Generation imaging technology (NGI), localized CRPC, locally advanced CRPC, regional CRPC, advanced CRPC, metastatic CRPC (mCRPC), mCRPC in patients with biallelic DNA repair Gene deficiency (DRD), mCRPC in patients with Single allele DRD, mCRPC in patients without DRD, mCRPC in patients with DRD and having received taxane and/or androgen receptor targeted therapy, CRPC in patients having received stress-hormone therapy (e.g., enzamide, dalutamide, apamide), CRPC in patients having received taxane therapy (e.g., docetaxel, mitoxantrone, cabazitaxel), chemotherapy-naive CRPC, chemotherapy naive mCRRPC, hormone naive CRPC, hormone naive mCRPC, with progress, CRPC with visceral metastasis, CRPC with visceral metastasis in patients who have received hormone therapy (e.g., enzalutamide, dallucamine, apalumide), CRPC with visceral metastasis in patients who have received taxane therapy (e.g., docetaxel, mitoxantrone, cabazitaxel), CRPC with visceral metastasis and progression, castration-sensitive prostate cancer (CSPC), non-metastatic CSPC (nmCSPC), localized CSPC, locally advanced CSPC, regional CSPC, advanced CSPC, metastatic CSPC (mCSPC), chemotherapy-naive CSPC, chemotherapy-naive mCSPC, hormone naive CSPC, hormone-sensitive mCSPC, hormone-sensitive prostate cancer (HSPC), hormone-dependent prostate cancer, androgen-sensitive prostate cancer, biochemically relapsed HSPC, metastatic HSPC (mhkc), hormone-resistant prostate cancer (HRPC), non-metastatic prostate cancer (nhrpc), localized ablation prostate cancer, regional metastatic prostate cancer, metastatic prostate cancer with distant prostate-specific metastasis, or combination thereof.

The subject or patient may be in a risk group selected from: very low risk, moderate beneficial risk, moderate adverse risk, high risk, very high risk, and regional risk.

The subject may be surgically castrated or chemically castrated.

Most, but not all, prostate cancers are adenocarcinomas and patients may have adenocarcinomas or sarcoma-based prostate cancers. In any of these cases, the prostate cancer may be metastatic.

Prior to the first dose of the free-dose or fixed-dose combination of nilapanib and abiraterone acetate, the patient may have undergone one or more other types of prostate cancer treatment. For example, the patient may have undergone taxane-based chemotherapy prior to administration of the free-dose combination or fixed-dose combination of nilapanib and abiraterone acetate. Additionally or alternatively, the patient may have undergone at least one-line androgen receptor targeted therapy, such as apalone, prior to administration of the free or fixed dose combination of nilapanib and abiraterone acetateAnd/or enzalutamideIn one aspect, prior to administration of the free-dose or fixed-dose combination of nilapanib and abiraterone acetate, the patient initially failed to respond to previous treatments or became refractory to these previous treatments. Optionally, a glucocorticoid (e.g., prednisone) may be administered in addition to a free-dose or fixed-dose combination of nilapanib and abiraterone acetate.

The time period between the end of the other treatment and the administration of the free-dose or fixed-dose combination of nilapamide and abiraterone acetate, and optionally plus a glucocorticosteroid (e.g., prednisone) according to the present disclosure may be years, months, weeks, days, or less than 24 hours.

Administration of a free-dose or fixed-dose combination of nilapanib and abiraterone acetate, and optionally a glucocorticoid (e.g., prednisone), may be on a once, twice or three times daily basis.

Daily administration includes administering to the patient a single Fixed Dose Combination (FDC) of nilapanib and abiraterone acetate once, twice or three times daily. Any dosage regimen covered by the foregoing description is contemplated. In one aspect, 1 tablet or capsule of FDC comprising nilapanib and abiraterone acetate is administered once daily. In one aspect, 2 tablets or capsules comprising FDC of nilapanib and abiraterone acetate are administered once daily. In one aspect, 3 tablets or capsules comprising FDC of nilapanib and abiraterone acetate are administered once daily. In one aspect, 1 tablet or capsule of FDC comprising nilapanib and abiraterone acetate is administered once daily for at least 1 hour before a meal or at least two hours after a meal. In one aspect, 2 tablets or capsules of FDC comprising nilapanib and abiraterone acetate are administered once daily at least 1 hour before a meal or at least two hours after a meal. In one aspect, 3 tablets or capsules comprising FDC of nilapanib and abiraterone acetate are administered once daily at least 1 hour before a meal or at least two hours after a meal. In one aspect, 1 tablet or capsule of FDC comprising nilapanib and abiraterone acetate is administered once daily, with water, on an empty stomach at least 1 hour before a meal or at least two hours after a meal. In one aspect, 2 tablets or capsules of FDC comprising nilapanib and abiraterone acetate are administered once daily, with water, on an empty stomach at least 1 hour before a meal or at least two hours after a meal. In one aspect, 3 tablets or capsules of FDC comprising nilapanib and abiraterone acetate are administered once daily, with water, on an empty stomach at least 1 hour before a meal or at least two hours after a meal.

In one aspect, the glucocorticoid is administered once or twice daily. In one aspect, the prednisone tablet or capsule is administered once or twice daily.

In one aspect, 1 or 2 tablets or capsules comprising FDC of nilapanib and abiraterone acetate are administered once daily and 1 tablet or capsule of a glucocorticoid (e.g., prednisone) is administered once or twice daily.

The amount of nilapanib equivalent administered to a patient may be about 30 to about 400 mg/day, about 50 to about 350 mg/day, about 66 to about 325 mg/day, about 100 to about 300 mg/day, about 100 to about 275 mg/day, about 125 to about 250 mg/day, about 150 to about 225 mg/day, about 175 to about 225 mg/day, or about 190 to about 210 mg/day, or about 30, about 33, about 40, about 50, about 60, about 66, about 67, about 70, about 80, about 90, about 99, about 100, about 110, about 120, about 130, about 132, about 134, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 201, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350 mg/day.

The amount of abiraterone acetate administered to a patient may be about 300 to about 2000 mg/day, about 500 to about 1500 mg/day, about 700 to about 1200 mg/day, about 800 to about 1200 mg/day, about 900 to about 1100 mg/day, about 950 to about 1050 mg/day, or may be about 300, about 333, about 500, about 600, about 666, about 700, about 750, about 800, about 850, about 875, about 900, about 925, about 950, about 999, about 1000, about 1025, about 1050, about 1075, about 1100, about 1125, or about 1500 mg/day.

The amount of prednisone administered to the patient may be about 1 to about 25 mg/day, about 2 to about 23 mg/day, about 3 to about 20 mg/day, about 4 to about 18 mg/day, about 5 to about 15 mg/day, about 6 to about 12 mg/day, about 7 to about 11 mg/day, about 8 to about 11 mg/day, about 9 to about 11 mg/day, or may be about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 mg/day. In some aspects, the patient has mCSPC and the amount of prednisone is 5 mg/day. In some aspects, the patient has mCRPC and the amount of prednisone is 10 mg/day.

When the FDC of nilapanib and abiraterone acetate is administered to a patient, the selected dosage level of each drug will depend on a variety of factors including, but not limited to, the activity of the particular compound, the severity of the individual symptoms, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, the other drugs, compounds and/or substances used in combination, and the age, sex, weight, condition, general health and prior medical history of the patient. The amount of nilapanib, the amount of abiraterone acetate, and optionally the amount of prednisone will ultimately be at the discretion of the physician, but typically the dosage will be such that local concentrations are achieved at the site of action which achieve the desired effect without causing substantial harm or deleterious side effects.

The FDC may comprise, for example, from about 33 to about 350mg of nilapanib, from about 100 to about 1500mg of abiraterone acetate.

For example, the composition of the present invention may comprise nilapanib equivalent in the following amounts: for example, 33 to about 350mg, about 33 to about 300mg, about 50 to about 200mg, about 50 to about 150mg, about 50 to about 100mg, about 33 to about 100mg, or may be about 30, about 33, about 50, about 67, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, or about 350mg. The compositions of the present invention may comprise nilapanib equivalent in an amount of about 33, about 50, about 67, or about 100 mg.

The composition of the invention may also comprise abiraterone acetate in the following amounts: for example, about 100 to about 1500mg, about 125 to about 1400mg, about 150 to about 1300mg, about 175 to about 1200mg, about 200 to about 1175mg, about 225 to about 1150mg, about 250 to about 1100mg, about 250 to about 1075mg, about 250 to about 1050mg, about 250 to about 1000mg, about 300 to about 950mg, about 350 to about 900mg, about 400 to about 850mg, about 450 to about 800mg, or about 500 to about 700mg, or may be about 100, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000, about 1050, about 1100, about 1150, about 1200, about 1250, about 1300, about 1350, about 1400mg, about 1450 mg, or about 1500mg. The compositions of the present invention may comprise abiraterone in an amount of about 333 or about 500mg.

