EA044464B1 - TABLET FOR POLYADENOSINE DIPHOSPATE Ribose POLYMERASE (PARP) INHIBITION - Google Patents

Description

Cross reference to related applications

This application claims priority to U.S. Provisional Application No. 62/563,535, filed September 26, 2017, the entire contents of which are incorporated herein.

Brief description of the invention

Niraparib is an orally active, potent poly(ADFribose) polymerase, or PARP, inhibitor. Niraparib and its pharmaceutically acceptable salts are described in international publication WO 2007/113596 and European patent EP 2007733 B1; international publication WO 2008/084261 and US patent No. 8,071,623; and in international publication WO 2009/087381 and US patent No. 8,436,185. Methods for the preparation of niraparib and its pharmaceutically acceptable salts are described in international publications WO 2014/088983 and WO 2014/088984. Methods of treating cancer with niraparib and its pharmaceutically acceptable salts are described in US provisional patent applications 62/356,461 and 62/402,427, as well as in international publication WO 2018/005818. The contents of each of the foregoing documents are incorporated herein by reference in their entirety.

PARP is a family of proteins involved in many cellular functions, including DNA repair, gene expression, cell cycle control, intracellular trafficking, and energy metabolism. PARP proteins play a key role in the repair of single-strand breaks through base excision repair. PARP inhibitors are active as monotherapy against tumors with existing DNA repair defects, such as BRCA1 and BRCA2, and as combination therapy when administered with antitumor agents that cause DNA damage.

Despite some advances in the treatment of ovarian cancer, most patients eventually relapse, and subsequent responses to additional treatment are often of limited duration. Women with germline mutations in BRCA1 or BRCA2 have an increased risk of developing high-grade serous ovarian cancer (HGSOC), and their tumors appear to be particularly sensitive to PARP inhibitor treatment. In addition, data published in the scientific literature indicate that patients with platinum-sensitive HGSOC who do not have germline BRCA1 or BRCA2 mutations may also benefit clinically from PARP inhibitor treatment.

It is estimated that 5% to 10% of women diagnosed with breast cancer, or more than 15,000 women per year, have germline mutations in the BRCA1 or BRCA2 genes. The development of cancer in these women is associated with dysfunction of a key DNA repair pathway known as homologous recombination. Although cancer cells can survive despite disruption of the homologous recombination pathway, they become especially vulnerable to chemotherapy if the alternative DNA repair pathway is disrupted. This phenomenon is known as synthetic lethality, a situation where loss of any one repair pathway is compatible with cell viability; but simultaneous loss of both pathways results in cancer cell death. Because PARP inhibitors block DNA repair, for cancer cells with a BRCA mutation, PARP inhibition results in synthetic lethality. For this reason, patients with germline BRCA mutations show marked clinical improvement after treatment with a PARP inhibitor.

Surprisingly, it has been found that the solid dosage forms of the present invention have the desired properties and exhibit excellent potency stability and disintegration profiles during storage. Thus, such dosage forms may be useful for use in treating subjects having diseases such as cancer. In some embodiments of the present invention, the solid dosage forms described herein provide tablet manufacturability, including reducing the stickiness of the active pharmaceutical ingredient during the manufacturing process.

One aspect of the present invention relates to a tablet for inhibiting polyadenosine diphosphate ribose polymerase (PARP), containing the following components in weight percentage:

(a) in the intragranular part:

(i) 40-50% 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1);

(ii) 9-11% first diluent;

(iii) 30-40% second diluent;

(iv) 1-3% binder;

(v) 0.1-2% disintegrant;

(vi) 2-4% glidant or adsorbent or absorbent; and (vii) 0.1-2% lubricant; and (b) in the extragranular part:

(i) 0.1-2% disintegrant;

(ii) 0.1-2% glidant or adsorbent or absorbent; and (iii) 0.1-2% lubricant.

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In embodiments of the present invention, said first diluent is lactose monohydrate.

In some embodiments of the present invention, said second diluent is microcrystalline cellulose.

In some embodiments of the present invention, said binder is povidone.

In some embodiments of the present invention, said intragranular disintegrant is crospovidone.

In some embodiments of the present invention, said glidant, adsorbent, or intragranular portion absorbent is silica.

In some embodiments of the present invention, said intragranular lubricant is magnesium stearate.

In some embodiments of the present invention, said extragranular disintegrant is crospovidone.

In some embodiments of the present invention, said glidant, adsorbent, or extragranular portion absorbent is silica.

In some embodiments of the present invention, said extragranular lubricant is magnesium stearate.

In some embodiments of the present invention, (i) the first intragranular moiety diluent is lactose monohydrate; (ii) the second intragranular part diluent is microcrystalline cellulose; (iii) the intragranular portion binder is povidone; (iv) the intragranular disintegrant is crospovidone; (v) the glidant, adsorbent or absorbent of the intragranular portion is silica; (vi) the intragranular lubricant is magnesium stearate; (vii) the disintegrating agent of the extragranular part is crospovidone; (viii) the glidant, adsorbent or extragranular portion absorbent is silica; and (ix) the extragranular lubricant is magnesium stearate.

In some embodiments of the present invention, the tablet further comprises a film coating.

In some embodiments of the present invention, the film coating is Opadry II.

In some embodiments of the present invention, the amount of 2-{4-[(3S)-piperidin-3yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1) per tablet is 100 mg, based on free niraparib base.

In some embodiments of the present invention, the amount of 2-{4-[(3S)-piperidin-3yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1) per tablet is 200 mg, based on free niraparib base.

In some embodiments of the present invention, the amount of 2-{4-[(3S)-piperidin-3yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1) per tablet is 300 mg, based on free niraparib base.

Quantitative determination of impurities or degradation products resulting from chemical changes of the active substance during the production and/or storage of the drug product under the influence of light, temperature, moisture or as a result of reaction with an excipient is carried out using available methods and equipment known to those skilled in the art. areas. Typical methods include chromatographic methods such as high performance liquid chromatography (HPLC) (eg, chiral chromatography, ion exchange chromatography, ion pair/affinity chromatography, reverse phase chromatography, and size exclusion chromatography); gas chromatography (GC) and thin layer chromatography (TLC). For example, a validated reverse-phase gradient HPLC method with UV detection and an external standard method may be a suitable method for assessing stability. Mass spectrometry (MS) can be used alone or in conjunction with chromatographic methods (eg, HPLC-MS or GC-MS). Spectrophotometry (eg, UV/visible spectrophotometry) can also be used. The levels of impurities in the medicinal product are adjusted and controlled in accordance with the requirements of the Q3B principles of the International Council of Harmonization (ICH).

Another aspect of the present invention relates to a tablet for inhibiting polyadenosine diphosphate ribose polymerase (PARP), containing the following components in weight percentage:

(c) in the intragranular part:

(i) 40-50% 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1);

(ii) 9-11% of a first diluent selected from lactose monohydrate, lactose anhydrous, mannitol and

- 2 044464 dibasic calcium phosphate;

(iii) 30-40% of a second diluent selected from microcrystalline cellulose, starch, polyethylene oxide and hydroxypropyl methylcellulose;

(iv) 1-3% of a binder selected from povidone, hydroxypropylcellulose and hydroxypropylmethylcellulose;

(v) 0.1-2% disintegrant selected from crospovidone and croscarmellose;

(vi) 2-4% glidant or adsorbent or absorbent selected from silica, tribasic calcium phosphate, calcium silicate, cellulose, magnesium silicate, magnesium trisilicate, starch, talc and mixtures thereof; and (vii) 0.1-2% magnesium stearate; and (d) in the extragranular part:

(i) 0.1-2% disintegrant selected from crospovidone and croscarmellose;

(ii) 0.1-2% glidant or adsorbent or absorbent selected from silica, tribasic calcium phosphate, calcium silicate, cellulose, magnesium silicate, magnesium trisilicate, starch, talc and mixtures thereof; and (iii) 0.1-2% magnesium stearate.

In embodiments of the present invention, the disintegrant is crospovidone.

In embodiments of the present invention, the silica is a medium pore mesoporous silica, preferably Syloid FP-244.

In embodiments of the present invention, the first diluent is lactose monohydrate.

In some embodiments of the present invention, the second diluent is microcrystalline cellulose.

In some embodiments of the present invention, the binder is povidone.

Inclusion via link

All publications, patents and patent applications mentioned herein are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent or patent application had been specifically and individually identified as being incorporated by reference.

Brief description of graphic materials

The features of the present invention are set out in detail in the accompanying claims. A better understanding of the features and advantages of the present invention can be obtained from the following detailed description, which sets forth illustrative embodiments of the invention using the principles of the present invention and the accompanying figures.

In fig. 1 is a flowchart of an exemplary process for preparing a niraparib tablet using wet granulation.

In fig. 2 is a flow chart of an exemplary process for preparing niraparib tablet using moisture activated dry granulation (MADG).

In fig. 3 is a flow diagram of an exemplary process for preparing niraparib tablet using dry granulation.

In fig. Figure 4 shows an illustrative Kaplan-Meier plot of progression-free survival in the gBRCAmut cohort based on IRC assessment (ITT population, N=203).

In fig. Figure 4 shows an illustrative Kaplan-Meier plot of progression-free survival in the non-gBRCAmut cohort based on IRC assessment (ITT population, N=350).

In fig. Table 6 provides stability data for an exemplary formulation presented as a 100 mg niraparib tablet when stored at 25 °C/60% relative humidity (RH).

In fig. Table 7 provides stability data for an exemplary formulation presented as a 100 mg niraparib tablet when stored at 40°C/75% relative humidity.

In fig. 8 provides stability data for an exemplary formulation presented as a 100 mg niraparib tablet when stored at 25°C/60% relative humidity.

In fig. Table 9 provides stability data for an exemplary formulation presented as a 100 mg niraparib tablet when stored at 40°C/75% relative humidity.

Detailed Description of the Invention

Various pharmaceutical products in tablet form are packaged for oral administration and are intended to release a pharmaceutically active composition in the human body. Pharmaceutical tablets for oral administration typically contain a specified amount of one or more pharmaceutically active compositions together with one or more inert excipients.

In some embodiments of the present invention, the oral pharmaceutical tablets described herein improve tablet processability by reducing the stickiness/adhesion of the active pharmaceutical ingredient during manufacture. In some embodiments of the present invention, the desired properties of the oral pharmaceutical tablets described herein are improved, namely those properties related to flow, tensile strength, hardness, disintegration, and binding of intragranular and extragranular materials. In some embodiments of the present invention, pharmaceutical tablets for oral administration described herein impart desirable tablet-enhancing properties to the final mixture that is used for compression into tablets. In some embodiments of the present invention, said pharmaceutical tablets for oral administration are prepared from granules of a desired particle size to provide good fluidity, tablet binding, and desired tablet disintegration profiles. In some embodiments of the present invention, the oral pharmaceutical tablets have a distribution of intragranular phase components and extragranular phase components that provides the desired disintegration profiles.

The tablet compositions described herein may also be used to provide improved treatments for cancer. For example, the tablet compositions described herein may result in reduced variability in PK parameters compared to other pharmaceutical dosage forms.

Definitions

The term AUC refers to the area under the plasma time/concentration curve following administration of a pharmaceutical composition. AUC ₀ . _Infinity denotes the area under the plasma concentration-time curve from 0 to infinity; AUC _{0_t} denotes the area under the plasma concentration-time curve from time 0 _to time t.

Binders are used to hold components together in a composition, such as a tablet composition. In some embodiments of the present invention, binders are used to form granules. Examples of suitable binders include, but are not limited to, the following: disaccharides such as sucrose and lactose; polysaccharides and their derivatives such as starches, microcrystalline cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose; sugar alcohols such as xylitol, sorbitol or maltitol, gelatin, polyvinylpyrrolidone (polyvidone or povidone), polyethylene glycol, polyvinyl alcohol and polymethacrylates. In some embodiments of the present invention, said binder is a liquid binder or a solution binder. Examples of liquid binders include, but are not limited to, water, gelatin, cellulose, cellulose derivatives, povidone, starch, sucrose and polyethylene glycol. In some embodiments of the present invention, gelatin, cellulose, cellulose derivatives, povidone, starch, sucrose or polyethylene glycol may be dissolved. For example, they can be dissolved in water. In some embodiments of the present invention, said liquid binder is povidone (PVP). In some embodiments of the present invention, said binder is a dry binder. Examples of suitable dry binders include, but are not limited to, cellulose, methylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol. In some embodiments of the present invention, said dry binder is hydroxypropyl cellulose (HPC). In some embodiments of the present invention, said liquid binder is a molten binder, the molten liquid being used as a binder. When using molten binders, there may be no need to use aqueous or organic solvents. Accordingly, a drying step may not be required, reducing overall processing time and reducing cost. In addition, water-sensitive materials can be processed using this non-aqueous granulation method. Molten binders may include hydrophilic polyethylene glycols (PEGs) and poloxamers, as well as hydrophobic fatty acids, fatty alcohols, waxes, hydrogenated vegetable oils and glycerides.

The term plasma concentration refers to the concentration of the compounds described herein in the blood plasma of a subject.

The term bioequivalent means that there is no significant difference in the rate and extent with which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of action of the drug when administered at the same molar dose under similar conditions in a properly designed study. In practice, two products are considered bioequivalent if the 90% confidence interval of _Cmax , AUC, or optionally _Tmax is between 80.00% and 125.00%.

As used herein, the term bulk density before compaction refers to the ratio of the mass of an unconsolidated powder sample to its volume, including the contribution of interparticle void volume. Bulk density before compaction indicates the mass of powder material that can be filled per unit volume. For example, granules contained in a pharmaceutical composition may have a bulk density before compaction greater than or equal to 0.5 g/cm ³ .

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The term _Cmax refers to the maximum concentration of niraparib in the blood after administration of the pharmaceutical composition.

The term cancer includes both solid tumors and hematologic malignancies. Cancer includes, but is not limited to, the following: ovarian cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, stomach cancer, bladder cancer, lung cancer (eg adenocarcinoma, NSCLC and SCLC), bone cancer (eg osteosarcoma), colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancer, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma (eg, liposarcoma), bladder cancer, liver cancer (eg, hepatocellular carcinoma), kidney cancer (eg, renal cell carcinoma), myeloid disorders (eg, AML, CML, myelodysplastic syndrome and promyelocytic leukemia) and lymphoid disorders (eg, leukemia, multiple myeloma, mantle cell lymphoma, ALL, CLL, B cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma).

The term composition, as in the expression pharmaceutical composition, is intended to mean a drug product containing niraparib or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof and other inert ingredient(s) (pharmaceutically acceptable Excipients). Such pharmaceutical compositions, in some embodiments of the present invention, may be synonymous with the terms composition and dosage form. The pharmaceutical compositions of the present invention include, but are not limited to, granules, tablets (single-layer tablets, multi-layer tablets, mini-tablets, bioadhesive tablets, caplets, matrix tablets, tablet-in-tablet, mucoadhesive tablets, modified-release tablets, disintegrating tablets). oral, pulsed-release tablets, timed-release tablets (delayed-release tablets, controlled-release tablets, extended-release tablets and delayed-release tablets), capsules (hard and soft or liquid-filled soft gelatin capsules), pills, molded lozenges, sachets, powders, microcapsules, mini-tablets, capsule tablets and microspheres, matrix compositions and the like.In some embodiments of the present invention, the pharmaceutical composition refers to tablets.In some embodiments of the present invention, the pharmaceutical composition covers a general mixture of compositions, provided herein, before processing into the final dosage form. In some embodiments of the present invention, the pharmaceutical composition includes an intermediate mixture or composition containing niraparib in a formulation with one or more composition excipients as described herein.

Immediate release refers to a dosage form that releases the active agent substantially immediately upon contact with gastric juices and provides substantially complete dissolution within about 1 hour. Immediate release (IR) components may also be referred to as immediate release components.

D ₅₀ means that 50% of particles have values below a certain measurement, and 50% of particles have values above a certain measurement. D ₅₀ can be used to describe various parameters (volume, length, quantity, area, etc.). As used herein, D50 means the volume-weighted median diameter, such as measured by laser/light scattering or equivalent, with 50% of the particles by volume having a smaller diameter and 50% of the particles by volume having a larger diameter. Volume-weighted _D50 also refers to the percentage of mass of a particle at a certain size. For example, D50 500 nm means that 50% of particles by mass have a diameter less than 500 nm, and 50% of particles by mass have a diameter greater than 500 nm. Particle size can be measured by conventional particle size measurement techniques well known to those skilled in the art. Such methods include, for example, in-line sedimentation field fractionation, photon correlation spectroscopy, light scattering (eg with the Microtrac UPA 150), laser diffraction and plate centrifugation. For purposes associated with the compositions, formulations and methods described herein, the effective particle size is the volumetric median diameter determined using laser/light scattering instruments and techniques, such as the Horiba LA-910 or Horiba LA-950. Similarly, D ₉₀ is the volume-weighted diameter, where 90% of the particles by volume have a smaller diameter, while 10% by volume have a larger diameter, and D ₁₀ is the volume-weighted diameter, where 10% of the particles by volume have smaller diameter, while 90% by volume have a larger diameter. It is sometimes useful to report a D ₅₀ value after sonication for 1 minute or less at approximately 40 watts at room temperature (temperature 15°C to 30°C). At such a low power and in such a short period it is possible to destroy very loose aggregates, which generally do not adversely affect the effectiveness of the composition in a subject in vivo.

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Diluents increase the bulk of the composition to facilitate compression, or provide sufficient bulk for a homogeneous mixture for tablet formulations. As used herein, the term diluent is synonymous with the term filler. Such compounds include, for example, lactose such as lactose monohydrate, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®; dibasic calcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressed sugar such as Di-Pac® (Amstar); mannitol, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, powdered sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite and the like. Combinations of one or more diluents may also be used. In some embodiments, said diluent is lactose monohydrate. In some embodiments, said diluent is anhydrous lactose. In some embodiments, said diluent is mannitol. In some embodiments of the present invention, said diluent is dibasic calcium phosphate. In some embodiments of the present invention, said diluent is microcrystalline cellulose. In some embodiments of the present invention, one or more diluents affect the friability of the composition. In some embodiments of the present invention, one or more diluents contribute to the plasticity of the composition. In some embodiments of the present invention, the first diluent is used to control the friability of the composition, and the second diluent is used to control the plasticity of the composition. In some embodiments of the present invention, said first diluent is lactose monohydrate, lactose anhydrous, mannitol, or dibasic calcium phosphate. In some embodiments of the present invention, said second diluent is microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC).

The disintegrant expands and dissolves when wet, causing the solid dosage form or tablet to break down, for example, in the digestive tract, releasing the active ingredients for absorption. Disintegrants ensure that when the tablet is in contact with water, it quickly breaks down into smaller fragments, which promotes dissolution. In some embodiments of the present invention, said disintegrant is crospovidone or croscarmellose.

As used herein, the terms effective amount or therapeutically effective amount refer to a sufficient amount of niraparib administered that is expected to reduce to some extent one or more symptoms of the disease or condition being treated. For example, administration of niraparib as described herein results in a reduction and/or amelioration of the signs, symptoms or causes of cancer. For example, an effective amount for therapeutic use is the amount of niraparib, including the formulation described herein, required to provide reduction or amelioration of disease symptoms without undue side effects. The term therapeutically effective amount includes, for example, a prophylactically effective amount. It should be understood that the effective amount or therapeutically effective amount in various embodiments of the present invention will vary from subject to subject and may depend on changes in the metabolism of the compound administered, age, body weight, general condition of the subject, the condition being treated, the severity of the condition, and the judgment of the physician. prescribing treatment.

The terms enhance or enhance refer to an increase or prolongation of the activity or duration of the desired effect of niraparib or a decrease in any adverse symptomatology that results from the administration of a therapeutic agent. Thus, with respect to the enhancement effect of niraparib described herein, the term enhancement refers to the ability to enhance or prolong, in effectiveness or duration, the effects of other therapeutic agents that are used in combination with niraparib as described herein. As used herein, the expression potency enhancing amount refers to an amount of niraparib or other therapeutic agent that is sufficient to enhance the effect of the other therapeutic agent or niraparib in the desired system. When used in a patient, amounts effective for that use will depend on the severity and course of the disease, disorder or condition, prior therapy, the patient's medical condition and response to medications, and the judgment of the prescribing physician.

The term excipient means a pharmacologically inactive component such as a diluent, lubricant, surfactant, carrier or the like. Excipients that are useful in the preparation of a pharmaceutical composition are usually

- 6 044464 but are safe, non-toxic and acceptable for pharmaceutical use in humans. A reference to an excipient includes either one such excipient or more than one. Co-processed excipients are also included within the scope of the present invention.

Bulking agents or excipients include compounds such as lactose, lactose monohydrate, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol , mannitol, sorbitol, sodium chloride, polyethylene glycol and the like.

Friability refers to the ability to be crushed, that is, the ability of a solid substance to be crushed into smaller pieces. Friability for certain solid dosage forms can be assessed according to: 1) European Pharmacopoeia: European Pharmacopoeia (Ph. Eur.): Supplement 6.6 (published June 2009, entered into force January 2010), Friability of Uncoated Tablets (ref. 01/ 2010:20907); 2) Japanese Pharmacopoeia: Japanese Pharmacopoeia (JP): The JP General Information 26. Tablet Friability Test as published in the JP Fifteenth Edition (March 31, 2006, The Ministry of Health, Labor and Welfare Ministerial Notification No. 285), officially updated in bulletins published by MHLW on 5 November 2008 at http://www.std.pmda.go.jp/jpPUB/Data/ENG/jpdata/H201105_jp15_errata. pdf; or 3) United States Pharmacopeia: 5.2.3 United States Pharmacopeia (USP): <1216> Tablet Friability included in USP 32, May 1, 2009. Each of the above references is incorporated herein by reference. Fragility can also be determined by updated versions of the above references, if available.

As used herein, the term granulation (granulation) refers to the process of binding particles of a dry powder composition through agglomeration to produce larger particles known as granules, thereby producing a pharmaceutical dosage form such as tablets. Granulation is most often divided into two types: wet granulation, which requires liquid in the process, and dry granulation, which does not require liquid. Wet granulation uses a granulating liquid (binder/solvent) to facilitate agglomeration by forming a wet mass through adhesion, while dry granulation uses mechanical compression such as impact compaction or compaction such as roller compaction, to facilitate agglomeration. When compacted in rolls, belts are produced by passing the specified mixture between the rollers of a roller press. Roller pressure and gap distance (set between two rollers) are key parameters that affect belt thickness. Belt thickness is important when setting the final particle size for granulation as it will affect the shredding efficiency of the belts. The thickness of the tape can be measured with a caliper throughout the process. One method of measuring thickness is to obtain a rectangular sample of tape measuring at least 1 inch (2.54 cm) during the compaction process. Dimensions (length, width and thickness) are measured using a caliper or other device to accurately measure to the nearest tenth or hundredth of an inch. Another parameter that can be measured is the density of the tape, which is calculated by dividing the mass of the tape sample by the approximate volume (length x width x thickness).

The term intragranular phase refers to the intragranular phase of the tablet, which contains the granules that are prepared for tableting, and contains the components or excipients in the composition until the granules are formed. The term extragranular phase refers to the extragranular phase of the tablet and contains excipients or components that are added to the composition after the formation of granules and before compression to obtain a tablet.

Lubricants and glidants are compounds that prevent, reduce or inhibit adhesion or friction of materials. Without being bound by any theory, glidants prevent, reduce or inhibit the adhesion of powders in a mixture. For example, they may prevent, reduce or inhibit intraparticle friction or may prevent, reduce or inhibit electrostatic charge of the powder. Lubricants can prevent, reduce or interfere with the adhesion of powder to surfaces with which it comes into contact. Although lubricants and lubricants can be any compound that provides the desired function, typical lubricants and lubricants include, for example, stearic acid, magnesium stearate, calcium hydroxide, talc, sodium stearyl fumarate, a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex®), higher fatty acids and their alkali and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerin, talc, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (eg PEG-4000) or methoxy polyethylene glycol such as Carbowax™, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil®, starch such as corn

- 7 044464 starch, silicone oil, surfactant and the like. In some embodiments of the present invention, the glidant is silica. In some embodiments of the present invention, said glidant is a mesoporous silica excipient with medium pore size.

When used interchangeably herein, the terms patient or subject refer to any organism to which a compound or compounds described herein are administered in accordance with the present invention, for example, for experimental, diagnostic, prophylactic and/or therapeutic purposes. Common subjects include animals. The term animal refers to any member of the animal kingdom. In some embodiments of the present invention, the term animal refers to a human being at any stage of development. In some embodiments of the present invention, the term animal refers to a non-human animal at any stage of development. In some embodiments of the present invention, the non-human animal is a mammal (eg, rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cattle, primate, and/or pig). In some embodiments of the present invention, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and/or worms. In some embodiments of the present invention, the animal may be a transgenic animal, a genetically modified animal, and/or a clone. In embodiments of the present invention, the animals are mammals such as mice, rats, rabbits, primates and humans; insects; worms; and so on. In some embodiments of the present invention, the subject is a human. In some embodiments of the present invention, the subject may have and/or be susceptible to a disease, disorder and/or condition (eg, cancer). As used herein, the term patient population or subject population refers to a plurality of patients or subjects.

The term pharmacodynamics refers to the factors that determine the biological response observed relative to drug concentration.

The term pharmacokinetics refers to the factors that determine the achievement and maintenance of appropriate drug concentrations.

The terms moisture-activated dry granulation (MADG) or wet granulation refers to a granulation process that uses a liquid, such as water, to activate the binder and initiate agglomeration. This process involves the wet agglomeration of powder particles, facilitated by the addition of some liquid such as water, and the absorption or distribution of moisture. Adsorption or moisture distribution involves the addition of a desiccant material or adsorbent or absorbent after agglomeration to facilitate the absorption of excess moisture. Examples of suitable desiccant materials or adsorbent or absorbent include, but are not limited to, microcrystalline cellulose or silica. In some embodiments, the adsorbent or absorbent is a large pore mesoporous silica excipient, bentonite, talc, microcrystalline cellulose, charcoal, colloidal silica, magnesium carbonate, or similar excipients.

Ready-to-use refers to pharmaceutical compositions or medical products that can be used without the need for further alteration, modification or optimization of said composition or product prior to administration, such as by dilution, reconstitution, sterilization, etc.

The terms sliver and sliver thickness are used in the context of a type of dry granulation that uses roll compaction or roller compaction. In some embodiments of roll compaction or roller compaction, the powder is fed by gravity or by an auger through two counter-rotating rollers, causing the particles to change their relative positions under the compaction pressure applied by the rollers, thereby compacting the resulting material. The material produced by rolling compaction or roller compaction is called strip, and the feeding system provides a uniform and continuous flow of material to form a strip of the desired strip thickness. The thickness of the tape can be measured by any of the typical methods used in the art.

Stable or stable in terms of particle size distribution means that the particle size distribution, e.g. _D50 or _D90 , does not change significantly (more than 50%) after determining the initial time (for example, after grinding or curing period (1 to 3 weeks)). For example, the stable niraparib particles described herein in a solid oral dosage form will not demonstrate an increase in effective particle size of more than 50% over 3, 6, 9, 12, 24, or 36 months of storage at room temperature ( from 15°C to 25°C). Stable or degradation stability of niraparib means that the amount of impurities or degradation products does not change significantly

- 8 044464 (more than 50%) after determining the initial time. In some embodiments of the present invention, the dosage forms described herein will not produce impurities resulting from the degradation of niraparib during 3, 6, 9, 12, 24, or 36 months of storage at room temperature (15°C to 25°C). °C) at individual levels greater than about 0.1 wt.% compared to the levels of impurities at the initial time.

The term storage, in relation to a composition, including in solid dosage form, means storage in packaging of any system or type intended for pharmaceutical use - in an article that contains or is intended to contain a medicinal product and is or may be in direct contact with it . Under certain storage conditions, the container must provide the dosage form with adequate protection from factors (eg, temperature, light) that may cause the dosage form to deteriorate during shelf life. Storage can be in a blister (for example, a multi-dose container consisting of two layers, one of which is shaped to hold individual doses), a bottle (for example, a container with a more or less pronounced neck and usually a flat bottom), a single-dose container (for example, in a container for single doses of solid, semi-solid or liquid preparations), blister packaging (for example, in a multi-dose container consisting of two layers, usually equipped with perforations, suitable for containing single doses of solid or semi-solid preparations), in a pouch (for example, in a container formed surfaces of flexible material, with or without a flat bottom, closed at the bottom and sides; the top may be closed by melting the material, depending on the intended use) or in an open cup.

The term subject is used to refer to an animal, preferably a mammal, including humans and non-human mammals. The terms patient and subject may be used interchangeably.

As used herein, the term tablet refers to a dosage dosage form in which particles of a drug or pharmaceutical agent, such as niraparib, and certain excipients, such as any of the excipients described herein, are compressed, compacted, or extruded together. Tablets can be made into a variety of shapes, including round or elongated, such as flattened ovoid or cylindrical shapes. In some embodiments of the present invention, said tablet is produced by direct compression using suitable dies or molds. In some embodiments of the present invention, said tablet is manufactured by injection molding or compression molding using suitable molds mounted on a compression device. In some embodiments of the present invention, the tablet is produced by granulation, such as, but not limited to, fluid bed granulation or high shear granulation or roller compaction followed by compression. In some embodiments of the present invention, said tablet is prepared by extruding a paste into a mold or extrudate for further cutting into pieces. In another embodiment of the present invention, the tablet is a solid tablet.

A therapeutically effective amount or effective amount is the amount of a pharmaceutical agent required to achieve a pharmacological effect. The term therapeutically effective amount includes, for example, a prophylactically effective amount. An effective amount of niraparib is the amount necessary to achieve the desired pharmacological effect or therapeutic improvement without undue side effects. The effective amount of niraparib will be selected by one skilled in the art depending on the individual patient and disease. It should be understood that the effective amount or therapeutically effective amount may vary from subject to subject and may depend on changes in the metabolism of niraparib, age, body weight, general condition of the subject, the condition being treated, the severity of the condition, and the judgment of the prescriber. As used herein, the term alleviation or reduction of symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any reduction in severity, delay of onset, slowing of progression or shortening of the duration of a disease, permanent or temporary, long-term or short-term, which correlates or is associated with with the introduction of the specified compound or composition.

The term tmax refers to the time in hours that _Cmax is reached after administration of the pharmaceutical composition.

The terms treat or treat as used herein include alleviating, reducing or mitigating a disease or condition, such as cancer; symptoms, prevention of additional symptoms, amelioration or prevention of underlying metabolic causes of symptoms, inhibition of a specified disease or condition, e.g., arresting the progression of a specified disease or condition, attenuation of a specified disease or condition, regression of a specified disease or condition, alleviation of a condition caused by a specified disease or condition, or

- 9 044464 cessation of symptoms of a specified disease or condition prophylactically and/or therapeutically.

Other objects, features and advantages of the methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples are provided for illustrative purposes only, although they provide certain embodiments of the present invention.

Dosage forms of niraparib

The present inventors recognize the need to provide improved niraparib dosage forms having desired disintegration profiles, pharmacokinetic characteristics, flow properties and/or good storage stability. In addition, such improved dosage forms may be useful in methods of treatment (eg, methods of treating cancer).

The present invention relates to a method for preparing a solid pharmaceutical composition for oral administration containing an inhibitor of poly(ADP-ribose) polymerase (PARP)-1 and -2, and its use for the prevention and/or treatment of diseases. The present invention relates to solid dosage forms containing niraparib and its pharmaceutically acceptable salts (eg, niraparib tosylate monohydrate) having desirable pharmacokinetic characteristics, exhibiting, for example, favorable storage properties and favorable disintegration properties.

Niraparib has the following structure:

°^/ ^NH 2

Niraparib is an orally available selective inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2. The chemical name of niraparib tosylate monohydrate is 2-{4[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7- carboxamide 4-methylbenzenesulfonate hydrate (1:1:1); it has the following chemical structure:

The empirical molecular formula of niraparib is C ₂₆ H ₃₀ N ₄ O ₅ S and its molecular weight is 510.61. The drug substance niraparib tosylate monohydrate is a white to off-white, non-hygroscopic crystalline solid. The solubility of niraparib is independent of pH below a pKa of 9.95, with the solubility of the free base in water ranging from 0.7 mg/mL to 1.1 mg/mL over the physiological pH range.

Niraparib is a selective inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2 that selectively kills tumor cells in vitro and in mouse xenograft models. PARP inhibition results in irreparable double-strand breaks (DSBs), utilization of an error-prone DNA repair pathway, resulting genomic instability, and ultimately cell death. In addition, PARP brought into genetic foci by suppressed autoPARylation may contribute to cytotoxicity.