The compositions of the present invention may comprise nilapanib equivalent in an amount of about 33mg and abiraterone in an amount of 333 mg. The compositions of the present invention may comprise nilapanib equivalent in an amount of about 67mg and abiraterone in an amount of 333 mg. The compositions of the present invention may comprise nilapanib in an amount of about 50mg and abiraterone in an amount of 500mg. The compositions of the present invention may comprise nilapanib equivalent in an amount of about 100mg and abiraterone in an amount of 500mg.

The treatment regimen of the present invention may also include the administration of a glucocorticoid (e.g., prednisone) alone in the following amounts: for example, from about 2 to about 15mg, from about 2 to about 14, from about 3 to about 13, from about 4 to about 12, from about 5 to about 11, from about 5 to about 10, from about 6 to about 11, from about 7 to about 11, from about 8 to about 11, from about 9 to about 11, or may be about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, or about 15mg.

The methods of the invention may comprise administering to the patient FDC of nilapanib and abiraterone acetate, and optionally a glucocorticoid or prednisone alone, for multiple days, weeks, months or years. Preferably, the administration of the FDC of nilapanib and abiraterone acetate occurs on a once, twice or three times daily basis, and optionally, the separate administration of prednisone occurs on a once, twice or three times daily basis. The amount of nilapanib, abiraterone acetate, and optionally prednisone administered alone may be constant over time (i.e., day-to-day), or may increase or decrease over time. For example, the amount of each of nilapanib, abiraterone acetate, and optionally prednisone administered alone, or two or all three of these, administered daily, may be increased or decreased after one day of administration, days of administration, a week of administration, and the new dosage amount may be maintained for any desired period of time, e.g., days, weeks, or months, or may be subsequently increased or decreased after desired intervals. In this manner, the present methods can include at least one increase or decrease in the administration of FDCs for nilapanib and abiraterone acetate over time (e.g., the amount of nilapanib and abiraterone acetate administered on a once daily basis, respectively). The methods of the invention may also or alternatively include increasing or decreasing the administration of prednisone (e.g., the total amount of prednisone administered on a daily basis) at least once over time. The amount of increase or decrease can be expressed in terms of a percentage, and in such cases, the amount of a single episode of increase or decrease can be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 80%, about 85%, about 90%, about 95%, about 100%, or greater than about 100%.

Described herein are methods for treating cancer, wherein a therapeutically effective amount of nilapanib, abiraterone acetate, and optionally a separately administered glucocorticoid (such as prednisone, prednisolone, hydrocortisone, methylprednisolone, and dexamethasone) is administered to a patient (e.g., a patient in need thereof) in combination with a therapeutically effective amount of at least one additional therapeutic agent including, but not limited to, anti-cancer agents (e.g., docetaxel, mitoxantrone, cabazitaxel, cisplatin, carboplatin, oxaliplatin, and etoposide), immunotherapeutic agents (e.g., pembrolizumab, sipuleucel-T), bone-targeted therapies (e.g., denosumab), zoledronic acid, alendronate, 223, strontium 89, samarium 153), gonadotropin-releasing hormone agonists (gnha, including but not limited to triptorelin (triptorelin), nafarelin (nafarelin), goserelin (goserelin), leuprorelin or leuprolide (leuprolide), histrelin (histrelin), gonadorelin (gonadorelin) and buserelin (buserelin), and hormonal therapies (e.g., nilutamide, flutamide, bicalutamide, goserelin, histrelin, leuprorelin, triptorelin, degarelix (degarelix), enzalutamide, apalutamide, daroluamide, ketoconazole, diethylstilbestrol, estrogens). Such methods may also provide effective treatment for individuals with refractory cancer, including individuals currently undergoing cancer treatment. Thus, the methods may involve treating chemotherapy-resistant prostate cancer in a patient, wherein a therapeutically effective amount of nilapanib and abiraterone acetate is administered to the patient currently receiving an anti-cancer agent.

In addition, the methods described herein for treating cancer may be combined with Androgen Deprivation Therapy (ADT). The methods for treating cancer described herein may be combined with radiation therapy, preferably in an HRD + population. In one aspect, the methods for treating cancer described herein can be combined with ADT and External Beam Radiation Therapy (EBRT). The methods for treating cancer described herein may be combined with alternative sources of performance such as High Intensity Focused Ultrasound (HIFU), cryosurgery, and laser therapy.

The FDC of the invention, and a separately administered glucocorticoid (e.g., prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferably prednisone or prednisolone) may be administered to a patient suffering from metastatic prostate cancer. In particular, the FDCs of the invention, and a separately administered glucocorticoid (e.g., prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferably prednisone or prednisolone) may be administered to a patient suffering from mCRPC, such as first line (L1) mCRPC (e.g., a subject that has not been treated with any therapy in a metastatic castration resistant setting, except Androgen Deprivation Therapy (ADT) and limited exposure to abiraterone acetate plus prednisone). The patient may be positive for HRD or not positive for HRD. Preferably, the patient is positive for HRD. Metastatic prostate cancer can be confirmed by metastatic lesions on positive bone scans or Computed Tomography (CT) or Magnetic Resonance Imaging (MRI). The patient may have a castration level of testosterone ≦ 50ng/dL and may be undergoing GnRHA therapy or have undergone bilateral orchiectomy. If no surgical castration is performed, the patient may continue to be treated with GnRHA during the treatment period. Patients may have an eastern cooperative oncology group performance score (ECOG PS) rating of 0 or 1.

ADT uses surgery or drugs to reduce the levels of androgens produced in the testes to prevent them from increasing prostate cancer cells. ADT includes but is not limited to surgical castration or orchiectomy; and drug castration, such as Luteinizing Hormone Releasing Hormone (LHRH) agonists, e.g. leuprolide, goserelin, triptorelin, histrelin; an LHRH antagonist; abiraterone acetate; ketoconazole; antiandrogens such as flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, dalutamide; or an estrogen.

FDCs of the invention, and a separately administered glucocorticoid (e.g., prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferably prednisone or prednisolone) may be administered to patients with mCSPC, e.g., a deleterious germline or somatic Homologous Recombination Repair (HRR) gene mutant mCSPC. The detrimental germline or somatic HRR gene mutation may be, but is not limited to, at least one of the following: BRCA1, BRCA2, ATM, BRIP1, CDK12, CDK17, CHEK2, FANCA, HDAC2, PALB2, PPP2R2A, RAD51B, and RAD54L. mCSPC can be confirmed by at least one bone lesion on the bone scan; bone metastases are preferably further confirmed by CT or MRI. mCSPC can be detected by NGIs such as PSMA-PET. The patient may have an eastern cooperative oncology group performance score (ECOG PS) rating of less than or equal to 2. The patient may be receiving androgen deprivation therapy (drug or surgical castration) and this therapy may have begun within 6 months prior to FDC plus prednisone (or prednisolone) treatment, preferably it may have begun at least 14 days prior to treatment with FDC plus prednisone (or prednisolone). The androgen deprivation therapy may continue throughout the FDC plus prednisone (or prednisolone) treatment. The first generation antiandrogen is preferably administered to those patients who have begun GnRHa therapy less than 28 days prior to FDC plus prednisone (or prednisolone) treatment, preferably for at least 14 days prior to FDC plus prednisone (or prednisolone) treatment. The antiandrogen must be stopped before beginning FDC plus prednisone (or prednisolone) therapy. The patient may have received prior docetaxel or cabazitaxel therapy; preferably, the patient has received docetaxel therapy for up to 6 cycles; preferably, the patient has received the last dose of docetaxel or cabazitaxel within 2 months prior to FDC plus prednisone (or prednisolone) treatment. Prior to FDC plus prednisone (or prednisolone) therapy, patients may have received radiation or surgical intervention to manage the symptoms of prostate cancer. The patient may have received abiraterone peracetic acid plus a glucocorticoid (e.g., prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone) prior to FDC plus prednisone (or prednisolone) therapy, preferably during one month prior to FDC plus prednisone (or prednisolone) therapy. Prior to FDC plus prednisone (or prednisolone) therapy, the patient may have received treatment for localized prostate cancer, preferably these treatments must have been completed at least 1 year prior to FDC plus prednisone (or prednisolone) therapy; for example, a patient may have undergone androgen deprivation therapy for up to 3 years; for example, the patient may have received radiation therapy, prostatectomy, lymph node dissection, or systemic therapy.

The FDC of the invention, and a separately administered glucocorticoid (e.g., prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferably prednisone or prednisolone) may be administered to patients suffering from metastatic castration resistant prostate cancer (mCRPC) with or without Homologous Recombination Defects (HRD) or DRD, and optionally with altered cyclin dependent kinase 12 (CDK 12) pathogenicity. FDC can be low-intensity: 100mg equivalent nilapanib/1000 mg abiraterone acetate, given as 2x FDC tablets (50 mg equivalent nilapanib/500 mg abiraterone acetate), were administered orally as a single dose under modified fasting conditions. FDC can be normal intensity: 200mg equivalent of nilapanib/1000 mg of abiraterone acetate, given as a 2x FDC tablet (100 mg equivalent of nilapanib/500 mg of abiraterone acetate), was administered orally as one daily dose under modified fasting conditions. If no surgical castration is performed (i.e., the subject has not undergone bilateral orchiectomy), the patient may be able to continue GnRHa therapy during FDC plus prednisone (or prednisolone) treatment. The patient may have an eastern cooperative oncology group competence status (ECOG PS) of less than or equal to 1. Prior to FDC plus prednisone (or prednisolone) treatment, the patient may have been exposed to an antiandrogen, including but not limited to nilutamide, flutamide, bicalutamide, enzalutamide, apalutamide, dalulomide, or abiraterone acetate; preferably, the prior antiandrogen therapy is suitably washed prior to administration of the first dose of FDC plus prednisone or prednisolone. In the case of bicalutamide, flutamide, and nilutamide, the wash time is about 2 weeks. For enzalutamide, the wash time is about 8 weeks. For apalutamine, the wash time is about 6 weeks.

FDC of the invention, and a separately administered glucocorticoid (e.g., prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferably prednisone or prednisolone) may be further administered in combination with leuprolide acetate (also known as leuprolide acetate) to patients with high risk and lymph node positive prostate cancer before, during, and after radiation therapy. The radiation therapy may be stereotactic volume radiation therapy (SBRT) or ultra-low fraction radiation therapy with a total dose of about 37.5 to 40Gy.

The FDC of the invention, and a separately administered glucocorticoid (e.g., prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferably prednisone or prednisolone) may be administered to patients with castration-naive prostate cancer with or without metastasis. If no surgical castration is performed (i.e., the subject has not undergone bilateral orchiectomy), the patient may be able to continue GnRHa therapy during FDC plus prednisone (or prednisolone) therapy.

In the disclosed compositions, the nilapanib itself can be present in a therapeutically effective amount, the abiraterone acetate itself can be present in a therapeutically effective amount, and the optional separately administered prednisone itself can be present in a therapeutically effective amount, or two or more of these conditions can be employed. In other examples, when considered together, the total amount of nilapanib, abiraterone acetate, and optionally separately administered prednisone may represent a therapeutically effective amount, i.e., the amount of nilapanib itself will not be therapeutically effective, the amount of abiraterone acetate itself will not be therapeutically effective, and if present, the amount of prednisone itself will not be therapeutically effective.

Also disclosed herein are kits comprising a composition comprising nilapanib and abiraterone acetate, and optionally a composition comprising prednisone, and printed instructions for administering the composition to a human patient suffering from prostate cancer. The instruction print may provide instructions for applying the respective composition once daily, twice daily, or multiple times daily. For example, the instructions printout can provide instructions for administering a composition comprising nilapanib and abiraterone acetate to a human patient having prostate cancer on a once-daily basis, and optionally for administering a composition comprising prednisone to a human patient on a twice-daily basis.

The present disclosure further relates to a method for determining the bioequivalence of a test fixed-dose combination (FDC) formulation of nilapanib and abiraterone acetate relative to an oral dosage form of the present disclosure, comprising i) measuring a bioequivalence parameter of the test FDC formulation and optionally measuring a bioequivalence parameter of an oral dosage form of the present disclosure, and ii) comparing the bioequivalence parameter of the test FDC formulation to a corresponding bioequivalence parameter of an oral dosage form of the present disclosure.

In one aspect, the bioequivalence parameter is selected from AUC _(0-t) 、AUC _(0-∞) Residual area, C _max And t _max 、AUC _(0-72h) Terminal rate constant (. Lamda.) _z )、t _1/2 、AUC _(0-τ) 、C _max,ss 、t _max,ss 、Ae _(0-t) And R _max These bioequivalence parameters are well known to those skilled in the art of bioequivalence and pharmacokinetics.

The invention is further defined in the following examples. It should be understood that these examples, while indicating the preferred embodiments of the invention, are given by way of illustration only and are not to be construed as limiting the appended claims. From the above discussion and these examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Examples of the invention

Example 1 composition of the formulation

Table 1: abiraterone acetate prepared according to the procedures of examples 2.1 and 2.2 nilapanib tosylate monohydrate 500 per equivalent of the composition of the 50mg core tablet.

^a Is removed in the course of processing

^b Salt factor =1.594;79.70mg of nilapanib tosylate equivalent to a 50.00mg dose of nilapanib (base)

Table 2: abiraterone acetate of table 1 prepared according to the procedure of example 2.3 nilapanib tosylate monohydrate 500 per equivalent of the composition of 50mg oral film coated tablets.

^a Is removed in the course of processing

Table 3: abiraterone acetate prepared according to the procedures of examples 2.1 and 2.2 Nilapanib tosylate monohydrate 500 per equivalent of the composition of the 100mg core tablet

^a Is removed in the course of processing

^b Salt factor =1.594;159.40mg of nilapanib tosylate equivalent to a dose of 100.00mg of nilapanib (base)

Table 4: abiraterone acetate of table 3 prepared according to the procedure of example 2.3, nilapanib tosylate monohydrate 500 per equivalent of the composition of 100mg oral film coated tablets.

^a Is removed in the course of processing

Table 5: abiraterone acetate prepared according to the procedures of examples 3.1, 3.2 and 3.3 nilapanib tosylate monohydrate 333 per equivalent of the composition of the 33mg core tablet.

^a Salt factor =1.594;53.13mg of nilapanib tosylate equivalent to a dose of 33.00mg of nilapanib (base)

Table 6: abiraterone acetate of table 5 prepared according to the procedure of example 3.4 nilapanib tosylate monohydrate 333 per equivalent of the composition of 33mg oral film coated tablets.

^a Is removed in the course of processing

Table 7: abiraterone acetate prepared according to the procedures of examples 3.1, 3.2 and 3.3 nilapanib tosylate monohydrate 333 per equivalent of the composition of the 67mg core tablet.

^a Salt factor =1.594

Table 8: abiraterone acetate of table 7 prepared according to the procedure of example 3.4: nilapanib tosylate monohydrate 333 per equivalent of composition of 67mg oral film coated tablets.

^a Is removed in the course of processing

Table 9: abiraterone acetate prepared according to the procedures of examples 4.1 and 4.2, nilapanib tosylate monohydrate 500 per equivalent of the composition of the 100mg core tablet.

^a Salt factor =1.594

Table 10: abiraterone acetate of table 9 prepared according to the procedure of example 4.3 nilapanib tosylate monohydrate 500 per equivalent of the composition of 100mg oral film coated tablets.

^a Is removed in the course of processing

Table 11: abiraterone acetate prepared according to the procedures of examples 4.1 and 4.2 nilapanib tosylate monohydrate 500 per equivalent of the composition of the 50mg core tablet.

^a Salt factor =1.594

Table 12: abiraterone acetate of table 9 prepared according to the procedure of example 4.3 nilapanib tosylate monohydrate 500 per equivalent of the composition of 50mg oral film coated tablets.

^a Is removed in the course of processing

Example 2-preparation of coated tablets comprising co-granules of abiraterone acetate and nilapanib tosylate monohydrate prepared by wet granulation

2.1 Wet granulation of Abiraterone acetate and Nilaparib tosylate monohydrate

The binder solution was prepared by: HPMC 2910 15mpa.s and sodium lauryl sulfate were dissolved in purified water until a clear solution was obtained. The ingredients abiraterone acetate, nilapanib tosylate monohydrate, lactose monohydrate, and crospovidone were sieved, pre-blended, and transferred to a suitable wet granulation apparatus, i.e., fluid bed granulator GPCG 30. These ingredients are warmed while fluidized. The complete binder solution is sprayed onto the ingredients using wet granulation techniques. The granulate is dried after spraying while being fluidized. The dried powder was collected and packaged in aluminum bags.

Table 13: granulate measurements of granulates produced by granulation of binder solutions with intragranulate phase ingredients having the compositions of table 1 and table 3

LOD profiles for pellets having the compositions of table 1 and table 3 are provided in fig. 6.

The sieve analysis for the pellets of table 1 is provided in fig. 7, and the sieve analysis for the pellets of table 3 is provided in fig. 8.

2.2 extragranular phase and compression

Silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and colloidal silicon dioxide are sieved and added to the fluidized bed granulation. All materials were sieved and blended in a suitable blender. Magnesium stearate was sieved and added to the container and all materials were blended again in a suitable blender. The blend was then compressed into core tablets using tablet press module S (KC 11).