Niraparib, trade name ZEJULA®, is indicated for the maintenance or treatment of adult patients with recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer after complete or partial response to platinum-based chemotherapy. Each ZEJULA capsule contains 100 mg of niraparib (as tosylate monohydrate). Hard capsules may have a white body with black 100 mg lettering and a purple cap with white niraparib lettering. The current recommended dose of ZEJULA as monotherapy is three 100 mg capsules taken orally once daily, equivalent to a total daily dose of 300 mg.

The present invention relates to a composition for oral administration containing niraparib or pharmaceutically acceptable salts thereof. In some embodiments of the present invention, the composition for oral administration contains from about 20 wt.% to about

- 10,044,464% by weight of niraparib for the treatment of a disorder or condition such as cancer; and a pharmaceutically acceptable carrier, wherein said niraparib is distributed throughout the pharmaceutically acceptable carrier. In some embodiments of the present invention, the composition for oral administration contains from about 20 wt.% to about 60 wt.% niraparib for the treatment of a disorder or condition, such as cancer; and a pharmaceutically acceptable carrier, wherein said niraparib is distributed with substantial uniformity throughout the pharmaceutically acceptable carrier. In some embodiments of the present invention, the composition for oral administration contains from about 35 wt.% to about 55 wt.% niraparib for the treatment of a disorder or condition, such as cancer; and a pharmaceutically acceptable carrier, wherein said niraparib is distributed with substantial uniformity throughout the pharmaceutically acceptable carrier.

In embodiments of the present invention, said oral composition is a tablet.

In some embodiments of the present invention, the disorder or condition is cancer, such as ovarian cancer.

In some embodiments of the present invention, niraparib is a pharmaceutically acceptable salt of niraparib. In some embodiments, the pharmaceutically acceptable salt of niraparib is niraparib tosylate monohydrate.

In some embodiments of the present invention, the pharmaceutical composition contains from about 10 mg to about 2000 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the pharmaceutical composition contains from about 10 mg to about 1000 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the pharmaceutical composition contains from about 10 mg to about 525 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the pharmaceutical composition contains from about 425 mg to about 525 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the pharmaceutical composition contains from about 50 mg to about 300 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the pharmaceutical composition contains from about 50 mg to about 525 mg of niraparib tosylate monohydrate. For example, the pharmaceutical composition may contain from about 100 mg to about 200 mg of niraparib tosylate monohydrate. For example, the pharmaceutical composition may contain from about 125 mg to about 1750 mg of niraparib tosylate monohydrate.

Said composition may contain one or more components, including niraparib. These components can be combined to form granules, which are then compressed to form tablets.

Niraparib may be present in said dosage form as a pharmaceutically acceptable salt. For example, said niraparib may be niraparib tosylate monohydrate.

Exemplary formulations include those described herein.

In one embodiment of the present invention, an exemplary niraparib formulation contains 478.0 mg niraparib tosylate monohydrate, 203.5 mg lactose monohydrate, 203.5 mg microcrystalline cellulose, 40.0 mg crospovidone, and 20.0 mg intragranular phase povidone; and 40.0 mg crospovidone, 5.0 mg silica, and 10.0 mg magnesium stearate for the extragranular phase. In one embodiment of the present invention, an exemplary niraparib formulation contains 47.8 wt% niraparib tosylate monohydrate, 20.4 wt% lactose monohydrate, 20.4 wt% microcrystalline cellulose, 4.0 wt% crospovidone, and 2.0 wt% .% povidone for intragranular phase; and 4.0 wt% crospovidone, 0.5 wt% silica and 1.0 wt% magnesium stearate for the extragranular phase.

In one embodiment of the present invention, an exemplary niraparib formulation contains 478.0 mg niraparib tosylate monohydrate, 193.5 mg lactose monohydrate, 193.5 mg microcrystalline cellulose, 40.0 mg croscarmellose, and 40.0 mg hydroxypropylcellulose for intragranular phase; and 40.0 mg croscarmellose sodium, 5.0 mg silica, and 10.0 mg magnesium stearate for the extragranular phase. In one embodiment of the present invention, an exemplary niraparib formulation contains 47.8 wt% niraparib tosylate monohydrate, 19.4 wt% lactose monohydrate, 19.4 wt% microcrystalline cellulose, 4.0 wt% croscarmellose, and 4.0 wt% .% hydroxypropylcellulose for intragranular phase; and 4.0 wt% croscarmellose sodium, 0.5 wt% silica and 1.0 wt% magnesium stearate for the extragranular phase.

In one embodiment of the present invention, an exemplary niraparib formulation contains 478.0 mg niraparib tosylate monohydrate, 178.5 mg lactose monohydrate, 178.5 mg microcrystalline cellulose, 40.0 mg crospovidone, and 25.0 mg intragranular phase silica; and 40.0 mg crospovidone, 10.0 mg silica, and 10.0 mg magnesium stearate for the extragranular phase. In one embodiment of the present invention, an exemplary niraparib formulation contains 47.8 wt% niraparib tosylate monohydrate, 17.9 wt% lactose monohydrate, 17.9 wt% microcrystalline cellulose, 4.0 wt% crospovidone, 4.0 wt .% povidone and 2.5 wt.% silica for intragranular phase; and 4.0 wt% crospovidone, 1.0 wt% silica and 1.0 wt% magnesium stearate for the extragranular phase.

- 11 044464

In one embodiment of the present invention, an exemplary niraparib formulation contains 478.0 mg niraparib tosylate monohydrate, 201.0 mg microcrystalline cellulose, 201.0 mg dibasic calcium phosphate, 40.0 mg crospovidone, 20.0 mg povidone, and 5.0 mg stearate magnesium for the intragranular phase; and 40.0 mg crospovidone, 5.0 mg silica, and 10.0 mg magnesium stearate for the extragranular phase. In one embodiment of the present invention, an exemplary niraparib formulation contains 47.8 wt% niraparib tosylate monohydrate, 20.1 wt% microcrystalline cellulose, 20.1 wt% dibasic calcium phosphate, 4.0 wt% crospovidone, 2.0 wt.% povidone and 0.5 wt.% magnesium stearate for intragranular phase; and 4.0 wt% crospovidone, 0.5 wt% silica and 1.0 wt% magnesium stearate for the extragranular phase.

In one embodiment of the present invention, an exemplary niraparib formulation contains 478.0 mg niraparib tosylate monohydrate, 201.0 mg microcrystalline cellulose, 201.0 mg mannitol, 40.0 mg croscarmellose sodium, 20.0 mg hydroxypropylcellulose, and 5.0 mg magnesium stearate for the intragranular phase; and 40.0 mg croscarmellose sodium, 5.0 mg silica, and 10.0 mg magnesium stearate for the extragranular phase. In one embodiment of the present invention, an exemplary niraparib formulation contains 47.8 wt% niraparib tosylate monohydrate, 20.1 wt% microcrystalline cellulose, 20.1 wt% mannitol, 4.0 wt% croscarmellose sodium, 2.0 wt% .% hydroxypropylcellulose and 0.5 wt.% magnesium stearate for intragranular phase; and 4.0 wt% croscarmellose sodium, 0.5 wt% silica and 1.0 wt% magnesium stearate for the extragranular phase.

In one embodiment of the present invention, an exemplary niraparib formulation contains 478.0 mg niraparib tosylate monohydrate, 201.0 mg microcrystalline cellulose, 201.0 mg mannitol, 40.0 mg crospovidone, 20.0 mg povidone, and 5.0 mg magnesium stearate for intragranular phase; and 40.0 mg crospovidone, 5.0 mg silica, and 10.0 mg magnesium stearate for the extragranular phase. In one embodiment of the present invention, an exemplary niraparib formulation contains 47.8 wt.% niraparib tosylate monohydrate, 20.1 wt.% microcrystalline cellulose, 20.1 wt.% mannitol, 4.0 wt.% crospovidone, 2.0 wt. % povidone and 0.5 wt.% magnesium stearate for intragranular phase; and 4.0 wt% crospovidone, 0.5 wt% silica and 1.0 wt% magnesium stearate for the extragranular phase.

Tablet compositions containing niraparib

Described herein are exemplary tablet compositions, including exemplary excipients.

Embodiments of the present invention provide a tablet composition containing niraparib in an amount effective to inhibit poly(ADP-ribose) polymerase (PARP) when administered to a subject in need thereof, wherein the tablet contains an intragranular phase and an extragranular phase, and wherein: (a) at least one component of said intragranular phase is a diluent, binder, disintegrating agent, glidant or lubricant; and/or (b) at least one component of said extragranular phase is a disintegrant, a glidant or a lubricant.

Another aspect of the present invention relates to a tablet composition containing niraparib in an amount effective to inhibit poly(ADP-ribose) polymerase (PARP) when administered to a subject in need thereof, said tablet comprising an intragranular phase and an extragranular phase.

In some embodiments of the present invention, the tablet composition contains niraparib in an amount from about 50 to about 350 mg based on niraparib free base. In some embodiments of the present invention, the tablet composition contains niraparib tosylate monohydrate in an amount from about 100 to about 550 mg. In embodiments of the present invention, the tablet composition contains niraparib tosylate monohydrate in an amount of approximately 40-50% by weight of the tablet composition.

In embodiments of the present invention, said intragranular phase contains a diluent (eg, a first diluent) in an amount of about 7.5-15%, about 814%, or about 9-11% by weight of said tablet composition. In embodiments of the present invention, said intragranular phase contains a second diluent in an amount of about 25-40%, about 30-40%, or about 30-35% by weight of said tablet composition. In embodiments of the present invention, said intragranular phase contains a binder in an amount of about 1-3% by weight of said tablet composition. In embodiments of the present invention, said intragranular phase contains a disintegrant in an amount of about 0.1-1.5%, or about 0.5%-1.5%, by weight of said tablet composition. In embodiments of the present invention, said intragranular phase contains a glidant, adsorbent, or absorbent in an amount of about 1-5% or about 2-4% by weight of said tablet composition. In embodiments of the present invention, said intragranular phase contains a lubricant in an amount of about 0.1-2% by weight of said tablet composition. In embodiments of the present invention, said extragranular phase

- 12 044464 contains a disintegrant in an amount of approximately 0.1-2% by weight of said tablet composition. In embodiments of the present invention, said extragranular phase contains a glidant or adsorbent or absorbent in an amount of about 0.1-2% by weight of said tablet composition. In embodiments of the present invention, said extragranular phase contains a lubricant in an amount of about 0.1-2% by weight of said tablet composition.

One aspect of the present invention provides a tablet composition containing: (a) an effective amount of niraparib to inhibit poly(ADP-ribose) polymerase (PARP) when administered to a subject in need thereof; b) a first diluent selected from lactose monohydrate, lactose anhydrous, mannitol and dibasic calcium phosphate; c) magnesium stearate; d) a second diluent selected from microcrystalline cellulose, starch, polyethylene oxide and hydroxypropyl methylcellulose (HPMC); and e) a binder selected from povidone (PVP), hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC).

Herein, another aspect of the present invention relates to a tablet composition containing the following components in weight percentage:

(a) in the intragranular part:

(i) about 40-50% niraparib tosylate monohydrate;

(ii) about 8-14% first diluent;

(iii) about 30-40% second diluent;

(iv) about 1-3% binder;

(v) about 0.1-2% disintegrant;

(vi) about 2-4% glidant or adsorbent or absorbent; and (vii) about 0.1-2% lubricant;

(b) in the extragranular part:

(i) about 0.1-2% disintegrant;

(ii) about 0.1-2% glidant or adsorbent or absorbent; and (iii) about 0.1-2% lubricant.

Herein, another aspect of the present invention relates to a tablet composition containing the following components in weight percentage:

(a) in the intragranular part:

(i) about 40-50% niraparib tosylate monohydrate;

(ii) about 9-11% first diluent;

(iii) about 30-40% second diluent;

(iv) about 1-3% binder;

(v) about 0.1-2% disintegrant;

(vi) about 2-4% glidant or adsorbent or absorbent; and (vii) about 0.1-2% lubricant;

(b) in the extragranular part:

(i) about 0.1-2% disintegrant;

(ii) about 0.1-2% glidant or adsorbent or absorbent; and (iii) about 0.1-2% lubricant.

Another aspect of the present invention relates to a composition containing the following components in weight percentage:

(a) in the intragranular part:

(i) about 40-50% niraparib tosylate monohydrate;

(ii) about 9-40% diluent;

(iii) about 1-3% binder;

(iv) about 0.1-2% disintegrant;

(v) about 2-4% glidant or adsorbent or absorbent; and (vi) about 0.1-2% lubricant;

(b) in the extragranular part:

(i) about 0.1-2% disintegrant;

(ii) about 0.1-2% glidant or adsorbent or absorbent; and (iii) about 0.1-2% lubricant.

In some embodiments of the present invention, said lubricant is magnesium stearate.

In some embodiments of the present invention, the diluent is lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC). In some embodiments of the present invention, said lactose is anhydrous, monohydrate, crystalline, or spray-dried. In some embodiments of the present invention, said mannitol is spray dried or crystalline.

- 13 044464

In some embodiments, said first diluent is lactose monohydrate. In some embodiments of the present invention, said lactose monohydrate is a specialized lactose monohydrate (eg, spray-dried lactose monohydrate). In some embodiments of the present invention, said lactose monohydrate is non-specialized (eg, lactose monohydrate powder). In some embodiments of the present invention, said lactose monohydrate is either crystalline. In some embodiments, said first diluent is mannitol. In some embodiments of the present invention, said mannitol is spray dried or crystalline. In some embodiments of the present invention, said first diluent is dibasic calcium phosphate.

In some embodiments of the present invention, the second diluent is microcrystalline cellulose. In some embodiments of the present invention, the second diluent is starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC).

In some embodiments of the present invention, the first diluent is lactose and the second diluent is microcrystalline cellulose. In some embodiments of the present invention, the first diluent is lactose and the second diluent is starch. In some embodiments of the present invention, the first diluent is lactose and the second diluent is polyethylene oxide. In some embodiments of the present invention, the first diluent is lactose and the second diluent is HPMC. In some embodiments of the present invention, the first diluent is lactose and the second diluent is mannitol. In some embodiments of the present invention, the first diluent is lactose and the second diluent is dibasic calcium phosphate.

In some embodiments of the present invention, the first diluent is lactose monohydrate and the second diluent is microcrystalline cellulose. In some embodiments of the present invention, the first diluent is lactose monohydrate and the second diluent is starch. In some embodiments of the present invention, the first diluent is lactose monohydrate and the second diluent is polyethylene oxide. In some embodiments of the present invention, the first diluent is lactose monohydrate and the second diluent is HPMC. In some embodiments of the present invention, the first diluent is lactose monohydrate and the second diluent is mannitol. In some embodiments of the present invention, the first diluent is lactose monohydrate and the second diluent is dibasic calcium phosphate.

In some embodiments of the present invention, the first diluent is mannitol and the second diluent is lactose (eg, lactose monohydrate). In some embodiments of the present invention, the first diluent is mannitol and the second diluent is microcrystalline cellulose. In some embodiments of the present invention, the first diluent is mannitol and the second diluent is starch. In some embodiments of the present invention, the first diluent is mannitol and the second diluent is polyethylene oxide. In some embodiments of the present invention, the first diluent is mannitol and the second diluent is HPMC. In some embodiments of the present invention, the first diluent is mannitol and the second diluent is dibasic calcium phosphate.

In some embodiments of the present invention, the first diluent is dibasic calcium phosphate and the second diluent is mannitol. In some embodiments of the present invention, the first diluent is dibasic calcium phosphate and the second diluent is lactose (eg, lactose monohydrate). In some embodiments of the present invention, the first diluent is dibasic calcium phosphate and the second diluent is microcrystalline cellulose. In some embodiments of the present invention, the first diluent is dibasic calcium phosphate and the second diluent is starch. In some embodiments of the present invention, the first diluent is dibasic calcium phosphate and the second diluent is polyethylene oxide. In some embodiments of the present invention, the first diluent is dibasic calcium phosphate and the second diluent is HPMC.

In some embodiments of the present invention, the first diluent is microcrystalline cellulose and the second diluent is lactose (eg, lactose monohydrate). In some embodiments of the present invention, the first diluent is microcrystalline cellulose and the second diluent is manganese.

- 14 044464 nits. In some embodiments of the present invention, the first diluent is microcrystalline cellulose and the second diluent is starch. In some embodiments of the present invention, the first diluent is microcrystalline cellulose and the second diluent is polyethylene oxide. In some embodiments of the present invention, the first diluent is microcrystalline cellulose and the second diluent is HPMC. In some embodiments of the present invention, the first diluent is microcrystalline cellulose and the second diluent is dibasic calcium phosphate.

In some embodiments of the present invention, the first diluent is starch and the second diluent is mannitol. In some embodiments of the present invention, the first diluent is starch and the second diluent is lactose (eg, lactose monohydrate). In some embodiments of the present invention, the first diluent is starch and the second diluent is microcrystalline cellulose. In some embodiments of the present invention, the first diluent is starch and the second diluent is polyethylene oxide. In some embodiments of the present invention, the first diluent is starch and the second diluent is HPMC. In some embodiments of the present invention, the first diluent is starch and the second diluent is dibasic calcium phosphate.

In some embodiments of the present invention, the first diluent is polyethylene oxide and the second diluent is mannitol. In some embodiments of the present invention, the first diluent is polyethylene oxide and the second diluent is lactose (eg, lactose monohydrate). In some embodiments of the present invention, the first diluent is polyethylene oxide and the second diluent is microcrystalline cellulose. In some embodiments of the present invention, the first diluent is polyethylene oxide and the second diluent is starch. In some embodiments of the present invention, the first diluent is polyethylene oxide and the second diluent is HPMC. In some embodiments of the present invention, the first diluent is polyethylene oxide and the second diluent is dibasic calcium phosphate.

In some embodiments of the present invention, the first diluent is HPMC and the second diluent is mannitol. In some embodiments of the present invention, the first diluent is HPMC and the second diluent is lactose (eg, lactose monohydrate). In some embodiments of the present invention, the first diluent is HPMC and the second diluent is microcrystalline cellulose. In some embodiments of the present invention, the first diluent is HPMC and the second diluent is polyethylene oxide. In some embodiments of the present invention, the first diluent is starch and the second diluent is starch. In some embodiments of the present invention, the first diluent is HPMC and the second diluent is dibasic calcium phosphate.

In some embodiments of the present invention, the binder is povidone (PVP). In some embodiments of the present invention, said binder is hydroxypropyl cellulose (HPC). In some embodiments of the present invention, said binder is hydroxypropyl methylcellulose (HPMC).

In some embodiments of the present invention, said disintegrant is crospovidone or croscarmellose. In some embodiments of the present invention, said disintegrant is crospovidone. In some embodiments of the present invention, said glidant is silica. In some embodiments of the present invention, said glidant is mesoporous silica with medium-sized pores. In some embodiments of the present invention, the medium pore mesoporous silica comprises Syloid FP-244.

In some embodiments of the present invention, the composition further comprises a disintegrant. In some embodiments of the present invention, said disintegrant is crospovidone or croscarmellose. In some embodiments of the present invention, said croscarmellose is croscarmellose sodium. In some embodiments of the present invention, the composition further comprises a large-pore mesoporous silica excipient as an adsorbent. In some embodiments of the present invention, the mesoporous silica excipient with large pores absorbs water. In some embodiments of the present invention, said composition

- 15 044464 additionally contains an auxiliary substance based on mesoporous silica with medium-sized pores as a gliding agent. In some embodiments of the present invention, the medium pore mesoporous silica comprises Syloid FP244. In some embodiments of the present invention, the composition further contains an additional excipient as an adsorbent, such as bentonite, talc, microcrystalline cellulose, charcoal, colloidal silica, magnesium carbonate or similar excipients.

In some embodiments of the present invention, the composition further comprises silicon dioxide. In some embodiments, said silica is present in an amount of from about 0.1 wt.% to about 10 wt.%. In some embodiments, said silica is present in an amount of from about 0.1 wt.% to about 5 wt.%. In some embodiments, said silica is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, about 1 wt.%, about 1.5 wt.%, about 2 wt. %, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt% or about 5 wt%.

In some embodiments of the present invention, the composition contains a povidone (PVP) binder. In some embodiments of the present invention, the composition further comprises a disintegrant. In some embodiments of the present invention, the disintegrant is crospovidone. In some embodiments of the present invention, the disintegrant is croscarmellose (eg, croscarmellose sodium). In some embodiments of the present invention, the composition further comprises silicon dioxide. In some embodiments, the composition does not contain magnesium stearate. In some embodiments of the present invention, the composition further comprises magnesium stearate.

In some embodiments of the present invention, the composition contains a hydroxypropylcellulose (HPC) binder. In some embodiments of the present invention, the composition further comprises a disintegrant. In some embodiments of the present invention, the disintegrant is crospovidone. In some embodiments of the present invention, the disintegrant is croscarmellose (eg, croscarmellose sodium). In some embodiments of the present invention, the composition further comprises silicon dioxide. In some embodiments, the composition does not contain magnesium stearate. In some embodiments of the present invention, the composition further comprises magnesium stearate.

In some embodiments of the present invention, the composition contains a hydroxypropyl methylcellulose (HPMC) binder. In some embodiments of the present invention, the composition further comprises a disintegrant. In some embodiments of the present invention, the disintegrant is crospovidone. In some embodiments of the present invention, the disintegrant is croscarmellose (eg, croscarmellose sodium). In some embodiments of the present invention, the composition further comprises silicon dioxide. In some embodiments, the composition does not contain magnesium stearate. In some embodiments of the present invention, the composition further comprises magnesium stearate.

In some embodiments of the present invention, the composition further comprises an intragranular phase. In some embodiments of the present invention, said intragranular phase comprises silica. In some embodiments of the present invention, said silica in said intragranular phase is present in an amount of from about 0.1 wt.% to about 10 wt.%. In some embodiments of the present invention, said silica in said intragranular phase is present in an amount of from about 0.1 wt.% to about 5 wt.%. In some embodiments, said silica in said intragranular phase is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt.%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, about 1 wt.%, about 1.5 wt.%, about 2% by weight, about 2.5% by weight, about 3% by weight, about 3.5% by weight, about 4% by weight, about 4.5% by weight, or about 5% by weight.

In some embodiments of the present invention, said intragranular phase does not contain magnesium stearate. In some embodiments of the present invention, said intragranular phase contains niraparib, lactose monohydrate, microcrystalline cellulose, crospovidone and povidone. In some embodiments of the present invention, said intragranular phase comprises niraparib, lactose monohydrate, microcrystalline cellulose, croscarmellose, and hydroxypropylcellulose (HPC). In some embodiments of the present invention, said intragranular phase comprises niraparib, lactose monohydrate, microcrystalline

- 16 044464 cellulose, croscarmellose and hydroxypropyl methylcellulose (HPMC). In some embodiments of the present invention, said intragranular phase comprises niraparib, lactose monohydrate, microcrystalline cellulose, crospovidone, povidone and a large pore mesoporous silica excipient as an adsorbent or absorbent or a medium pore mesoporous silica excipient. as a gliding agent. In some embodiments of the present invention, the intragranular phase contains niraparib, lactose monohydrate, microcrystalline cellulose, crospovidone, povidone and a large pore mesoporous silica excipient as an adsorbent or absorbent. In some embodiments, the intragranular phase comprises niraparib, lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, and a medium-pore mesoporous silica excipient as a glidant.

In some embodiments of the present invention, said intragranular phase contains magnesium stearate. In some embodiments of the present invention, the intragranular phase contains niraparib, microcrystalline cellulose, dibasic calcium phosphate, crospovidone, povidone and magnesium stearate. In some embodiments of the present invention, the intragranular phase contains niraparib, microcrystalline cellulose, mannitol, croscarmellose, hydroxypropylcellulose (HPC) and magnesium stearate. In some embodiments of the present invention, the intragranular phase contains niraparib, microcrystalline cellulose, mannitol, croscarmellose, hydroxypropyl methylcellulose (HPMC) and magnesium stearate. In some embodiments of the present invention, said intragranular phase contains niraparib, microcrystalline cellulose, mannitol, crospovidone, povidone and magnesium stearate.

In some embodiments of the present invention, the composition further comprises an extragranular phase. In some embodiments of the present invention, said extragranular phase contains magnesium stearate. In some embodiments of the present invention, said extragranular phase contains crospovidone. In some embodiments of the present invention, said extragranular phase contains croscarmellose.

In some embodiments of the present invention, said extragranular phase comprises silica. In some embodiments of the present invention, said silica in said extragranular phase is present in an amount of from about 0.1 wt.% to about 10 wt.%. In some embodiments of the present invention, said silica in said extragranular phase is present in an amount of from about 0.1 wt.% to about 5 wt.%. In some embodiments of the present invention, said silica in said extragranular phase is present in an amount of from about 0.1 wt.% to about 2.5 wt.%. In some embodiments of the present invention, said silica in said extragranular phase is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0 .5 wt.%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, about 1 wt.%, about 1.5 wt. %, about 2 wt.%, about 2.5 wt.%, about 3 wt.%, about 3.5 wt.%, about 4 wt.%, about 4.5 wt.% or about 5 wt.%.

In some embodiments, said niraparib is present in an amount of about 5-90% by weight. In some embodiments, said niraparib is present in an amount of about 5-80% by weight. In some embodiments, said niraparib is present in an amount of about 5-70% by weight. In some embodiments, said niraparib is present in an amount of about 5-60% by weight. In some embodiments, said niraparib is present in an amount of about 5-50% by weight. In some embodiments, said niraparib is present in an amount of about 5-40% by weight. In some embodiments, said niraparib is present in an amount of about 5-30% by weight. In some embodiments, said niraparib is present in an amount of about 5-20% by weight. In some embodiments, said niraparib is present in an amount of about 5-10% by weight. In some embodiments, said niraparib is present in an amount of about 10-90% by weight. In some embodiments, said niraparib is present in an amount of about 10-80% by weight. In some embodiments, said niraparib is present in an amount of about 10-70% by weight. In some embodiments, said niraparib is present in an amount of about 10-60% by weight. In some embodiments, said niraparib is present in an amount of about 10-50% by weight. In some embodiments, said niraparib is present in an amount of about 10-40% by weight. In some embodiments, said niraparib is present in an amount of about 10-30% by weight. In some embodiments, said niraparib is present in an amount of about 10-20% by weight. In some embodiments, said niraparib is present in an amount of about 20-90% by weight. In some embodiments, said niraparib is present in an amount of about 20-80% by weight. In some embodiments, said niraparib is present in an amount of about 20-70% by weight. In some embodiments, said niraparib is present in an amount of about 20-60% by weight. In some embodiments, said niraparib is present in an amount of about

- 17 044464

20-50 wt.%. In some embodiments, said niraparib is present in an amount of about 20-40% by weight. In some embodiments, said niraparib is present in an amount of about 20-30% by weight. In some embodiments, said niraparib is present in an amount of about 30-90% by weight. In some embodiments, said niraparib is present in an amount of about 30-80% by weight. In some embodiments, said niraparib is present in an amount of about 30-70% by weight. In some embodiments, said niraparib is present in an amount of about 30-60% by weight. In some embodiments, said niraparib is present in an amount of about 30-50% by weight. In some embodiments, said niraparib is present in an amount of about 30-40% by weight. In some embodiments, said niraparib is present in an amount of about 40-90% by weight. In some embodiments, said niraparib is present in an amount of about 40-80% by weight. In some embodiments, said niraparib is present in an amount of about 40-70% by weight. In some embodiments, said niraparib is present in an amount of about 40-60% by weight. In some embodiments, said niraparib is present in an amount of about 40-50% by weight. In some embodiments, said niraparib is present in an amount of about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%. , about wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about wt.%, wt.%, wt.%, wt.%, wt.% , wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately about wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt. .%, wt.%, wt.%, about about about about about about about about about about about about about about about about about about about wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, about about about about about about about about about about about about about about about about about about about weight%, 25 wt.%, 30 wt.%, 35 wt.%, 40 wt.%, 45 wt.%, 50 wt.%, 55 wt.%, 60 wt.%, 65 wt.%, 70 wt.%, 75 wt.%, 80 wt.%, 85 wt.%, about about about about about about about about about about about about about about about about about about wt.%, wt.%, wt.%, wt.%, wt.%, wt. .%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, about about about about about about about about about about about about about about about about about about weight .%, about 89 wt.%, or about 90 wt.%. In some embodiments of the present invention, said niraparib is a pharmaceutically acceptable salt of niraparib. In some embodiments of the present invention, said niraparib is niraparib tosylate monohydrate.

In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 5-90 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 5-80 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 5-70 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 5-60 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 5-50 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 5-40 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 5-30 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 5-20 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 5-10 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 10-90 weight percent. In some embodiments of the present invention, said second diluent (e.g., microcrystalline cellulose, starch, polyethylene oxide, and hydrochloride)

- 18 044464 xypropyl methylcellulose (HPMC)) is present in an amount of approximately 10-80 wt.%. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 10-70 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 10-60 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 10-50 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 10-40 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 10-30 weight percent. In some embodiments of the present invention, said second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide, and hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 10-20 weight percent. In some embodiments of the present invention, the diluent (e.g., microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC)) is present in an amount of about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%. , about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight .%, about 26 wt.%, about 27 wt.%, about 28 wt.%, about 29 wt.%, about 30 wt.%, about 31 wt.%, about 32 wt.%, about 33 wt.% , about 34 wt.%, about 35 wt.%, about 36 wt.%, about 37 wt.%, about 38 wt.%, about 39 wt.%, about 40 wt.%, about 41 wt.%, about 42 wt.%, about 43 wt.%, about 44 wt.%, about 45 wt.%, about 46 wt.%, about 47 wt.%, about 48 wt.%, about 49 wt.%, about 50 wt. .%, about 51 wt.%, about 52 wt.%, about 53 wt.%, about 54 wt.%, about 55 wt.%, about 56 wt.%, about 57 wt.%, about 58 wt.% , about 59 wt.%, about 60 wt.%, about 61 wt.%, about 62 wt.%, about 63 wt.%, about 64 wt.%, about 65 wt.%, about 66 wt.%, about 67 wt.%, about 68 wt.%, about 69 wt.%, about 70 wt.%, about 71 wt.%, about 72 wt.%, about 73 wt.%, about 74 wt.%, about 75 wt. .%, about 76 wt.%, about 77 wt.%, about 78 wt.%, about 79 wt.%, about 80 wt.%, about 81 wt.%, about 82 wt.%, about 83 wt.% , about 84 wt.%, about 85 wt.%, about 86 wt.%, about 87 wt.%, about 88 wt.%, about 89 wt.%, or about 90 wt.%.

In some embodiments, said microcrystalline cellulose is present in an amount of about 5-90% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 5-80% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 5-70% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 5-60% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 5-50% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 5-40% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 5-30 wt.%. In some embodiments, said microcrystalline cellulose is present in an amount of about 5-20 wt.%. In some embodiments, said microcrystalline cellulose is present in an amount of about 5-10% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 10-90% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 10-80% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 10-70% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 10-60% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 10-50% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 1040 wt.%. In some embodiments, said microcrystalline cellulose is present in an amount of about 10-30% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 10-20% by weight. In some embodiments, said microcrystalline cellulose is present in an amount of about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt. %, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, about 21 wt.%, at

- 19 044464 approximately 22 wt.%, about 23 wt.%, about 24 wt.%, about 25 wt.%, about 26 wt.%, about 27 wt.%, about 28 wt.%, about 29 wt.% , about 30 wt.%, about 31 wt.%, about 32 wt.%, about 33 wt.%, about 34 wt.%, about 35 wt.%, about 36 wt.%, about 37 wt.%, about 38 wt.%, about 39 wt.%, about 40 wt.%, about 41 wt.%, about 42 wt.%, about 43 wt.%, about 44 wt.%, about 45 wt.%, about 46 wt. .%, about 47 wt.%, about 48 wt.%, about 49 wt.%, about 50 wt.%, about 51 wt.%, about 52 wt.%, about 53 wt.%, about 54 wt.% , about 55 wt.%, about 56 wt.%, about 57 wt.%, about 58 wt.%, about 59 wt.%, about 60 wt.%, about 61 wt.%, about 62 wt.%, about 63 wt.%, about 64 wt.%, about 65 wt.%, about 66 wt.%, about 67 wt.%, about 68 wt.%, about 69 wt.%, about 70 wt.%, about 71 wt. .%, about 72 wt.%, about 73 wt.%, about 74 wt.%, about 75 wt.%, about 76 wt.%, about 77 wt.%, about 78 wt.%, about 79 wt.% , about 80 wt.%, about 81 wt.%, about 82 wt.%, about 83 wt.%, about 84 wt.%, about 85 wt.%, about 86 wt.%, about 87 wt.%, about 88 wt.%, about 89 wt.%, or about 90 wt.%.