The LOD, angle of repose, bulk density, and tap density of the final blends having the compositions of tables 1 and 3 can be found in table 14.

Table 14: LOD, angle of repose, and Density of Final blends having the compositions of Table 1 and Table 3

The results of blend homogeneity (BU) of the final blends having the compositions of table 1 and table 3 are given in table 15 and table 16, respectively, while the results of the homogeneity of the stratification content are presented in table 17 and table 18, respectively. The BU results showed that both blends were well mixed and that both APIs were evenly distributed within the blend. The stratified content uniformity results demonstrate a good and uniform distribution of abiraterone acetate and nilapanib tosylate monohydrate within the core tablet during the complete manufacturing process. For the compositions of table 3, content uniformity was also determined and can be seen in table 19.

Table 15: blend uniformity results for the compositions of Table 1

Table 16: blend uniformity results for the compositions of Table 3

Table 17: results for the stratified content uniformity of the compositions of Table 1

Table 18: results of the stratification content uniformity of the compositions of Table 3

Table 19: content uniformity results for the compositions of Table 3

The resulting tablets were tested for weight, thickness, hardness, and disintegration time, and the results are shown in table 20. The tablets are collected and packaged in suitable containers.

Table 20: tablet weight, thickness, hardness and disintegration time of the compositions of Table 1 and Table 3

All these results indicate that abiraterone acetate/nilapanib tosylate, two clinical batches with the compositions of tables 1 and 3, can be successfully made.

2.3 film coating

The coating suspension was prepared by: the coated powder was dispersed in purified water until a suspension was obtained. The core tablets are transferred to a suitable coating pan. The coating solution is then sprayed onto the core ingredients using film coating techniques. The film coated tablets were dried in the same coating pan after spraying. The coated tablets are collected and packaged in suitable containers.

The resulting film coated tablets of table 2 showed no scratches and no other defects were observed.

The resulting film-coated tablets of table 4 showed no scratch defect on the surface thereof and no white spots.

In conclusion, these film coated tablets of tables 2 and 4 were successfully manufactured without defects.

Example 3-preparation of coated tablets comprising abiraterone acetate granules prepared by fluid bed granulation and nilapanib tosylate monohydrate granules (the latter prepared by dry granulation)

3.1 Dry granulation of Nilaparib tosylate monohydrate

Nilapanib tosylate monohydrate, lactose monohydrate, microcrystalline cellulose, povidone K30, crospovidone, colloidal anhydrous silicon dioxide, and magnesium stearate are screened and blended using a suitable blender. Subsequently, the blend is ground and the ground material is further blended with a suitable blender. The dry particulates are made using a suitable compaction technique (e.g., a roller press) and further ground using a suitable dry mill.

3.2 Wet granulation of Abiraterone acetate

Abiraterone acetate, lactose monohydrate, and croscarmellose sodium are mixed and optionally sieved. A binder solution comprising hypromellose, sodium Lauryl Sulfate (SLS) and purified water was prepared and added to a mixture of abiraterone acetate, lactose monohydrate, and croscarmellose sodium. Granules are then formed by fluid bed granulation and subsequently dried.

3.3 extragranular phase and compression

The obtained abiraterone acetate and nilapanib tosylate monohydrate particles were sieved and blended in a suitable blender with silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and colloidal anhydrous silicon dioxide. Magnesium stearate was sieved and added to the container and all materials were blended again in a suitable blender.

The blend containing the nilapanib tosylate monohydrate particles and the abiraterone acetate particles was then compressed into core tablets using a suitable tablet press. The tablets are collected and packaged in suitable containers.

3.4 film coating

4.1 Dry granulation of Nilaparib tosylate monohydrate and Abiraterone acetate

Abiraterone acetate, nilapanib tosylate monohydrate, lactose monohydrate, crospovidone, sodium lauryl sulfate, colloidal anhydrous silicon dioxide, microcrystalline cellulose, and magnesium stearate are sieved and blended using a suitable blender. Subsequently, the blend is ground and the ground material is further blended with a suitable blender. The dry particulates are made using a suitable compaction technique (e.g., a roller press) and further ground using a suitable dry mill.

4.2 extragranular phase and compression

The obtained abiraterone acetate and nilapanib tosylate monohydrate co-particles were sieved and blended in a suitable blender with silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and colloidal anhydrous silicon dioxide. Magnesium stearate was sieved and added to the container and all materials were blended again in a suitable blender.

The blend is then compressed into core tablets using a suitable tablet press. The tablets are collected and packaged in suitable containers.

4.3 film coating

Example 5-stability data for the prepared dried particles of tables 1 and 3

After preparing the dried particles of tables 1 and 3, the stability data showed no degradation of abiraterone acetate and nilapanib tosylate monohydrate. The oxidative degradation of abiraterone acetate remained within specification after 12 months at 5 ℃, 25 ℃/60% rh and 30 ℃/75% rh and after 6 months at 40 ℃/75% rh.

EXAMPLE 6 dissolution method for testing the in vitro Release of the active pharmaceutical ingredient of the prepared composition

The parameters of the dissolution process are summarized in table 21 below.

TABLE 21

USP = united states pharmacopeia; JP = japan; ph.eur = european pharmacopeia; SLS = sodium lauryl sulfate; UHPLC = ultra high performance liquid chromatography; UV = ultraviolet; w/v = weight/volume.

In vitro dissolution curves for abiraterone acetate and nilapanib acetate for the following are provided in figures 5A and 5B, respectively: a combination of single agents as 1 capsule of 100-mg equivalent nilapanib (in its tosylate monohydrate form), and 2 tablets of 250-mg abiraterone acetate;

FDC tablets having the composition of Table 2 (50-mg equivalent nilapanib (in its tosylate monohydrate form), and 500-mg abiraterone acetate); and

FDC tablets having the composition of Table 4 (100-mg equivalent nilapanib (in its tosylate monohydrate form), and 500-mg abiraterone acetate).

Example 7-combination of Nilaparib with abiraterone acetate and prednisone phase 3 randomized, placebo-controlled, double-blind study (intensity (MAGNITUDE))

The primary objective of this study was to evaluate the effectiveness of nilapanib and abiraterone acetate plus prednisone (AAP) compared to abiraterone acetate plus prednisone and placebo as determined by radiographic progression free survival (rPFS).

The study consisted of 5 phases; pre-screening phase, treatment phase, follow-up phase, and expansion phase (open label or long term, depending on cohort assignment) for biomarker evaluation only. The treatment period was defined as 28 days.

Group 1: subjects with mCRPC and having HRR gene alterations

Group 1 nilapanib and AAP in combination with placebo and AAP were evaluated in subjects with L1 mCRPC (i.e., not treated with any therapy in a metastatic castration resistant setting except ADT and limited exposure to AAP) and with HRR gene alterations. Approximately 400 subjects were recruited to this cohort.

Group 2: subjects with mCRPC and no HRR gene alterations

Group 2 nilapanib and AAP in combination with placebo and AAP were evaluated in subjects with L1 mCRPC (i.e., not treated with any therapy in a metastatic castration resistant setting except ADT and limited exposure to AAP) and without HRR gene alterations. The cohort may recruit approximately 600 subjects. A pre-assigned invalidity analysis was performed after approximately 200 subjects were recruited and approximately 125 progression events had occurred in this cohort.

Group 3: subjects with mCRPC, FDC receiving Nilaparib and Abiraterone acetate

To evaluate the clinical efficacy and safety of the FDC tablet formulations of nilapanib and abiraterone acetate, a separate open label cohort was added to the study (cohort 3). Up to about 100 subjects may be enrolled into cohort 3 according to the same inclusion/exclusion criteria and subjected to the same study procedure as cohort 1 except that subjects in cohort 3 receive the open label nilapanib + abiraterone acetate as an FDC tablet formulation rather than as a single agent.

Study population

Intention-to-treat (ITT) population: randomized subjects from both cohorts 1 and 2.

Safety population: subjects in groups 1 and 2 who received at least one dose of study drug.

FDC population: subjects in cohort 3 who received at least one dose of FDC.

Evaluation of

Efficacy evaluation included the following:

progression-free survival by o-radiographic imaging (rPFS; primary endpoint): by using CT or MRI scans and whole-body bone scans: ( ^99m Tc) was evaluated. Scans are collected and reviewed by a central provider.

Serum prostate specific antigen (measured at the central laboratory) assessed by the prostate cancer working group 3 (PCWG 3) standard.

o survival status.

o for subsequent systemic therapy of prostate cancer.

Cancer-related radiotherapy or surgical procedures.

o symptomatic progression.

o patient reports outcome.

PK evaluation. Blood samples for measuring plasma levels of nilapanib and its metabolites (if judged relevant) were obtained on day 1 of cycles 2 to 7. Population PK parameters and derived exposure for nilapanib were also determined. Blood samples for measuring the plasma levels of abiraterone were obtained prior to dosing on day 1 of cycles 2 and 3.