In some embodiments of the present invention, the first diluent, such as lactose monohydrate, anhydrous lactose, mannitol, and dibasic calcium phosphate, is present in an amount of about 5-90 wt.%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, anhydrous lactose, mannitol, and dibasic calcium phosphate, is present in an amount of about 5-80 wt.%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 5-70 wt%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 5-60 wt%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 5-50 wt%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, anhydrous lactose, mannitol, and dibasic calcium phosphate, is present in an amount of about 5-40 wt.%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, anhydrous lactose, mannitol, and dibasic calcium phosphate, is present in an amount of about 5-30 wt.%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 5-20 wt%. In some embodiments of the present invention, said first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 5-10 wt%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 10-90 wt%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 10-80 wt%. In some embodiments of the present invention, said first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 10-70 wt%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 10-60 wt%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 10-50 wt%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 10-40 wt%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 10-30 wt%. In some embodiments of the present invention, the first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 10-20 wt%. In some embodiments of the present invention, said first diluent, such as lactose monohydrate, lactose anhydrous, mannitol, and dibasic calcium phosphate, is present in an amount of about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%. , about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight .%, about 26 wt.%, about 27 wt.%, about 28 wt.%, about 29 wt.%, about 30 wt.%, about 31 wt.%, about 32 wt.%, about 33 wt.% , about 34 wt.%, about 35 wt.%, about 36 wt.%, about 37 wt.%, about 38 wt.%, about 39 wt.%, about 40 wt.%, at

- 20 044464 approximately 41 wt.%, about 42 wt.%, about 43 wt.%, about 44 wt.%, about 45 wt.%, about 46 wt.%, about 47 wt.%, about 48 wt.% , about 49 wt.%, about 50 wt.%, about 51 wt.%, about 52 wt.%, about 53 wt.%, about 54 wt.%, about 55 wt.%, about 56 wt.%, about 57 wt%, about 58 wt%, about 59 wt%, about 60 wt%, about 61 wt%, about 62 wt%, about 63 wt%, about 64 wt%, about 65 wt .%, about 66 wt.%, about 67 wt.%, about 68 wt.%, about 69 wt.%, about 70 wt.%, about 71 wt.%, about 72 wt.%, about 73 wt.% , about 74 wt.%, about 75 wt.%, about 76 wt.%, about 77 wt.%, about 78 wt.%, about 79 wt.%, about 80 wt.%, about 81 wt.%, about 82% by weight, about 83% by weight, about 84% by weight, about 85% by weight, about 86% by weight, about 87% by weight, about 88% by weight, about 89% by weight, or about 90% by weight .%.

In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 5-90 wt.%. In some embodiments of the present invention, said lactose is anhydrous, monohydrate, crystalline, or spray-dried. In some embodiments of the present invention, said mannitol is spray dried or crystalline. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 5-80 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 5-70 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 5-60 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 5-50 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 5-40 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 5-30 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 5-20 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 5-10 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 10-90 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 10-80 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 10-70 wt%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 10-60 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 10-50 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 10-40 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 10-30 wt.%. In some embodiments of the present invention, said diluent such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose,

- 21 044464 starch, polyethylene oxide or hydroxypropyl methylcellulose (HPMC), is present in an amount of approximately 10-20 wt.%. In some embodiments of the present invention, the diluent, such as lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC), is present in an amount of about 5 wt.%, about 6 wt.%, about 7 wt. %, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, about 21 wt.%, about 22 wt.%, about 23 wt.%, about 24 wt.%, about 25 wt.%, about 26 wt.%, about 27 wt.%, about 28 wt.%, about 29 wt.%, about 30 wt.%, about 31 wt.%, about 32 wt. %, about 33 wt.%, about 34 wt.%, about 35 wt.%, about 36 wt.%, about 37 wt.%, about 38 wt.%, about 39 wt.%, about 40 wt.%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt.%, about 50 wt.%, about 51 wt.%, about 52 wt.%, about 53 wt.%, about 54 wt.%, about 55 wt.%, about 56 wt.%, about 57 wt. %, about 58 wt.%, about 59 wt.%, about 60 wt.%, about 61 wt.%, about 62 wt.%, about 63 wt.%, about 64 wt.%, about 65 wt.%, about 66 wt.%, about 67 wt.%, about 68 wt.%, about 69 wt.%, about 70 wt.%, about 71 wt.%, about 72 wt.%, about 73 wt.%, about 74 wt.%, about 75 wt.%, about 76 wt.%, about 77 wt.%, about 78 wt.%, about 79 wt.%, about 80 wt.%, about 81 wt.%, about 82 wt. %, about 83 wt.%, about 84 wt.%, about 85 wt.%, about 86 wt.%, about 87 wt.%, about 88 wt.%, about 89 wt.% or about 90 wt.%.

In some embodiments, said lactose is present in an amount of about 590% by weight. In some embodiments, said lactose is present in an amount of about 580 weight percent. In some embodiments, said lactose is present in an amount of about 570 weight percent. In some embodiments, said lactose is present in an amount of about 560% by weight. In some embodiments, said lactose is present in an amount of about 550% by weight. In some embodiments, said lactose is present in an amount of about 540% by weight. In some embodiments, said lactose is present in an amount of about 530% by weight. In some embodiments, said lactose is present in an amount of about 520% by weight. In some embodiments, said lactose is present in an amount of about 510 weight percent. In some embodiments, said lactose is present in an amount of about 1090 wt.%. In some embodiments, said lactose is present in an amount of about 1080 weight percent. In some embodiments, said lactose is present in an amount of about 1070 wt.%. In some embodiments, said lactose is present in an amount of about 1060 wt.%. In some embodiments, said lactose is present in an amount of about 1050 wt.%. In some embodiments, said lactose is present in an amount of about 1040 wt.%. In some embodiments, said lactose is present in an amount of about 1030 wt.%. In some embodiments, said lactose is present in an amount of about 1020% by weight. In some embodiments, said lactose is present in an amount of about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%. , about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight .%, about 29 wt.%, about 30 wt.%, about 31 wt.%, about 32 wt.%, about 33 wt.%, about 34 wt.%, about 35 wt.%, about 36 wt.% , about 37 wt.%, about 38 wt.%, about 39 wt.%, about 40 wt.%, about 41 wt.%, about 42 wt.%, about 43 wt.%, about 44 wt.%, about 45 wt.%, about 46 wt.%, about 47 wt.%, about 48 wt.%, about 49 wt.%, about 50 wt.%, about 51 wt.%, about 52 wt.%, about 53 wt. .%, about 54 wt.%, about 55 wt.%, about 56 wt.%, about 57 wt.%, about 58 wt.%, about 59 wt.%, about 60 wt.%, about 61 wt.% , about 62 wt.%, about 63 wt.%, about 64 wt.%, about 65 wt.%, about 66 wt.%, about 67 wt.%, about 68 wt.%, about 69 wt.%, about 70 wt.%, about 71 wt.%, about 72 wt.%, about 73 wt.%, about 74 wt.%, about 75 wt.%, about 76 wt.%, about 77 wt.%, about 78 wt. .%, about 79 wt.%, about 80 wt.%, about 81 wt.%, about 82 wt.%, about 83 wt.%, about 84 wt.%, about 85 wt.%, about 86 wt.% , about 87 wt.%, about 88 wt.%, about 89 wt.%, or about 90 wt.%.

In some embodiments, said lactose monohydrate is present in an amount of about 5-90% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 5-80% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 5-70% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 5-60% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 5-50% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 5-40% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 5-30% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 5-20% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 5-10% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 10-90% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 10-80% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 10-70% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 10-60% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 1050 weight percent. In some embodiments, said lactose monohydrate is present in an amount of about 10-40% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 10-30% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 10-20% by weight. In some embodiments, said lactose monohydrate is present in an amount of about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, wt%, wt%, wt%, wt%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, approximately approximately approximately approximately approximately approximately about about about about about about about about about about about about wt.%, about 10 wt.%, about wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt. .%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, about about about about about about about about about about about about about about about about about about about about weight%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt. %, wt.%, approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt. .%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately about wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, wt. .%, wt.%, wt.%, wt.%, about about about about about about about about about about about about about about about about about about about about about wt.%, about 89 wt.%, or about 90 wt.%.

In some embodiments of the present invention, the binder, such as povidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose, is present in an amount of about 1-40% by weight. In some embodiments of the present invention, the binder, such as povidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose, is present in an amount of about 1-30% by weight. In some embodiments of the present invention, the binder, such as povidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose, is present in an amount of about 1-20% by weight. In some embodiments of the present invention, the binder, such as povidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose, is present in an amount of about 1-10% by weight. In some embodiments of the present invention, the binder, such as povidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose, is present in an amount of about 1-5% by weight. In some embodiments of the present invention, the binder, such as povidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose, is present in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about about about about about about about about wt%, about 10 wt%, about wt%, wt%, wt%, wt% , wt.%, approximately approximately approximately approximately approximately wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, approximately approximately approximately approximately approximately approximately wt.%, wt.%, wt.% %, wt.%, wt.%, approximately approximately approximately approximately approximately approximately wt.%, wt.%, wt.%, wt.%, wt.%, wt.%, approximately approximately approximately approximately approximately approximately wt.%, wt. .%, wt.%, wt.%, wt.%, wt.%, about 39 wt.%, about 40 wt.%.

In some embodiments, said povidone is present in an amount

5-90 wt.%. In some embodiments, said povidone is present in

5-80 wt.%. In some embodiments, said povidone is present in

5-70 wt.%. In some embodiments, said povidone is present in

5-60 wt.%. In some embodiments, said povidone is present in

5-50 wt.%. In some embodiments, said povidone is present in

5-40 wt.%. In some embodiments, said povidone is present in

5-30 wt.%. In some embodiments, said povidone is present in an amount an amount an amount an amount an amount an amount of about about about about about about about about about

- 23 044464

5-20 wt.%. In some embodiments, said povidone is present in an amount of about 5-10% by weight. In some embodiments, said povidone is present in an amount of about 10-90% by weight. In some embodiments, said povidone is present in an amount of about 10-80% by weight. In some embodiments, said povidone is present in an amount of about 10-70% by weight. In some embodiments, said povidone is present in an amount of about 10-60% by weight. In some embodiments, said povidone is present in an amount of about 10-50% by weight. In some embodiments, said povidone is present in an amount of about 10-40% by weight. In some embodiments, said povidone is present in an amount of about 10-30% by weight. In some embodiments, said povidone is present in an amount of about 10-20% by weight. In some embodiments, the povidone is present in an amount of about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%. , about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight .%, about 29 wt.%, about 30 wt.%, about 31 wt.%, about 32 wt.%, about 33 wt.%, about 34 wt.%, about 35 wt.%, about 36 wt.% , about 37 wt.%, about 38 wt.%, about 39 wt.%, about 40 wt.%, about 41 wt.%, about 42 wt.%, about 43 wt.%, about 44 wt.%, about 45 wt.%, about 46 wt.%, about 47 wt.%, about 48 wt.%, about 49 wt.%, about 50 wt.%, about 51 wt.%, about 52 wt.%, about 53 wt. .%, about 54 wt.%, about 55 wt.%, about 56 wt.%, about 57 wt.%, about 58 wt.%, about 59 wt.%, about 60 wt.%, about 61 wt.% , about 62 wt.%, about 63 wt.%, about 64 wt.%, about 65 wt.%, about 66 wt.%, about 67 wt.%, about 68 wt.%, about 69 wt.%, about 70 wt.%, about 71 wt.%, about 72 wt.%, about 73 wt.%, about 74 wt.%, about 75 wt.%, about 76 wt.%, about 77 wt.%, about 78 wt. .%, about 79 wt.%, about 80 wt.%, about 81 wt.%, about 82 wt.%, about 83 wt.%, about 84 wt.%, about 85 wt.%, about 86 wt.% , about 87 wt.%, about 88 wt.%, about 89 wt.%, or about 90 wt.%.

In some embodiments, the disintegrant, such as crospovidone or croscarmellose, is present in an amount of about 0.1-40% by weight. In some embodiments, the disintegrant, such as crospovidone or croscarmellose, is present in an amount of about 0.1-30% by weight. In some embodiments, the disintegrant, such as crospovidone or croscarmellose, is present in an amount of about 0.1-20% by weight. In some embodiments, the disintegrant, such as crospovidone or croscarmellose, is present in an amount of about 0.1-10% by weight. In some embodiments, the disintegrant, such as crospovidone or croscarmellose, is present in an amount of about 0.1-5 wt%. In some embodiments, the disintegrant, such as crospovidone or croscarmellose, is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 2 wt% , about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt .%, about 20 wt.%, about 21 wt.%, about 22 wt.%, about 23 wt.%, about 24 wt.%, about 25 wt.%, about 26 wt.%, about 27 wt.% , about 28 wt.%, about 29 wt.%, about 30 wt.%, about 31 wt.%, about 32 wt.%, about 33 wt.%, about 34 wt.%, about 35 wt.%, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight, about 40% by weight.

In some embodiments, said crospovidone is present in an amount of about 0.1-40% by weight. In some embodiments, said crospovidone is present in an amount of about 0.1-30% by weight. In some embodiments, said crospovidone is present in an amount of about 0.1-20% by weight. In some embodiments, said crospovidone is present in an amount of about 0.1-10% by weight. In some embodiments, said crospovidone is present in an amount of about 0.1-5% by weight. In some embodiments, said crospovidone is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt .%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 20 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, about 22 wt.%, about 23 wt.%, about 24 wt.%, about 25 wt.%, about 27 wt.%, about 28 wt.%, about 29 wt.% %, approximately 30 wt.%, approximately

- 24 044464 wt.%, about 32 wt.%, about 33 wt.%, about 34 wt.%, about 35 wt.%, about 36 wt.%, about 37 wt.%, about 38 wt.%, about 39 wt.%, about 40 wt.%.

In some embodiments, said croscarmellose is present in an amount of about 0.1-40% by weight. In some embodiments, said croscarmellose is present in an amount of about 0.1-30% by weight. In some embodiments, said croscarmellose is present in an amount of about 0.1-20% by weight. In some embodiments, said croscarmellose is present in an amount of about 0.1-10% by weight. In some embodiments, said croscarmellose is present in an amount of about 0.1-5% by weight. In some embodiments, said croscarmellose is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt .%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.% , about 21 wt.%, about 22 wt.%, about 23 wt.%, about 24 wt.%, about 25 wt.%, about 26 wt.%, about 27 wt.%, about 28 wt.%, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight .%, about 38 wt.%, about 39 wt.%, about 40 wt.%. In some embodiments of the present invention, said croscarmellose is croscarmellose sodium.

In some embodiments, said glidant, such as silica, is present in an amount of about 0.1 to 40 weight percent. In some embodiments, said glidant, such as silica, is present in an amount of about 0.1 to 30 weight percent. In some embodiments, said glidant, such as silica, is present in an amount of about 0.1 to 20 weight percent. In some embodiments, said glidant, such as silica, is present in an amount of about 0.1 to 10 weight percent. In some embodiments, said glidant, such as silica, is present in an amount of about 0.1-5 weight percent. In some embodiments, said glidant, such as silica, is present in an amount of about 0.1 wt.%, about 0.2 wt.%, about

0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about

0.8 wt%, about 0.9 wt%, about 1 wt%, about 2 wt%, about 3 wt%, about 5 wt%, about 5 wt%, about 6 wt%, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35 wt.%, about 40 wt.%.

In about 11 wt.%, about 16 wt.%, about 21 wt.%, about 26 wt.%, about 31 wt.%, about 36 wt.%, about 12 wt.%, about 17 wt.%, about 22 wt.%, about 27 wt.%, about 32 wt.%, about 37 wt.%, about 13 wt.%, about 18 wt.%, about 23 wt.%, about 28 wt.%, about 33 wt. .%, about 38 wt.%, about 14 wt.% about 19 wt.% about 24 wt.% about 29 wt.% about 34 wt.% about 39 wt.% in some embodiments, said silica is present in an amount of about 0.1-40 wt.%. In some embodiments, said silica is present in an amount of about 0.1 to 30 weight percent. In some embodiments, said silica is present in an amount of about 0.1-20% by weight. In some embodiments, said silica is present in an amount of about 0.1-10% by weight. In some embodiments, said silica is present in an amount of about 0.1-5 weight percent. In some embodiments, said silica is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 20 wt.% , about 21 wt.%, about 22 wt.%, about 23 wt.%, about wt.%, about 25 wt.%, about 26 wt.%, about 27 wt.%, about 28 wt.%, about wt. .%, about 30 wt.%, about 31 wt.%, about 32 wt.%, about 33 wt.%, about 35 wt.%, about 36 wt.%, about 37 wt.%, about 38% by weight, about 40% by weight, about 40% by weight.

In some embodiments of the present invention, the lubricant, such as magnesium stearate, is present in the intragranular phase or extragranular phase in an amount of about 0.1-40 wt.%. In some embodiments of the present invention, the lubricant, such as magnesium stearate, is present in the intragranular phase or extragranular phase in an amount of about 0.1-30% by weight. In some embodiments of the present invention, said lubricant, such as magnesium stearate, is present in the intragranular phase or extragranular phase in an amount of about 0.1-20% by weight. In some embodiments of the present invention, the lubricant, such as magnesium stearate, is present in the intragranular phase or extragranular phase in an amount of about 0.1-10 wt.%. In some embodiments of the present invention, the lubricant, such as magnesium stearate, is present in the intragranular phase or extragranular phase in an amount of about 0.1-5 wt.%. In some embodiments of the present invention, the lubricant, such as magnesium stearate, is present in the intragranular phase or extragranular phase in an amount of about 0.1-2.5 wt.%. In some embodiments of the present invention, the lubricant, such as magnesium stearate, is present in the intragranular phase or extragranular phase in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0 .4 wt.%, about 0.5 wt.%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, about 1 wt. %, about 1.5 wt.%, about 2 wt.%, about 2.5 wt.%, about 3 wt.%, about 3.5 wt.%, about 4 wt.%, about 4.5 wt. %, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, about 21 wt.%, about 22 wt.%, about 23 wt.%, about 24 wt.%, about 25 wt.%, about 26 wt.%, about 27 wt.%, about 28 wt.%, about 29 wt. %, about 30 wt.%, about 31 wt.%, about 32 wt.%, about 33 wt.%, about 34 wt.%, about 35 wt.%, about 36 wt.%, about 37 wt.%, about 38 wt.%, about 39 wt.%, about 40 wt.%.

In some embodiments of the present invention, said magnesium stearate is present in the intragranular phase in an amount of about 0.1-40% by weight. In some embodiments of the present invention, said magnesium stearate is present in the intragranular phase in an amount of about 0.1-30% by weight. In some embodiments of the present invention, said magnesium stearate is present in the intragranular phase in an amount of about 0.1-20% by weight. In some embodiments of the present invention, said magnesium stearate is present in the intragranular phase in an amount of about 0.1-10% by weight. In some embodiments of the present invention, said magnesium stearate is present in the intragranular phase in an amount of about 0.1-5 wt.%. In some embodiments of the present invention, said magnesium stearate is present in the intragranular phase in an amount of about 0.1-2.5 wt%. In some embodiments of the present invention, said magnesium stearate in the intragranular phase is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0. 5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.5 wt% , about 2 wt.%, about 2.5 wt.%, about 3 wt.%, about 3.5 wt.%, about 4 wt.%, about 4.5 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 14 wt.% %, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 22 wt.%, about 19 wt.%, about 20 wt.%, about 21 wt.%, about 22 wt.%, about wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about wt%, about 29 wt%, about 30 wt%, about 31 wt% , about 32 wt.%, about 34 wt.%, about 35 wt.%, about 36 wt.%, about 37 wt.%, about 39 wt.%, about 40 wt.% .%.

In some embodiments of the present invention, said magnesium stearate in the extragranular phase is present in an amount of about 0.1-40 wt.%. In some embodiments of the present invention, said magnesium stearate in the extragranular phase is present in an amount of about 0.1-30 wt.%. In some embodiments of the present invention, said magnesium stearate in the extragranular phase is present in an amount of about 0.1-20 wt.%. In some embodiments of the present invention, said magnesium stearate is present in the extragranular phase in an amount of about 0.1-10% by weight. In some embodiments of the present invention, said magnesium stearate in the extragranular phase is present in an amount of about 0.1-5 wt.%. In some embodiments of the present invention, said magnesium stearate is present in the extragranular phase in an amount of about 0.1-2.5 wt%. In some embodiments of the present invention, said extragranular phase magnesium stearate is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0. 5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.5 wt% , about 2 wt.%, about 2.5 wt.%, about 3 wt.%, about 3.5 wt.%, about 4 wt.%, about 4.5 wt.%, about 5 wt.%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt .%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 20 wt.%, about 21 wt.%, about 22 wt.%, about 23 wt.%, about 25 wt.%, about 26 wt.%, about 27 wt.%, about 28 wt.%, about 30 wt.%, about 31 wt.% %, about 32 wt.%, about 33 wt.%, about

- 26 044464 wt.%, about 35 wt.%, about 36 wt.%, about 37 wt.%, about 38 wt.%, about 39 wt.%, about 40 wt.%.

In another aspect, the present invention provides a tablet composition containing (a) an effective amount of niraparib to inhibit poly(ADP-ribose) polymerase (PARP) when administered to a subject in need thereof; and (b) silicon dioxide; wherein said effective amount of niraparib is from about 50 to about 350 mg based on niraparib free base.

In some embodiments of the present invention, the effective amount of niraparib is from about 75 to about 125 mg based on niraparib free base. In some embodiments, the effective amount of niraparib is about 50 mg, about 100 mg, or about 150 mg based on niraparib free base. In some embodiments of the present invention, said effective amount of niraparib is about 100 mg based on niraparib free base. In some embodiments of the present invention, the effective amount of niraparib is from about 175 mg to about 225 mg based on niraparib free base. In some embodiments, the effective amount of niraparib is about 150 mg, about 200 mg, or about 250 mg based on niraparib free base. In some embodiments of the present invention, said effective amount of niraparib is about 200 mg based on niraparib free base. In some embodiments of the present invention, the effective amount of niraparib is from about 275 mg to about 325 mg based on niraparib free base. In some embodiments, the effective amount of niraparib is about 250 mg, about 300 mg, or about 350 mg based on niraparib free base. In some embodiments of the present invention, said effective amount of niraparib is about 300 mg based on niraparib free base. In some embodiments of the present invention, said niraparib comprises niraparib free base or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of niraparib is niraparib tosylate.

In some embodiments of the present invention, silica provides improved flow properties. In some embodiments of the present invention, silica improves the tensile strength, hardness, and/or bonding of intragranular materials. In some embodiments, the silica improves the properties of the niraparib-containing composition that is directly compressed into a tablet, for example, reducing the adhesion or stickiness of the composition.

In some embodiments of the present invention, said silica is present in the intragranular phase. In some embodiments of the present invention, said silica in the intragranular phase is present in an amount of about 0.1-40 wt.%. In some embodiments of the present invention, said silica in the intragranular phase is present in an amount of about 0.1-30 wt.%. In some embodiments of the present invention, said silica in the intragranular phase is present in an amount of about 0.1-20 wt.%. In some embodiments of the present invention, said silica in the intragranular phase is present in an amount of about 0.1-10 wt.%. In some embodiments of the present invention, said silica in the intragranular phase is present in an amount of about 0.1-5 wt.%. In some embodiments of the present invention, said silica in the intragranular phase is present in an amount of about 0.1-2.5 wt%. In some embodiments of the present invention, said intragranular phase silica is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0. 5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.5 wt% , about 2 wt.%, about 2.5 wt.%, about 3 wt.%, about 3.5 wt.%, about 4 wt.%, about 4.5 wt.%, about 5 wt.%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt .%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 21 wt.%, about 22 wt.%, about 23 wt.%, about 24 wt.%, about 26 wt.%, about 27 wt.%, about 28 wt.%, about 29 wt.%, about 31 wt.% %, about 32 wt.%, about 33 wt.%, about 34 wt.%, about 39 wt.%, about 36 wt.%, about 37 wt.%, about 38 wt.%, about 39 wt.%, about wt.%.

In some embodiments of the present invention, said silica is present in the extragranular phase. In some embodiments of the present invention, said silica in the extragranular phase is present in an amount of about 0.1-40 wt.%. In some embodiments of the present invention, said silica in the extragranular phase

- 27 044464 is present in an amount of approximately 0.1-30 wt.%. In some embodiments of the present invention, said silica in the extragranular phase is present in an amount of about 0.1-20% by weight. In some embodiments of the present invention, said silica in the extragranular phase is present in an amount of about 0.1-10 wt.%. In some embodiments of the present invention, said silica in the extragranular phase is present in an amount of about 0.1-5 wt.%. In some embodiments of the present invention, said silica in the extragranular phase is present in an amount of about 0.1-2.5 wt.%. In some embodiments of the present invention, said extragranular phase silica is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0. 5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.5 wt% , about 2 wt.%, about 2.5 wt.%, about 3 wt.%, about 3.5 wt.%, about 4 wt.%, about 4.5 wt.%, about 5 wt.%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt .%, about 15 wt.%, about 16 wt.%, about wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, about 21 wt.%, about wt.%, about 23 wt.%, about 24 wt.%, about 25 wt.%, about 26 wt.%, about 31 wt.%, about 28 wt.%, about 29 wt.%, about 30 wt.%, about 31 wt.% %, about wt.%, about 33 wt.%, about 34 wt.%, about 35 wt.%, about 36 wt.%, about wt.%, about 38 wt.%, about 39 wt.%, about 40 wt.%.

Intragranular phase/extragranular phase distribution

In some embodiments of the present invention, the distribution of intragranular phase components and extragranular phase components provides the desired disintegration profiles. Another aspect of the present invention relates to a tablet composition containing: an effective amount of niraparib to inhibit poly(ADP-ribose) polymerase (PARP) when administered to a subject in need thereof; wherein said tablet further comprises an intragranular phase and an extragranular phase; and said tablet is characterized by at least one of the following: a) the amount of components used to produce said intragranular phase is from about 50% to about 98% by weight of said tablet composition; and b) the amount of components used to obtain said extragranular phase is from about 2% to about 50% by weight of said tablet composition.

In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 50% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 55% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 60% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 65% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 70% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 75% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 80% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 85% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 90% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 92.5% to about 97.5% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is approximately 95% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%

- 28 044464 or approximately 98% by weight of the specified tablet composition.

In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 50% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 45% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 40% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 35% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 30% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 25% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 20% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 15% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 10% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 5% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2.5% to about 7.5% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is approximately 5% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5 %, approximately 5.5%, approximately 6.0%, approximately 6.5%, approximately 7.0%, approximately 7.5%, approximately 8.0%, approximately 8.5%, approximately 9.0%, about 9.5%, about 10.0%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight of said tablet composition.

Pharmacodynamics

Niraparib inhibits the enzymes PARP-1 and PARP-2 in vitro with IC ₅₀ of 3.8 nM (0.82 ng/ml) and 2.1 nM (0.67 ng/ml), respectively. Niraparib inhibits intracellular PARP activity with an IC ₅₀ of 4 nM (1.28 mg/ml) and an IC ₉₀ of 50 nM (16 ng/ml). A single dose of niraparib 50 mg/kg in tumor models resulted in >90% PARP inhibition, and with daily dosing resulted in tumor regression. At a dose of 50 mg/kg, tumor concentrations of ~4567 ng/ml were achieved after 6 hours, which exceeded PARP IC ₉₀ and resulted in tumor regression. In the same model, a dose of niraparib 75 mg/kg did not lead to tumor regression; Tumor regression was achieved when the dosage was changed to a niraparib dose of 50 mg/kg.

As used herein, fasting human pharmacokinetic studies include both single-dose fasting human pharmacokinetic studies and multiple-dose fasting human pharmacokinetic studies. Fasting multiple dose human pharmacokinetic studies were performed in accordance with US Food and Drug Administration (FDA) guidance documents and/or equivalent European Medicines Agency (EMEA) guidance documents. Steady-state pharmacokinetic parameters can be determined directly from multiple-dose fasting human pharmacokinetic studies or can be easily determined by extrapolation from single-dose data using standard methods or industry standard software such as WinNonlin version 5.3 or higher.

In some embodiments of the present invention, oral administration of a niraparib composition described herein to a human once daily provides an average peak plasma concentration ( _Cmax ) of 600 ng/mL to 1000 ng/mL. For example, oral administration of a niraparib composition described herein once daily to a human may provide mean peak plasma concentrations ( _Cmax ) of 600 ng/mL, 625 ng/mL, 650 ng/mL, 675 ng/mL. 700 ng/ml, 725 ng/ml, 750 ng/ml, 775 ng/ml, 800 ng/ml, 825 ng/ml, 850 ng/ml, 875 ng/ml, 900 ng/ml, 925 ng/ml, 950 ng/ml, 975 ng/ml or 1000 ng/ml. For example, oral administration of a composition

- 29 044464 niraparib described herein, once daily in a human, can provide an average peak plasma concentration ( _Cmax ) of 804 ng/ml.

In some embodiments of the present invention, oral administration of a niraparib composition described herein once daily to a human provides an average peak plasma concentration ( _Cmax ) in 0.5-6 hours. For example, oral administration of a niraparib composition described herein , a person once a day can provide an average peak plasma concentration ( _Cmax ) after approximately 0.5 hours, 0.75 hours, 1 hour, 1.25 hours, 1.5 hours, 1.75 hours, 2 hours, 2.25 h, 2.5 h, 2.75 h, 3 h, 3.25 h, 3.5 h, 3.75 h, 4 h, 4.25 h, 4.5 h, 4.75 h , 5 hours, 5.25 hours, 5.5 hours, 5.75 hours or 6 hours.

In some embodiments of the present invention, the Cmax of a tablet containing niraparib is from about 50% to about 150% compared to the _Cmax of a capsule containing an equivalent amount of niraparib. In some embodiments of the present invention, the Cmax of a tablet containing niraparib is from about 60% to about 140% compared to the Cmax of a capsule containing niraparib. In some embodiments of the present invention, the Cmax of a tablet containing niraparib is from about 70% to about 130% compared to the _Cmax of a capsule containing niraparib. In some embodiments of the present invention, the _Cmax of a tablet containing niraparib is from about 80% to about 120% compared to the _Cmax of a capsule containing niraparib. In some embodiments of the present invention, the _Cmax of a tablet containing niraparib is approximately 80% of the _{Cmax of} a capsule containing niraparib. In some embodiments of the present invention, the C _max of a tablet containing niraparib is about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, approximately 125% or approximately 130% compared to the C _max of a capsule containing niraparib. In some embodiments, the Cmax of a tablet containing niraparib is about 80%, about 85%, about 90%, about 95%, about 100%, or about 105% compared to the Cmax of a capsule containing niraparib. In some embodiments of the present invention, the Cmax of a tablet containing niraparib is about 85% or about 105% of the _Cmax of a capsule containing niraparib.

In some embodiments of the present invention, the AUC _{0_t} of a tablet containing niraparib is from _about 50% to about 150% compared to the AUC _{0_t of} a capsule containing an equivalent amount of niraparib. In some embodiments of the present invention, the AUC _{0_t} of a tablet containing niraparib is from about 60% to about 140% compared to the _{AUC 0_t of} a capsule containing niraparib. In some embodiments of the present invention, the AUC _{0_t} of a tablet containing niraparib is from about 70% to about 130% compared to the AUC _{0_t of a} capsule containing niraparib. In some embodiments of the present invention, the AUC _{0_t} of a tablet containing niraparib is from about 80% to about 120% compared to the AUC _{0_t of a} capsule containing niraparib. In some embodiments of the present invention, the AUC _{0_t of} a tablet containing niraparib is approximately 80% compared to the AUC _{0_t of} a capsule containing niraparib. In some embodiments of the present invention, the AUC _{0_t of} a tablet containing niraparib is about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120 %, approximately 125% or approximately 130% compared to the AUC _{0_t of} a capsule containing niraparib. In some embodiments of the present invention, the AUC _{0_t of} a tablet containing niraparib is about 80%, about 85%, about 90%, about 95%, about 100%, or about 105% compared to the AUC _{0_t of} a capsule containing niraparib. . In some embodiments, the AUC _{0_t} of a tablet containing niraparib is about 85% or about 105% of the AUC _{0_t of} a capsule _containing niraparib.