Biomarker evaluation: HRR gene alteration status is assessed from blood and tumor tissue (archival or recently collected) samples. Other exploratory biomarker analyses will also be performed where local regulations allow.

Safety evaluation: the safety assessment is based on a medical review of adverse event reports and the results of vital sign measurements, physical examinations, clinical safety laboratory tests, eastern cooperative oncology group physical ability scoring, ECG, and other safety assessments at specified time points.

Pre-screening qualification standard

1. The Informed Consent (ICF) has been signed.

2. More than or equal to 18 years old (or local legal consenting age)

3. Histologically confirmed prostate cancer.

4. Blood samples can be provided for determining HRR gene alterations.

5. Tumor tissue samples (archival or recently collected) are willing to be provided for determining HRR gene alterations selected from BRCA1, BRCA2, CDK12, FANCA, PALB2, CHEK2, BRIP1, HDAC2, and ATM.

6. Metastatic prostate cancer in the context of castration levels of testosterone (i.e., taking gonadotropin releasing hormone analogue (GnRHa) at the time of study entry, or with a history of bilateral orchiectomy).

Inclusion criteria

Hrr gene alteration status is as follows:

a. group 1: positive for HRR Gene alteration

b. Group 2: not positive for HRR gene alteration (i.e., no HRR gene alteration)

c. Group 3: positive for HRR gene alteration and received FDC

2. Metastatic disease documented by metastatic disease on positive bone scans or Computed Tomography (CT) or Magnetic Resonance Imaging (MRI).

3. Metastatic prostate cancer in an environment where castration levels of testosterone are ≤ 50ng/dL when subjected to GnRHa or bilateral orchiectomy, as evidenced by Prostate Specific Antigen (PSA) progression or radiographic progression.

4. GnRHa can continue during the study if surgical castration is not performed.

5. Eastern cooperative oncology group Performance score (ECOG PS) rating of 0 or 1

6. Score ≦ 3 on the concise Pain scale-profile (BPI-SF) questionnaire #3 (worst Pain over the last 24 hours).

7. Clinical laboratory values at screening:

a. absolute Neutrophil Count (ANC) of not less than 1.5x10 ⁹ /L。

b. Hemoglobin ≧ 9.0g/dL (transfusion-independent) for at least 30 days.

c. Platelet count is greater than or equal to 100x10 ⁹ /L。

d. The serum albumin is more than or equal to 3.0g/dL.

e. Creatinine clearance ≧ 30mL/min calculated or measured directly via 24-hour urine collection.

f. The serum potassium is more than or equal to 3.5mmol/L.

g. Serum total bilirubin ≦ 1.5x Upper Limit of Normal (ULN) or direct bilirubin ≦ 1x ULN (note: in subjects with Gilbert's syndrome, direct bilirubin and indirect bilirubin are measured if total bilirubin >1.5x ULN, and if direct bilirubin ≦ 1.5x ULN, the subject may be eligible as determined by a medical inspector).

h. Aspartate Aminotransferase (AST) and alanine Aminotransferase (ALT) are less than or equal to 3x ULN.

8. The entire study drug tablets and capsules can be swallowed.

9. While receiving the study drug and within 3 months after the last dose of study drug, the male subject must agree to use sufficient contraceptive methods as deemed appropriate by the investigator, and agree not to donate sperm.

10. Willing and able to comply with the restrictions and constraints specified in this protocol.

Exclusion criteria

1. Prior treatment with PARP inhibitors.

Systemic therapy in the context of mcrpc (i.e., novel second generation AR targeted therapies such as enzalutamide, apalutamide, or dalutamide; taxane-based chemotherapy; or AAP for more than 4 months prior to randomization); or AAP outside of the mCRPC environment.

3. For subjects receiving 2 to 4 months of AAP for mCRPC treatment prior to randomization, there is evidence of progression of PSA during the screening period (according to PCWG 3). During the pre-screening and screening phases, these potential subjects need to have 2 PSA values. The second PSA value should be within 2 weeks of randomization. If the PSA elevation is thought to be due to reflected light spots, the investigator should confirm that there was no radiographic progress.

4. Symptomatic brain metastases.

5. History or current diagnosis of myelodysplastic syndrome (MDS)/Acute Myeloid Leukemia (AML).

6. Other prior malignancies ≦ 2 years before randomization (except: fully treated basal or squamous cell skin carcinoma, superficial bladder carcinoma, or any other in situ carcinoma that is currently in full remission), or malignancies currently in need of active systemic therapy.

7. Severe or unstable angina, myocardial infarction or ischemia requiring coronary artery bypass grafting or stenting within the previous 6 months, symptomatic congestive Heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attack), or clinically significant ventricular arrhythmias within 6 months prior to randomization, or New York Heart Association (NYHA) class II to IV Heart disease.

8. The presence of uncontrolled hypertension (sustained systolic blood pressure [ BP ] >160 mmHg or diastolic BP >100 mmHg). Subjects with a history of hypertension are admitted if BP is controlled within these limits by antihypertensive therapy.

9. Current indications of any one of the following:

a. any medical condition that would render prednisone use contraindicated.

b. Any chronic medical condition requiring a corticosteroid dose of greater than 10mg prednisone (or equivalent) once daily.

10. Active or symptomatic viral hepatitis or chronic liver disease (as evidenced by ascites, encephalopathy, or bleeding disorders secondary to liver dysfunction).

11. History of adrenal gland dysfunction

12. Known allergy, hypersensitivity, or intolerance to AA or nilapanib or corresponding excipients.

13. Subjects who were receiving opioid analgesics at the time of screening.

14. A Human Immunodeficiency Virus (HIV) positive subject with 1 or more of:

a. not receiving highly active antiretroviral therapy.

b. Receiving antiretroviral therapy that may interfere with the study drug.

c. Changes in antiretroviral therapy within 6 months of initiation of screening (unless changes are made to avoid potential drug-drug interactions with the study drug).

d. CD4 count at screening <350.

e. Acquired immunodeficiency syndrome within 6 months of the start of screening defines opportunistic infections.

15. Subjects who received the following on days ≦ 28 before randomization:

a. blood transfusion (platelets or red blood cells).

b. Hematopoietic growth factors.

c. Investigational agents directed to prostate cancer.

d. Major surgery (sponsor consulted about what constitutes major surgery).

e. Radiation therapy.

Example 8-combination of Nilaparib with Abiraterone acetate and prednisone phase 3 randomized, placebo-controlled, double-blind study (AMPLITUDE (AMPLITUDE))

The purpose of this study was:

determining whether nilapanib and abiraterone acetate plus prednisone provide superior efficacy in improving radiographic progression free survival (rPFS) compared to abiraterone acetate plus prednisone in participants with deleterious germline or somatic HRR gene mutant mCSPC;

assessing the clinical benefit of nilapanib and abiraterone acetate plus prednisone compared to abiraterone acetate plus prednisone in participants with deleterious germline or somatic HRR gene mutant mCSPC;

the safety profiles of nilapanib and abiraterone acetate plus prednisone compared to abiraterone acetate plus prednisone in participants with deleterious germline or somatic HRR gene mutant mCSPC were characterized.

Approximately 788 participants were randomly assigned to the following in a1 ratio: nilaparib 200mg and abiraterone acetate 1000mg daily, plus prednisone 5mg; or 1000mg abiraterone acetate plus 5mg prednisone per day. All participants had to receive background androgen deprivation therapy (ADT; i.e., gonadotropin releasing hormone analogue or surgical castration). The study consisted of 4 phases: pre-screening, treatment, and follow-up phases for biomarker evaluation only for eligibility.

Inclusion criteria

1. Each potential participant had to meet all of the following criteria to be recruited into the study:

2.>18 years of age (or local legal agreement on age).

3. Diagnosis of prostate adenocarcinoma.

4. By passing ^99m Tc bone scan >1 bone lesion and documented metastatic disease.

The participants have

5. A single bone lesion must have bone metastases confirmed by CT or MRI.

6. It is necessary to have at least one deleterious germline or somatic HRR gene alteration selected from the group consisting of BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B, and RAD54L.

7. Eastern cooperative oncology group physical performance status (ECOG PS) rating <2.

8. Androgen deprivation therapy (drug or surgical castration) must have begun >14 days prior to randomization and is willing to continue throughout the treatment period. Participants who started the GnRH agonist <28 days before randomization were asked to take the first generation antiandrogen >14 days before randomization. Antiandrogens must be inactivated prior to randomization.

9. Participants who have received prior docetaxel treatment must meet the following criteria:

a. docetaxel therapy for mCSPC receiving up to 6 cycles

b. (iv) received the last dose of docetaxel <2 months prior to randomization

c. Stable disease or better response to docetaxel was maintained prior to randomization (imaging or PSA assessed by investigators).

10. Other allowed prior therapies for mCSPC:

a. a maximum of 1 course of radiation or surgical intervention to manage the symptoms of prostate cancer. Radiation with a healing intent is not allowed. The irradiation must be completed before randomization.

b. ADT <6 months prior to randomization.

c. Abiraterone acetate plus prednisone (if required) for the allowed 30 days.

11. Allowed prior treatment for localized prostate cancer (all treatments must be completed ≧ 1 year before randomization):

a. ADT of less than or equal to 3 years in total

b. All other forms of prior therapy include radiation therapy, prostatectomy, lymph node dissection, and systemic therapy.

12. Clinical laboratory values at screening:

a. absolute neutrophil count of 1.5x10 or more ⁹ /L

b. Hemoglobin ≥ 9.0g/dL (independent of blood transfusion), for at least 28 days

c. Platelet count is greater than or equal to 100x10 ⁹ /L

d. Creatinine <2x upper limit of Normal value (ULN)

e. Serum potassium is more than or equal to 3.5mmol/L

f. Serum total bilirubin ≦ 1.5 × ULN or direct bilirubin ≦ 1 × ULN (note: in participants with Gilbert syndrome, if total bilirubin >1.5 × ULN, direct bilirubin and indirect bilirubin are measured, and if direct bilirubin ≦ 1.5 × ULN, the participants may be eligible)

AST or ALT ≦ 3 × ULN

13. The entire study drug tablet can be swallowed.

14. An informed consent form (written or remote/virtual) must be signed, indicating that he knows the purpose of the study and the procedures required for the study, and is willing to participate in the study (including providing a DNA sample).

15. While receiving the study drug and within 3 months after the last dose of study drug, the male participants must agree to use sufficient contraceptive means as the investigator deems appropriate.

16. The male participants must agree not to donate sperm while receiving the study drug and within 3 months after the last dose of study drug.

Exclusion criteria

Any potential participants who met any of the following criteria were excluded from participation in the study:

1. is in line with the pathological findings of small cell ductal carcinoma or neuroendocrine carcinoma of the prostate.

2. Prior treatment with PARP inhibitors.

3. Previous AR targeted therapies (e.g., ketoconazole, apaluramine, enzalutamide, dallolumide for prostate cancer), immunotherapy, or radiopharmaceuticals, with the exception of abiraterone acetate plus prednisone, which was allowed only 30 days prior to randomization.

4. Treatment with bisphosphonates or denosumab was initiated <28 days prior to randomization to manage bone metastases.

5. History of adrenal gland dysfunction

6. Systemic administration of corticosteroids (> 5mg prednisone or equivalent) was not allowed for long term use during the study. Short-term use (< 4 weeks, including tapering) and topical administration (e.g., inhalation, topical, ophthalmic, and intra-articular) of steroids is permitted if clinically needed.

7. Active malignancies (i.e., progressed within the last 24 months or required treatment changes) other than the disease being treated in the study. Only the following exceptions are allowed:

a. non-muscle invasive bladder cancer;

b. skin cancer treated within the last 24 months considered to be a complete cure (non-melanoma or melanoma);

c. breast cancer-well-treated lobular carcinoma in situ or ductal carcinoma in situ;

d. malignant tumors are considered to be cured and have a minimal risk of recurrence.

History or current diagnosis of MDS/AML.

9. Current signs of any of the following within 6 months prior to randomization: severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, a clinically significant arterial or venous thromboembolic event (e.g., pulmonary embolism), or a clinically significant ventricular arrhythmia.

10. The presence of persistent uncontrolled hypertension (systolic blood pressure >160mm Hg or diastolic blood pressure >100mm Hg). Participants with a history of hypertension were allowed provided that blood pressure was controlled within these limits by antihypertensive treatment.

11. Known allergies, hypersensitivity, or intolerance to nilapanib, abiraterone acetate, or excipients of nilapanib/abiraterone acetate FDC.

12. Would make there current evidence of any medical condition for which prednisone use is contraindicated.

13. Receiving a research intervention (including a research vaccine) or using an invasive research medical device within 30 days prior to the planned first dose of the research drug.

14. Participants who received the following items ≦ 28 days before randomization:

a. blood transfusion (platelets or red blood cells);

b. a hematopoietic growth factor;

c. major surgery (sponsor consulted about what constitutes major surgery).

15. A human immunodeficiency virus positive participant with 1 or more of:

a. not receiving highly active antiretroviral therapy or receiving antiretroviral therapy for less than 4 weeks.

b. Antiretroviral therapy was received that might interfere with the study drug (counseling sponsor with review of drug prior to enrollment).

c. Changes in antiretroviral therapy within 6 months of initiation of screening (unless changes are made to avoid potential drug-drug interactions with study drugs after negotiation with the sponsor regarding exclusion criteria).

d. CD4 count at screening <350.

f. Human immunodeficiency virus load >400 copies/mL.

16. Active or symptomatic viral hepatitis or chronic liver disease; encephalopathy, ascites or hemorrhagic disorder secondary to liver dysfunction.

17. Severe liver damage class C according to the Child-Pugh classification system.

Claims

1. A particulate composition comprising abiraterone acetate, nilapanib, and a pharmaceutically acceptable carrier.

2. The particulate composition of claim 1, wherein the particulates consist essentially of abiraterone acetate, nilapanib, and a pharmaceutically acceptable carrier.

3. The particulate composition of claim 2, wherein the particle size distribution of the particles has a d of about 200 to about 500 μ ι η, or about 231 to about 396 μ ι η ₅₀ 。

4. The particulate composition of claim 2 or 3, wherein the particles have a particle size distribution with a d of about 50 to about 250 μm, or about 93 to about 192 μm ₁₀ 。

5. The particulate composition of any one of claims 2-4, wherein the particle size distribution of the particulates has a d of about 500 to about 900 μm, or about 616 to about 723 μm ₉₀ 。

6. The particulate composition of claim 1, wherein a first portion of the particulates consists essentially of abiraterone acetate and a pharmaceutically acceptable carrier; and a second portion of the particles consisting essentially of nilapanib and a pharmaceutically acceptable carrier.

7. A particulate composition according to any one of claims 1 to 6 wherein nilapanib is in the form of a salt of tosylate monohydrate, sulphate, phenylsulphate, fumarate, succinate, camphorate, mandelate, camphorsulphonate, lauryl sulphate, or a mixture of tosylate monohydrate and lauryl sulphate.

8. A particulate composition according to any one of claims 1 to 6, wherein the nilapanib is in the form of a salt of nilapanib tosylate monohydrate.

9. A particulate composition as claimed in claim 7 or 8 wherein the nilapanib tosylate monohydrate is in crystalline form.

10. The granule composition of any one of claims 1-9, wherein the pharmaceutically acceptable carrier comprises a wetting agent, a diluent, a disintegrant, an optional glidant, an optional lubricant, and an optional binder.

11. A particulate composition as claimed in claim 10 wherein the diluent is lactose and wherein lactose also acts as a binder.

12. The granule composition of claim 10 or 11, wherein the disintegrant is crospovidone.

13. An oral dosage form comprising the particulate composition of any one of claims 1-12.

14. The oral dosage form of claim 13, wherein the oral dosage form comprises about 50mg equivalent of nilapanib and about 500mg of abiraterone acetate; about 100mg equivalent of nilapanib and about 500mg of abiraterone acetate; about 50mg equivalent of nilapanib and about 375mg of abiraterone acetate; about 100mg equivalent of nilapanib and about 375mg of abiraterone acetate; about 50mg equivalent of nilapanib and about 250mg of abiraterone acetate; about 100mg equivalent of nilapanib and about 250mg of abiraterone acetate; about 33mg equivalent of nilapanib and about 333mg of abiraterone acetate; or about 67mg equivalent of nilapanib and about 333mg of abiraterone acetate.

15. The oral dosage form of claim 13 or 14, wherein said oral dosage form is a tablet, wherein the pharmaceutically acceptable carrier comprises a wetting agent, diluent, disintegrant, glidant, lubricant, optional binder, and optional coating material.

16. The oral dosage form of claim 15, wherein the wetting agent is Sodium Lauryl Sulfate (SLS) and is present in the dosage form at a percentage of from about 3% to 6% (w/w).

17. The oral dosage form of claim 15 or 16, wherein the humectant is SLS and is present in the final dosage form in a ratio by weight to abiraterone acetate of: about 0.05.

18. The oral dosage form of any one of claims 15-17, wherein SLS is present in both the intragranular and extragranular phases of the tablet.

19. The oral dosage form of any one of claims 15-18, wherein the disintegrant is crospovidone and is present in both the intragranular phase and the extragranular phase of the tablet.

20. The oral dosage form of any one of claims 15-19, wherein the diluent of the extra-granular phase is silicified microcrystalline cellulose.