In some embodiments of the present invention, AUC ₀ . _Infinity tablets containing niraparib range from approximately 50% to approximately 150% of the AUC ₀ . _Infinity capsule containing an equivalent amount of niraparib. In some embodiments of the present invention, AUC ₀ . _Infinity tablets containing niraparib range from approximately 60% to approximately 140% of the AUC ₀ . _Infinity capsules containing niraparib. In some embodiments of the present invention, AUC ₀ . _Infinity tablets containing niraparib range from approximately 70% to approximately 130% of the AUC ₀ . _Infinity capsules containing niraparib. In some embodiments of the present invention, AUC ₀ . _Infinity tablets containing niraparib range from approximately 80% to approximately 120% of the AUC ₀ . _Infinity capsules containing niraparib. In some embodiments of the present invention, AUC ₀ . _Infinity tablets containing niraparib are approximately 80% AUC ₀ . _Infinity capsules containing niraparib. In some embodiments of the present invention, AUC ₀ . _Infinity tablet containing niraparib is about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, or about 130% compared to AUC ₀ . _Infinity capsules containing niraparib. In some embodiments of the present invention, AUC ₀ . _Infinity tablets containing niraparib are approximately 80%, approximately 85%, approximately 90%, approximately 95%, approximately 100%, or approximately 105% of the AUC ₀ . _Infinity capsules containing niraparib. In some

- 30 044464 embodiments of the present invention, the AUC _{of a 0-Infinity} tablet containing niraparib is about 85% or about 105% compared to the AUC _{of a 0-Infinity} capsule containing niraparib.

In some embodiments of the present invention, the absolute bioavailability of niraparib provided in the composition described herein is approximately 60-90%. For example, the absolute bioavailability of niraparib provided in the composition described herein may be about 60%, 65%, 70%, 75%, 80%, 85%, or 90%. For example, the absolute bioavailability of niraparib provided in the composition described herein may be approximately 73%.

In some embodiments of the present invention, concomitant ingestion of a high-fat meal does not significantly affect the pharmacokinetics of the niraparib composition described herein following administration of a dose described herein. For example, concomitant ingestion of a high-fat meal may not have a significant effect on the pharmacokinetics of the niraparib composition described herein following administration of a 50, 100, 150, 200, 250, 300, 350, or 400 mg dose of niraparib.

In some embodiments of the present invention, niraparib is a protein that is moderately bound to human plasma after administration to a human. For example, following administration to humans, approximately 60%, 65%, 70%, 75%, 80%, 85%, or 90% of niraparib is protein bound to human plasma. For example, after administration to humans, approximately 83% of niraparib is protein bound to human plasma.

In some embodiments of the present invention, the apparent volume of distribution (Vd/F) of niraparib is from about 500 L to about 2000 L after administration to a human. For example, the apparent volume of distribution (Vd/F) of niraparib may be approximately 500 L, 550 L, 600 L, 650 L, 700 L, 750 L, 800 L, 850 L, 900 L, 950 L, 1000 L, 1100 L, 1200 L, 1300 L, 1350 L, 1400 L, 1450 L, 1500 L, 1600 L, 1700 L, 1800 L, 1900 L or 2000 L after administration to humans. For example, the apparent volume of distribution (Vd/F) of niraparib may be approximately 1220 L after administration to humans. For example, the apparent volume of distribution (Vd/F) of niraparib may be approximately 1074 L after administration to humans.

In some embodiments of the present invention, after administration of niraparib provided in the composition described herein, the average terminal half-life (t _1/2 ) of niraparib is from about 40 to 60 hours. For example, after administration of niraparib provided in the composition described in Herein, the mean terminal half-life (ti/ ₂ ) of niraparib may be approximately 40 hours, 42 hours, 44 hours, 46 hours, 48 hours, 50 hours, 52 hours, 54 hours, 56 hours, 58 hours, or 60 hours. For example After administration of niraparib provided in the composition described herein, the mean terminal half-life (t _1/2 ) of niraparib may be from about 48 hours to 51 hours. For example, after administration of niraparib provided in the composition described herein, The mean terminal half-life (t1 _/2 ) of niraparib may be approximately 48 hours, 49 hours, 50 hours, or 51 hours.

In some embodiments of the present invention, after administration of niraparib provided in the composition described herein, the apparent total clearance (CL/F) of niraparib is from about 10 L/hour to about 20 L/hour. For example, following administration of niraparib provided in the composition described herein, the apparent total clearance (CL/F) of niraparib may be approximately 10 L/h, 11 L/h, 12 L/h, 13 L/h, 14 L/h. h, 15 l/h, 16 l/h, 17 l/h, 18 l/h, 19 l/h or 20 l/h. For example, following administration of niraparib provided in the composition described herein, the apparent total clearance (CL/F) of niraparib may be approximately 16.2 L/hour.

In some embodiments of the present invention, the dosage forms described herein provide the release of niraparib from the composition within 1 minute, or within 5 minutes, or within 10 minutes, or within 15 minutes, or within 30 minutes, or within 60 min, or within 90 min. In other embodiments of the present invention, a therapeutically effective amount of niraparib is released from the composition within 1 minute, or within 5 minutes, or within 10 minutes, or within 15 minutes, or within 30 minutes, or within 60 minutes, or within 90 min. In some embodiments of the present invention, the composition comprises a tablet formulation of niraparib that provides immediate release of niraparib. In some embodiments, the composition comprises a tablet formulation of niraparib that provides immediate release of niraparib within 1 minute, or within 5 minutes, or within 10 minutes, or within 15 minutes, or within 30 minutes, or within 60 minutes. min, or within 90 min.

The niraparib dosage forms and dosage forms described herein demonstrate pharmacokinetic profiles that can result in niraparib plasma C _min levels at steady state from about 10 ng/mL to about 100 ng/mL. In one embodiment of the present invention, the dosage forms of niraparib described herein provide blood plasma levels immediately before the next dose (C _min ) at steady state from about 25 ng/ml to about 100 ng/ml. In another embodiment

- 31 044464 tions of the present invention, the niraparib dosage forms described herein provide steady state plasma C _min levels of from about 40 ng/mL to about 75 ng/mL. In another embodiment of the present invention, the dosage forms of niraparib described herein provide plasma C _min levels at steady state of approximately 50 ng/ml.

The dosage forms of niraparib described herein are administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, site and route of administration, schedule of administration, and other factors known to medical practitioners. For human treatment, the dosage forms described herein deliver dosage forms of niraparib that maintain a therapeutically effective amount of niraparib of at least 10 ng/mL, or typically at least about 100 ng/mL, in plasma at steady state, and simultaneously reduce side effects associated with increased Niraparib _Cmax levels in blood plasma.

In some embodiments of the present invention, greater than about 95%; or more than about 90%; or more than about 80%; or more than about 70% of niraparib dosed by weight is absorbed into the bloodstream within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 18, or 24 hours after administration .

Niraparib concentration/amount

Using the methods and compositions described herein, dosage forms can be prepared that achieve the desired disintegration characteristics and target pharmacokinetic profiles described herein. For example, therapeutically effective doses of niraparib can be administered once, twice or three times daily in tablets using the methods of preparation and compositions described herein to achieve these results. In some embodiments of the present invention, niraparib or a pharmaceutically acceptable prodrug or salt thereof is present in an amount of about 20-80 wt%, 45-70 wt%, 40-50 wt%, 45-55 wt%, 50-60 wt.%, 55-65 wt.%, 60-70 wt.%, 65-75 wt.%, 70-80 wt.% or 40-60 wt.%. In some embodiments of the present invention, the specified niraparib or a pharmaceutically acceptable prodrug or salt thereof is present in an amount of about 40-60 wt.% by weight of the tablet core (for example, the total weight of intragranular and extragranular components). In some embodiments of the present invention, the specified niraparib or a pharmaceutically acceptable prodrug or salt thereof is present in an amount of about 40-60 wt.% of the total weight of the tablet (for example, the total weight of intragranular and extragranular components and coating). In some embodiments of the present invention, the specified niraparib or a pharmaceutically acceptable prodrug or salt thereof is present in an amount of about 40-50 wt.% by weight of the tablet core (for example, the total weight of intragranular and extragranular components). In some embodiments of the present invention, the specified niraparib or a pharmaceutically acceptable prodrug or salt thereof is present in an amount of about 40-50 wt.% of the total weight of the tablet (for example, the total weight of intragranular and extragranular components and coating).

In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib or a pharmaceutically acceptable prodrug or salt thereof is from about 1% to about 70%, from about 5% to about 70%, from about 10% to about 70 %, from about 15% to about 70%, from about 20% to about 70%, from about 25% to about 70%, from about 30% to about 70%, from about 35% to about 70%, from about 40 % to about 70%, from about 45% to about 70%, from about 50% to about 70%, from about 55% to about 70%, from about 60% to about 70%, from about 65% to about 70% by weight of the specified composition.

In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib or a pharmaceutically acceptable prodrug or salt thereof is from about 1% to about 65%, from about 5% to about 65%, from about 10% to about 65 %, from about 15% to about 65%, from about 20% to about 65%, from about 25% to about 65%, from about 30% to about 65%, from about 35% to about 65%, from about 40 % to about 65%, from about 45% to about 65%, from about 50% to about 65%, from about 55% to about 65%, from about 60% to about 65% by weight of the specified composition.

In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib or a pharmaceutically acceptable prodrug or salt thereof is from about 1% to about 60%, from about 5% to about 60%, from about 10% to about 60 %, from about 15% to about 60%, from about 20% to about 60%, from about 25% to about 60%, from about 30% to about 60%, from about 35% to about 60%, from about 40 % to about 60%, from about 45% to about 60%, from about 50% to about 60%, from about 55% to about 60% by weight of the specified composition.

In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib or a pharmaceutically acceptable prodrug thereof or

- 32 044464 salt is from about 1% to about 55%, from about 5% to about 55%, from about 10% to about 55%, from about 15% to about 55%, from about 20% to about 55%, from about 25% to about 55%, from about 30% to about 55%, from about 35% to about 55%, from about 40% to about 55%, from about 45% to about 55%, from about 50% to approximately 55% by weight of said composition.

In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib or a pharmaceutically acceptable prodrug or salt thereof is from about 1% to about 50%, from about 5% to about 50%, from about 10% to about 50 %, from about 15% to about 50%, from about 20% to about 50%, from about 25% to about 50%, from about 30% to about 50%, from about 35% to about 50%, from about 40 % to about 55%, from about 45% to about 50% by weight of said composition.

In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib or a pharmaceutically acceptable prodrug or salt thereof is from about 1% to about 45%, from about 5% to about 45%, from about 10% to about 45 %, from about 15% to about 45%, from about 20% to about 45%, from about 25% to about 45%, from about 30% to about 45%, from about 35% to about 45%, from about 40 % to about 45% by weight of said composition.

In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib or a pharmaceutically acceptable prodrug or salt thereof is from about 1% to about 40%, from about 5% to about 40%, from about 10% to about 40 %, from about 15% to about 40%, from about 20% to about 40%, from about 25% to about 40%, from about 30% to about 40%, from about 35% to about 40% by weight of the said composition .

In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib or a pharmaceutically acceptable prodrug or salt thereof is from about 1% to about 35%, from about 5% to about 35%, from about 10% to about 35 %, from about 15% to about 35%, from about 20% to about 35%, from about 25% to about 35%, from about 30% to about 35% by weight of the specified composition.

In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib or a pharmaceutically acceptable prodrug or salt thereof is about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% by weight of said composition. In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib tosylate monohydrate is approximately 19.16% by weight of the composition. In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib tosylate monohydrate is approximately 38.32% by weight of the composition. In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib tosylate monohydrate is approximately 47.8% by weight of the composition. In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib tosylate monohydrate is approximately 57.48% by weight of the composition. In some embodiments of the present invention, in the compositions described herein, the concentration of niraparib tosylate monohydrate is approximately 76.64% by weight of the composition.

In some embodiments of the present invention, in the compositions described herein, the amount of niraparib or a pharmaceutically acceptable prodrug or salt thereof is from about 1 mg to 5 mg, from 5 mg to 10 mg, from 10 mg to 20 mg, from 20 mg up to 25 mg, from 25 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg to 175 mg, from 170 mg to 195 mg, from 190 mg to 215 mg, from 210 mg to 235 mg, from 230 mg to 255 mg, from

250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from 330 mg to 355 mg, from

350 mg to 375 mg, from 370 mg to 400 mg, from 400 mg to 450 mg, from 450 mg to 500 mg, from 500 mg to 550 mg, from

550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from

800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg up to 1550 mg, from 1550 mg to 1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg to 1850 mg, from 1850 mg to 1900 mg, from 1900 mg to 1950 mg or from 1950 mg to 2000 mg. For example, in the compositions described herein, the amount of niraparib tosylate monohydrate is from about 1 mg to about 2000 mg, for example, from about 1 mg to 5 mg, from 5 mg to 10 mg, from 10 mg to 20 mg, from 20 mg to 25 mg, from 25 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg up to 175 mg, from 170 mg to 195 mg, from 190 mg to 215 mg, from 210 mg to 235 mg, from 230 mg to 255 mg, from 250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from 330 mg to 355 mg, from 350 mg to 375 mg, from 370 mg to

- 33 044464

400 mg, from 400 mg to 450 mg, from 450 mg to 500 mg, from 500 mg to 550 mg, from 550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg , from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg to 1550 mg, from 1550 mg to 1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg to 1850 mg, 1850 mg to 1900 mg, 1900 mg to 1950 mg, or 1950 mg to 2000 mg.

In some embodiments of the present invention, in the compositions described herein, the amount of niraparib or a pharmaceutically acceptable prodrug or salt thereof is about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg , 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg or 2000 mg. For example, in the compositions described herein, the amount of niraparib tosylate monohydrate may be about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg , 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg or 2000 mg.

In some embodiments of the present invention, in the compositions described herein, the amount of niraparib or a pharmaceutically acceptable prodrug or salt thereof is about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg , about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg or about 2000 mg. For example, in the compositions described herein, the amount of niraparib tosylate monohydrate may be about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg or about 2000 mg. In some embodiments of the present invention, in the compositions described herein, the amount of niraparib tosylate monohydrate may be about 79.7 mg. In some embodiments of the present invention, in the compositions described herein, the amount of niraparib tosylate monohydrate may be about 159.4 mg. In some embodiments of the present invention, in the compositions described herein, the amount of niraparib tosylate monohydrate may be about 318.8 mg. In some embodiments of the present invention, in the compositions described herein, the amount of niraparib tosylate monohydrate may be about 478.0 mg.

Pharmaceutically acceptable salts

In some embodiments, the niraparib used in the composition described herein is in the form of a free base, a pharmaceutically acceptable salt, a prodrug, an analog, or a complex. In some cases, niraparib contains a pharmaceutically acceptable salt form. In some embodiments of the present invention, the pharmaceutically acceptable salt of niraparib in the composition includes, but is not limited to, 4-methylbenzene sulfonates, sulfates, benzene sulfates, fumarates, succinates, and stereoisomers or tautomers thereof. In some embodiments of the present invention, the pharmaceutically acceptable salt of niraparib in the composition includes, but is not limited to, tosylates. In some embodiments of the present invention, the pharmaceutically acceptable monohydrate salt of niraparib in the composition includes, but is not limited to, tosylate monohydrates.

Additional Pharmaceutically Acceptable Excipients In some aspects, the pharmaceutical composition described herein further contains one or more pharmaceutically acceptable excipients. In some embodiments of the present invention, the one or more pharmaceutically acceptable excipients are present in an amount of about 0.1-99% by weight. Illustrative pharmaceutically acceptable

- 34 044464 excipients for the purposes of the pharmaceutical compositions described herein include, but are not limited to, binders, disintegrants, superdisintegrants, lubricants, diluents, fillers, flavorings, lubricants, sorbents, solubilizers, chelating agents, emulsifiers, thickeners, dispersants, stabilizers, suspending agents, absorbents, granulating agents, preservatives, buffers, coloring agents and sweeteners or combinations thereof. Examples of binders include microcrystalline cellulose, hydroxypropyl methylcellulose, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinylpolypyrrolidone, calcium carboxymethylcellulose, sodium carboxymethylcellulose, locust bean gum, chitosan, cottonseed oil, dextrates, dextrin, ethylcellulose, gelatin, glucose, glyceryl behenate, galactate omannan polysaccharide, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose , hypromellose, inulin, lactose, magnesium aluminum silicate, maltodextrin, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene glycol, polyethylene oxide, polymethacrylates, sodium alginate, sorbitol, starch, sucrose, sunflower oil, vegetable oil, tocophersolan, zein or combinations thereof. Examples of disintegrants include hydroxypropyl methylcellulose (HPMC), low-substituted hydroxypropylcellulose (L-HPC), croscarmellose sodium, sodium starch glycolate, lactose, magnesium aluminum silicate, methylcellulose, polacrilin potassium, sodium alginate, starch, or combinations thereof. Examples of the lubricant include stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, glycerol monostearate, glyceryl palmitostearate, magnesium lauryl sulfate, mineral oil, palmitic acid, myristic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, talc, zinc stearate ka, Potassium benzoate, magnesium stearate or combinations thereof. Examples of diluents include talc, ammonium alginate, calcium carbonate, calcium lactate, calcium phosphate, calcium silicate, calcium sulfate, cellulose, cellulose acetate, corn starch, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt , kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, microcrystalline cellulose, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sucrose, β-cyclodextrin sulfobutyl ether, gum tragacanth, trehalose , xylitol or combinations thereof. In some embodiments of the present invention, said pharmaceutically acceptable excipient is hydroxypropyl methylcellulose (HPMC). In some embodiments of the present invention, said pharmaceutically acceptable excipient is low-substituted hydroxypropylcellulose (low-substituted HPC, L-HPC). In some embodiments of the present invention, the pharmaceutically acceptable excipient is lactose. In some embodiments of the present invention, said pharmaceutically acceptable excipient is lactose monohydrate. In some embodiments of the present invention, the pharmaceutically acceptable excipient is magnesium stearate. In some embodiments of the present invention, said pharmaceutically acceptable excipient is lactose monohydrate or magnesium stearate.