21. The oral dosage form of any one of claims 15-20, wherein the tablet has a hardness of 250 to 350N.

22. The oral dosage form of any one of claims 15-21, wherein the tablet has a stratified content uniformity of from 75% to 125%, or from 90% to 110%.

23. The oral dosage form of any one of claims 15-22, wherein the tablet has a blend uniformity with a relative standard deviation of up to 3%.

24. The oral dosage form of any one of claims 15-23, wherein the tablet comprises about 500mg of abiraterone acetate and about 50mg equivalent of nilapanib in its tosylate monohydrate form; and wherein when measured by USP paddle method at 75rpm in 900mL of an aqueous solution comprising 0.05mM sodium phosphate buffer and 0.25% (w/v) sodium lauryl sulfate at a pH of 4.5 and a temperature of 37.0 ℃ ± 0.5 ℃, (i) greater than 40%, or about 50% of the abiraterone acetate dissolved after 5 minutes, (ii) greater than 75%, or about 80% or 81% of the abiraterone acetate dissolved after 10 minutes, (iii) greater than 85%, or about 89% or 90% of the abiraterone acetate dissolved after 15 minutes, (iv) greater than 87%, or about 92% of the abiraterone acetate dissolved after 20 minutes, (v) greater than 90%, or about 95% of the abiraterone acetate dissolved after 30 minutes, (vii) greater than 91%, or about 96% of the abiraterone acetate dissolved after 45 minutes, (vii) greater than 92%, or about 97% of the abiraterone acetate dissolved after 60 minutes, (vi) greater than 93%, or about 98% of the abiraterone acetate dissolved after 60 minutes, (vii) greater than 93% of the abiraterone acetate dissolved after 90, or about 98 minutes.

25. The oral dosage form of any one of claims 15-23, wherein the tablet comprises about 500mg of abiraterone acetate and about 100mg equivalent of nilapanib in the form of its tosylate monohydrate; and wherein when measured by USP paddle method at 75rpm in 900mL of an aqueous solution comprising 0.05mM sodium phosphate buffer and 0.25% (w/v) sodium lauryl sulfate at a pH of 4.5 and a temperature of 37.0 ℃ ± 0.5 ℃, (i) greater than 36%, or about 41% of the abiraterone acetate dissolved after 5 minutes, (ii) greater than 67%, or about 72% of the abiraterone acetate dissolved after 10 minutes, (iii) greater than 76%, or about 81% of the abiraterone acetate dissolved after 15 minutes, (iv) greater than 81%, or about 86% of the abiraterone acetate dissolved after 20 minutes, (v) greater than 85% or 86%, or about 90% or 91% of the abiraterone acetate dissolved after 30 minutes, (vii) greater than 90%, or about 95% of the abiraterone acetate dissolved after 45 minutes, (vii) greater than 90% or 91%, or about 95% of the abiraterone acetate dissolved after 60 minutes, (vii) greater than 90% or about 99% of the abiraterone acetate dissolved after 60 minutes, (vi) greater than 90%, or about 99% of the abiraterone acetate dissolved after 45 minutes, (vii) dissolved after 90% of the abiraterone acetate dissolved after 90% or about 99 minutes.

26. The oral dosage form of any one of claims 15-23, wherein the tablet comprises about 500mg of abiraterone acetate and about 50mg equivalent of nilapanib in the form of its tosylate monohydrate; and wherein when measured by the USP paddle method at 75rpm in 900mL of an aqueous solution comprising 0.05mM sodium phosphate buffer and 0.25% (w/v) sodium lauryl sulfate at a pH of 4.5 and a temperature of 37.0 ℃ ± 0.5 ℃, (i) greater than 30% or 35%, or about 39% or 40% of the nilapanib is dissolved after 5 minutes, (ii) greater than 79% or 80%, or about 84% or 85% of the nilapanib is dissolved after 10 minutes, (iii) greater than 90%, or about 95% of the nilapanib is dissolved after 15 minutes, (iv) greater than 92%, or about 97% of the nilapanib is dissolved after 20 minutes, (v) greater than 93%, or about 98% of the nilapanib is dissolved after 30 minutes, (vi) greater than 93%, or about 98% of the nilapanib is dissolved after 45 minutes, (vii) greater than 93%, or about 98% of the nilapanib is dissolved after 60 minutes, (vii) greater than 93%, or about 98% of the nilapanib is dissolved after 120 minutes, (i) greater than 93%, or about 98% of the nilapanib is dissolved after 90%, or about 98% of the nilapanib is dissolved after 45 minutes (vii) after 60 minutes.

27. The oral dosage form of any one of claims 15-23, wherein the tablet comprises about 500mg of abiraterone acetate and about 100mg equivalents of nilapanib in its tosylate monohydrate form; and wherein when measured by USP paddle method at 75rpm in 900mL of an aqueous solution comprising 0.05mM sodium phosphate buffer and 0.25% (w/v) sodium lauryl sulfate at a pH of 4.5 and 37.0 ℃ ± 0.5 ℃, (i) greater than 23%, or about 28% of the nilapanib is dissolved after 5 minutes, (ii) greater than 64%, or about 69% of the nilapanib is dissolved after 10 minutes, (iii) greater than 80% or 81%, or about 85% or 86% of the nilapanib is dissolved after 15 minutes, (iv) greater than 87%, or about 92% of the nilapanib is dissolved after 20 minutes, (v) greater than 90%, or about 95% of the nilapanib is dissolved after 30 minutes, (vi) greater than 91%, or about 96% of the nilapanib is dissolved after 45 minutes, (vii) greater than 92%, or about 97% of the nilapanib is dissolved after 60 minutes, (ii) greater than 92%, or about 97% of the nilapanib is dissolved after 120 minutes, (vii) greater than 92%, or about 97% of the nilapanib is dissolved after 45 minutes.

28. The oral dosage form of any one of claims 24-27, wherein the dosage form is bioequivalent to a free dose combination of abiraterone acetate and nilapanib, when administered orally on an equivalent dose basis.

29. The oral dosage form of claim 13 or 14, wherein the oral dosage form is a capsule or sachet, optionally further comprising a diluent.

30. The oral dosage form of any one of claims 13-29, wherein the oral dosage form is Fixed Dose Combination (FDC).

31. The oral dosage form of any one of claims 13-30, for use in treating prostate cancer in a patient.

32. The oral dosage form for use of claim 31, wherein the prostate cancer is metastatic prostate cancer, advanced prostate cancer, regional prostate cancer, locally advanced prostate cancer, localized prostate cancer, non-metastatic advanced prostate cancer, non-metastatic regional prostate cancer, non-metastatic locally advanced prostate cancer, non-metastatic localized prostate cancer, hormone-naive prostate cancer, chemotherapy-naive prostate cancer, castration-naive cancer with or without metastasis, radiation-naive prostate cancer, castration-resistant prostate cancer (CRPC), non-metastatic CRPC (nmCRPC), localized CRPC, locally advanced CRPC, regional CRPC, advanced CRPC, metastatic CRPC (mCRPC), mCRPC of patients with biallelic DNA repair gene defects (DRD) or HRD, mCRPC of patients with biallelic DRD or HRD mCRPC in patients without DRD or HRD, mCRPC in patients who have DRD or HRD and have received taxane and/or androgen receptor targeted therapy, mCRPC in patients who have received docetaxel or cabazitaxel, CRPC in patients who have received overactive hormone therapy (e.g., enzalutamide, dalutamide, apalumide), CRPC in patients who have received taxane therapy (e.g., docetaxel, mitoxantrone, cabazitaxel), chemotherapy naive CRPC, chemotherapy naive mCRPC, hormone naive CRPC, hormone naive mCRRPC, progressive CRPC, CRPC with visceral metastasis in patients who have received overactive hormone therapy (e.g., enzalutamide, dalutamide, apalumide), CRPC with visceral metastasis in patients who have received taxane therapy (e.g., docetaxel, HRPD, HRD, and/or HRD), CRPC with paclitaxel, mitoxantrone, cabazitaxel), CRPC with visceral metastasis and progression, castration-sensitive prostate cancer (CSPC), non-metastatic CSPC (nmCSPC), localized CSPC, locally advanced CSPC, regional CSPC, advanced CSPC, metastatic CSPC (mCSPC), chemotherapy-naive CSPC, chemotherapy-naive mCSPC, hormone-naive CSPC, hormone-naive mCSPC, hormone-sensitive prostate cancer (HSPC), hormone-dependent prostate cancer, androgen-sensitive prostate cancer, biochemically relapsed HSPC, metastatic HSPC (mhpc), hormone-resistant prostate cancer (HRPC), non-metastatic HRPC (nmHRPC), localized HRPC, locally advanced HRPC, regional HRPC, advanced HRPC, metastatic HRPC (mHRPC), recurrent prostate cancer, prostate cancer with persistent or recurrent prostate-specific antigen (PSA) after prostatectomy, with or without distant metastasis, prostate cancer, radiation-resistant prostate cancer, and any combination thereof.

33. The oral dosage form for use of claim 31, wherein the prostate cancer is first line (L1) mCRPC and the patient is positive for DRD or HRD.

34. The oral dosage form for use of claim 31, wherein the prostate cancer is detrimental germline or somatic Homologous Recombination Repair (HRR) gene mutant mCSPC.

35. The oral dosage form for use of claim 31, wherein the prostate cancer is mCRPC with or without DNA repair gene defects (DRD) or HRD, and optionally with a cyclin dependent kinase 12 (CDK 12) pathogenicity alteration.

36. The oral dosage form for use of claim 31, wherein the prostate cancer is high risk localized prostate cancer.

37. The oral dosage form for use of claim 31 or 32, wherein the patient is in a risk group selected from: very low, moderately favorable, moderately unfavorable, high, very high, and regional.

38. The oral dosage form for use of any one of claims 31-37, wherein the use comprises administration of about 666 to about 1500 mg/day of abiraterone acetate; administering about 999 to about 1500 mg/day of abiraterone acetate; administering about 666 mg/day abiraterone acetate; or about 1000 mg/day of abiraterone acetate.

39. The oral dosage form for use of any of claims 31-38, wherein the use comprises administering about 33 to about 300 mg/day of nilapanib equivalent; administering about 100 to about 200 mg/day of nilapanib equivalent; administering about 66 mg/day of nilapanib equivalent; administering about 100 mg/day of nilapanib equivalent; administering about 134 mg/day of nilapanib equivalent; or about 200 mg/day equivalent of nilapanib.

40. The oral dosage form for use of any one of claims 31-39, wherein the use comprises administering 1, 2, or 3 oral dosage forms per day.

41. The oral dosage form for use of any one of claims 31-40, wherein the use comprises administration of the one or more oral dosage forms once a day (q.d.) or twice a day (b.i.d.); preferably at least 1 hour before a meal or at least two hours after a meal, once a day.

42. The oral dosage form for use of any one of claims 31-41, wherein the use comprises administration of about 1 to about 60 mg/day of prednisone alone; about 5 to about 15 mg/day of prednisone; about 9 to about 11 mg/day of prednisone; about 10 mg/day of prednisone; about 5 mg/day prednisone; or about 5 mg/day of prednisone.

43. A process for the preparation of a particulate composition as claimed in any one of claims 1 to 5 and 7 to 12 comprising the steps of:

(a) Preparing a binder solution comprising a wetting agent;

(c) Wet granulating the blend obtained from step (b);

(d) Drying the product obtained from step (c).

44. The method of claim 43, wherein the binder solution comprises a binder, the wetting agent, and a solvent.

45. The method of claim 43 or 44, wherein the inlet air temperature during the wet granulation of step c) is from 25 ℃ to 65 ℃.

46. The method of any one of claims 43-45, wherein the spray rate during the wet granulation of step c) is from 190 to 300g/min.

47. The method of any of claims 43-46, wherein the inlet air flow rate during the wet granulation of step c) is from 800 to 1300m ³ /h。

48. A process for preparing a particulate composition as claimed in any one of claims 1-2 and 7-12, comprising the steps of:

(b) Dry granulating the blend obtained from step (a);

(c) Grinding the dry granulated product obtained from step (b);

49. A process for preparing a particulate composition as claimed in any one of claims 1 and 6 to 12 comprising the steps of:

b) Dry granulating the blend obtained from step (a);

c) Grinding the dry granulated blend obtained from step (b);

d) Preparing a binder solution comprising a wetting agent;

f) Wet granulating the blend obtained from step (e);

g) Drying the product obtained from step (f);

50. The method of any one of claims 43-49, wherein the obtained particulate composition is further compressed into a tablet, optionally with a lubricant.

51. The method of claim 50, further comprising preparing a coating suspension and coating the tablet with said suspension.

52. The method of any one of claims 43-49, wherein the obtained particulate composition is further dosed into a capsule or sachet, optionally with a diluent.

53. A method for treating prostate cancer in a patient, said method comprising administering to the patient an oral dosage form of any one of claims 13-30.

54. The method according to claim 53, wherein, wherein the prostate cancer is metastatic prostate cancer, advanced prostate cancer, regional prostate cancer, locally advanced prostate cancer, localized prostate cancer, non-metastatic advanced prostate cancer, non-metastatic regional prostate cancer, non-metastatic locally advanced prostate cancer, non-metastatic localized prostate cancer, hormone-naive prostate cancer, chemotherapy-naive prostate cancer, castration-naive cancer with or without metastasis, radiation-naive prostate cancer, castration-resistant prostate cancer (CRPC), non-metastatic CRPC (nmCRPC), localized CRPC, locally advanced CRPC, regional CRPC, advanced CRPC, metastatic CRPC (mCRPC), mCRPC of patients with biallelic DNA repair gene defects (DRD) or HRD, mCRPC of patients with biallelic DRD or HRD mCRPC in patients without DRD or HRD, mCRPC in patients who have DRD or HRD and have received taxane and/or androgen receptor targeted therapy, mCRPC in patients who have received docetaxel or cabazitaxel, CRPC in patients who have received overactive hormone therapy (e.g., enzalutamide, dalutamide, apalumide), CRPC in patients who have received taxane therapy (e.g., docetaxel, mitoxantrone, cabazitaxel), chemotherapy naive CRPC, chemotherapy naive mCRPC, hormone naive CRPC, hormone naive mCRRPC, progressive CRPC, CRPC with visceral metastasis in patients who have received overactive hormone therapy (e.g., enzalutamide, dalutamide, apalumide), CRPC with visceral metastasis in patients who have received taxane therapy (e.g., docetaxel, HRPD, HRD, and/or HRD), CRPC with paclitaxel, mitoxantrone, cabazitaxel), CRPC with visceral metastasis and progression, castration-sensitive prostate cancer (CSPC), non-metastatic CSPC (nmCSPC), localized CSPC, locally advanced CSPC, regional CSPC, advanced CSPC, metastatic CSPC (mCSPC), chemotherapy-naive CSPC, chemotherapy-naive mCSPC, hormone-naive CSPC, hormone-naive mCSPC, hormone-sensitive prostate cancer (HSPC), hormone-dependent prostate cancer, androgen-sensitive prostate cancer, biochemically relapsed HSPC, metastatic HSPC (mhpc), hormone-resistant prostate cancer (HRPC), non-metastatic HRPC (nmHRPC), localized HRPC, locally advanced HRPC, regional HRPC, advanced HRPC, metastatic HRPC (mHRPC), recurrent prostate cancer, prostate cancer with persistent or recurrent prostate-specific antigen (PSA) after prostatectomy, with or without distant metastasis, prostate cancer, radiation-resistant prostate cancer, and any combination thereof.

55. The method of claim 53, wherein the prostate cancer is first line (L1) mCRPC and the patient is positive for DRD or HRD.

56. The method of claim 53, wherein the prostate cancer is detrimental germline or somatic Homologous Recombination Repair (HRR) gene mutant mCSC.

57. The method of claim 53, wherein the prostate cancer is mCRPC with or without DNA repair gene deficiency (DRD) or HRD, and optionally with alterations in cyclin dependent kinase 12 (CDK 12) pathogenicity.

58. The method of claim 53, wherein the patient has a high risk localized prostate cancer.

59. The method of claim 53 or 54, wherein the patient is in a risk group selected from: very low, moderately favorable, moderately unfavorable, high, very high, and regional.

60. The method of any one of claims 53-59, wherein the method comprises administering about 666 to about 1500 mg/day of abiraterone acetate; administering about 999 to about 1500 mg/day of abiraterone acetate; administering about 666 mg/day abiraterone acetate; or about 1000 mg/day of abiraterone acetate.

61. The method of any one of claims 53-60, wherein the method comprises administering about 33 to about 300 mg/day of nilapanib equivalent; administering about 100 to about 200 mg/day of nilapanib equivalent; administering about 66 mg/day of nilapanib equivalent; administering about 100 mg/day of nilapanib equivalent; administering about 134 mg/day of nilapanib equivalent; or about 200 mg/day equivalent of nilapanib.

62. The method of any one of claims 53-61, wherein the method comprises administering 1, 2, or 3 dosage forms per day.

63. The method of any one of claims 53-62, wherein the method comprises administering the one or more dosage forms once per day (q.d.) or twice per day (b.i.d.); preferably once per day; preferably at least 1 hour before a meal or at least two hours after a meal, once a day.

64. The method of any one of claims 53-63, wherein the method comprises administering separately from about 1 to about 60 mg/day of prednisone; about 5 to about 15 mg/day of prednisone; about 9 to about 11 mg/day of prednisone; about 10 mg/day of prednisone; about 5 mg/day prednisone; or about 5 mg/day prednisone.