Various suitable fillers or diluents include, but are not limited to, the following: calcium carbonate (Barcroft™, MagGran™, Millicarb™, Pharma-Carb™, Precarb™, Sturcal™, Vivapres Ca™), calcium phosphate, dibasic anhydrous (Emcompress Anhydrous ™, Fujicalin™), calcium phosphate, dibasic dihydrate (Calstar™, Di-Cafos™, Emcompress™, tribasic calcium phosphate (Tri-Cafos™, TRI-TAB™), calcium sulfate (Destab™, Drierite™, Snow White™ , Cal-Tab™, Compactrol™), powdered cellulose (Arbocel™, Elcema™, Sanacet™), silicated microcrystalline cellulose, cellulose acetate, compressed sugar (Di-Pac™), powdered sugar, dexrates (Candex™, Emdex™ ), dextrin (Avedex™, Caloreen™, Primogran W™), dextrose (Caridex™, Dextrophin™, Tab fine D-IOO™), fructose (Fmctofin™, Krystar™), kaolin (Lion™, Sim 90™), lactitol (Finlac DC™, Finlac MCX™), lactose (Anhydrox™, CapsuLac™, Fast-Flo™, FlowLac™, GranuLac™, InhaLac™, Lactochem™, Lactohaie™, Lactopress™, Microfme™, Microtose™, Pharmatose™ , Prisma Lac™, Respitose™, SacheLac™, SorboLac™, SuperTab™, Tablettose™, Wyndale™, Zeparox™), lactose monohydrate, magnesium carbonate, magnesium oxide (MagGran MO™), maltodextrin (C*Dry MD™, Lycatab DSH™, Maldex™, Maitagran™, Maltrin™, Maltrin QD™, Paselli MD 10 PH™, Star-Dri™), maltose (Advantose 100™), mannitol (Mannogem™, Pearlitol™), microcrystalline cellulose (Avicel PH™ , Celex™, Celphere™, Ceolus KG™, Emcocel™, Pharmacel™, Tabulose™, Vivapur™), polydextrose (Litesse™), simethicone (Dow Corning Q7-2243 LVA™, Dow Corning Q7-2587™, Sentry Simethicone™ ), sodium alginate (Keltone™, Protanal™), sodium chloride (Alberger™), sorbitol (Liponec 70-NC™, Liponic 76-NCv, Meritol™, Neosorb™, Sorbitol Instant™, Sorbogem™), starch (Flufiex W ™, Instant Pure-Cote™, Melojei™, Meritena Paygel 55™, Perfectamyl D6PH™, Pure-Cote™, Pure-Dent™, Pure-Gel™, Pure-Set™, Purity 21™, Purity 826™, Tablet White ™), pregelatinized starch, sucrose, trehalose and xylitol or mixtures thereof.

Various useful disintegrants include, but are not limited to, the following: alginic

- 35 044464 acid (Protacid™, Satialgine H8™), tribasic calcium phosphate (TRI-TAB™), calcium carboxymethylcellulose (ECG 505™), sodium carboxymethylcellulose (Akucell™, Finnfix™, Nymcel Tylose CB™), colloidal silicon dioxide ( Aerosil™, Cab-O-Sil™, Wacker HDK™), croscarmellose sodium (Ac-DiSol™, Pharmacel XL™, Primellose™, Solutab™, Vivasol™), crospovidone (Collison CL™, Collison CL-M™, Polyplasdone XL™), sodium docusate, guar gum (Meyprodor™, MiMeyprofm™, Meyproguar™), low-substituted hydroxypropylcellulose, magnesium aluminum silicate (Magnabite™, Neusilin™, Pharmsorb™, Veegum™), methylcellulose (Methocel™, Metolose™), microcrystalline cellulose (Avicel PH™, Ceoius KG™, Emcoel™, Ethispheres™, Fibrocel™, Pharmacel™, Vivapur™), povidone (Collison™, Plasdone™), sodium alginate (Kelcosol™, Ketone™, Protanal™), starch glycolate sodium, potassium polacrilin (Amberlite IRP88™), silicated microcrystalline cellulose (ProSotv™), starch (Aytex P™, Fluftex W™, Melojel™, Meritena™, Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, Pure-Cote ™, Pure-Dent™, Purity 21™, Purity 826™, Tablet White™) or pregelatinized starch (Lycatab PGS™, Merigel™, National 78-1551™, Pharma-Gel™, Prejel™, Sepistab ST 200™, Spress B820™, Starch 1500 G™, Tablitz™, Unipure LD™) or mixtures thereof. In some embodiments, the disintegrant is optionally used in an amount of about 0.1 to 99 weight percent. In some embodiments, the disintegrant is optionally used in an amount of about 0.1 to 50 weight percent. In some embodiments, the disintegrant is optionally used in an amount of about 0.110 weight percent. In some embodiments of the present invention, the disintegrant is optionally used in an amount of from about 0.1 mg to 0.5 mg, from 0.5 mg to 1 mg, from 1 mg to 2 mg, from 2 mg to 2.5 mg, from 2.5 mg to 5 mg, from 5 mg to 7.5 mg, from 7 mg to 9.5 mg, from 9 mg to 11.5 mg, from 11 mg to 13.5 mg, from 13 mg to 15, 5 mg, from 15 mg to 17.5 mg, from 17 mg to 19.5 mg, from 19 mg to 21.5 mg, from 21 mg to 23.5 mg, from 23 mg to 25.5 mg, from 25 mg to 27.5 mg, from 27 mg to 30 mg, from 29 mg to 31.5 mg, from 31 mg to 33.5 mg, from 33 mg to 35.5 mg, from 35 mg to 37.5 mg, from 37 mg to 40 mg, from 40 mg to 45 mg, from 45 mg to 50 mg, from 50 mg to 55 mg, from 55 mg to 60 mg, from 60 mg to 65 mg, from 65 mg to 70 mg, from 70 mg to 75 mg, 75 mg to 80 mg, 80 mg to 85 mg, 85 mg to 90 mg, 90 mg to 95 mg, or 95 mg to 100 mg. In some embodiments of the present invention, the disintegrant is present in amounts of about 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 5 mg, 7 mg, 9 mg, 11 mg, 13 mg, 15 mg , 17 mg, 19 mg, 21 mg, 23 mg, 25 mg, 27.5 mg, 30 mg, 31.5 mg, 33.5 mg, 35.5 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg.

Various beneficial lubricants include, but are not limited to, the following: calcium stearate (HyQual™), glycerol monostearate (Imwitor™ 191 and 900, Kessco GMS5™, 450 and 600, Myvaplex 600P™, Myvatex™, Rita GMS™, Stepan GMS ™, Tegin™, Tegin™ 503 and 515, Tegin 4100™, Tegin M™, Unimate GMS™), glyceryl behenate (Compritol 888 ATO™), glyceryl palmitostearate (Precirol ATO 5™), hydrogenated castor oil (Castorwax MP 80™, Croduret™, Cutina HR™, Fancol™, Simulsol 1293™), Type I Hydrogenated Vegetable Oil (Sterotex™, Dynasan P60™, Hydrocote™, Lipovol HS-K™, Sterotex HM™), Magnesium Lauryl Sulfate, Magnesium Stearate, Medium Chain triglycerides (Captex 300 ™, Labrafac CC ™, Miglyol 810 ™, NeobeM5 ™, Nesatol ™, Waglinol 3/9280 ™), Pluronic ™, Synperonic ™, polyethylene 5 glycol (Carbowax Sentry ™, L IPO ™, Lipoxol ™, Lutrol E™, Pluriol E™), sodium benzoate (Antimol™), sodium chloride, sodium lauryl sulfate (Elfan 240™, Texapon Kl 2P™), sodium stearyl fumarate (Pruv™), stearic acid (Hystrene™, Industrene™, Kortacid 1895 ™, Pristerene™), talc (Altaic™, Luzenac™, Luzenac Pharma™, Magsil Osmanthus™, 0 Magsil Star™, Superiore™), sucrose stearate (Surfhope SE Pharma D-1803 F™) and zinc stearate (HyQual™) or mixtures thereof. Examples of suitable lubricants include, but are not limited to, the following: magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, glyceryl behenate, polyethylene glycol, polyethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silicon dioxide and others known in the art. In some embodiments of the present invention, the lubricant is magnesium stearate.

Various beneficial glidants include, but are not limited to: tribasic calcium phosphate (TRI-TAB™), calcium silicate, powdered cellulose (Sanacel™, SolkaFloe™), colloidal silica (Aerosil™, Cab-O-Sil M -5P™, Wacker HDK™), magnesium silicate, magnesium trisilicate, starch (Melojel™, Meritena™, Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, PureCote™, Pure-Dent™, Pure-Gel™, Pure -Set™, Purity 21™, Purity 826™, Tablet White™) and talc (Luzenac Pharma™, Magsil Osmanthus™, Magsil Star™, Superiore™) or mixtures thereof. In some embodiments, the glidant is optionally used in an amount of about 0-15 weight percent. In some embodiments of the present invention, the glidant is optionally used in an amount of from about 0.1 mg to 0.5 mg, from 0.5 mg to 1 mg, from 1 mg to 2 mg, from 2 mg to 2.5 mg, from 2.5 mg to 5 mg, from 5 mg to 7.5 mg, from 7 mg to 9.5 mg, from 9 mg to 11.5 mg, from 11 mg to 13.5 mg, from 13 mg to 15, 5 mg, from 15 mg to 17.5 mg, from 17 mg to 19.5 mg, from 19 mg to 21.5 mg, from 21 mg to 23.5 mg, from 23 mg to 25.5 mg, from 25 mg to 27.5 mg, from 27 mg to 30 mg, from 29 mg to 31.5 mg, from 31 mg to 33.5 mg, from 33 mg to 35.5 mg, from 35 mg to 37.5 mg, from 37 mg to 40 mg, from 40 mg to 45 mg, from 45 mg to 50 mg, from 50 mg to 55 mg, from 55 mg to 60 mg, from 60 mg to 65 mg, from 65 mg to 70 mg, from 70 mg to 75 mg, from 75 mg to 80 mg, from 80 mg to 85 mg, from 85 mg to 90 mg, from 90 mg

- 36 044464 up to 95 mg or from 95 mg to 100 mg. In some embodiments of the present invention, the glidant is present in amounts of about 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 5 mg, 7 mg, 9 mg, 11 mg, 13 mg, 15 mg , 17 mg, 19 mg, 21 mg, 23 mg, 25 mg, 27.5 mg, 30 mg, 31.5 mg, 33.5 mg, 35.5 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg.

Pharmaceutically acceptable surfactants include, but are not limited to, nonionic and ionic surfactants suitable for use in pharmaceutical dosage forms. Ionic surfactants may contain one or more anionic, cationic or zwitterionic surfactants. Various useful surfactants include, but are not limited to, sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or other polyoxyethylene sorbitan ester, dioctyl sodium sulfosuccinate (DOSS), lecithin, stearyl alcohol, cetostearyl alcohol, cholesterol, polyoxyethylene castor oil, polyoxyethylene glycerides fatty acids, poloxamers or any other commercially available co-surfactants such as SEPITRAP® 80 or SEPITRAP® 4000 and mixtures thereof. In some embodiments, the surfactant is optionally used in an amount of about 0-5 weight percent. In some embodiments of the present invention, the surfactant is optionally used in an amount of from about 0.1 mg to 0.5 mg, from 0.5 mg to 1 mg, from 1 mg to 2 mg, from 2 mg to 2.5 mg , from 2.5 mg to 5 mg, from 5 mg to 7.5 mg, from 7 mg to 9.5 mg, from 9 mg to 11.5 mg, from 11 mg to 13.5 mg, from 13 mg to 15.5 mg, from 15 mg to 17.5 mg, from 17 mg to 19.5 mg, from 19 mg to 21.5 mg, from 21 mg to 23.5 mg, from 23 mg to 25.5 mg, from 25 mg to 27.5 mg, from 27 mg to 30 mg, from 29 mg to 31.5 mg, from 31 mg to 33.5 mg, from 33 mg to 35.5 mg, from 35 mg to 37.5 mg, from 37 mg to 40 mg, from 40 mg to 45 mg, from 45 mg to 50 mg, from 50 mg to 55 mg, from 55 mg to 60 mg, from 60 mg to 65 mg, from 65 mg to 70 mg , 70 mg to 75 mg, 75 mg to 80 mg, 80 mg to 85 mg, 85 mg to 90 mg, 90 mg to 95 mg, or 95 mg to 100 mg. In some embodiments of the present invention, the surfactant is present in amounts of about 0.1 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 5 mg, 7 mg, 9 mg, 11 mg, 13 mg, 15 mg, 17 mg, 19 mg, 21 mg, 23 mg, 25 mg, 27.5 mg, 30 mg, 31.5 mg, 33.5 mg, 35.5 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg.

Illustrative Tablet Compositions

Exemplary tablet compositions include dosage forms 1-6 described herein in Examples 1 and 2. Other exemplary compositions may include those described in Table 1. 1-12, where the total weight of the tablet core includes the total weight of intragranular components and extragranular components.

In embodiments of the present invention, the tablet composition is any dosage form described in table. 1, containing approximately 478 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the tablet composition is composition 7. In some embodiments of the present invention, the tablet composition is composition 8. In some embodiments of the present invention, the tablet composition is composition 9.

- 37 044464

Table 1

Exemplary tablets containing 300 mg niraparib (Formulations 7-9)

Component Mass. %* Composition 7 Composition 8 Composition 9 Intragranular phase (~ 94-98% of the total mass of the tablet core) Active agent approximately 40- 50 niraparib tosylate monohydrate Thinner 1 approximately 8- 14 lactose monohydrate Thinner 2 approximately 30- 40 microcrystalline cellulose Binder approximately 1-3 povidone Disintegrant approximately 0.1-2 crospovidone glidant/adsorbent/absorbent approximately 2-4 silica lubricating substance approximately 0.1-2 Magnesium stearate Extra granular phase (~ 2-6% of the total weight of the tablet core) Disintegrant glidant / adsorbent / absorbent lubricant approximately 0.1-2 approximately 0.1-2 approximately 0.1-2 crospovidone silicon dioxide magnesium stearate Total weight of tablet core - ~950-1050 mg ~1050-1150 mg ~1150-1250 mg * based on the total mass of the tablet core (sum of intragranular phase + extragranular phase)

In embodiments of the present invention, the tablet composition is any dosage form described in table. 2, containing approximately 478 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the tablet composition is composition 10. In some embodiments of the present invention, the tablet composition is composition 11. In some embodiments of the present invention, the tablet composition is composition 12.

- 38 044464

table 2

Exemplary tablets containing 300 mg niraparib (Formulations 10-12)

Component Intragranular^ Active agent Thinner 1 Thinner 2 Binder Disintegrating agent Mass. %* h phase 94-98 approximately 4050 approximately 814 approximately 3040 approximately 1-3 approximately 0.1-2 Composition 10 Composition 11 Composition 12 % of the total weight of the tablet core) niraparib tosylate monohydrate anhydrous lactose microcrystalline cellulose povidone crospovidone glidant/adsorbent/absorbent approximately 2-4 silica lubricating substance approximately 0.1-2 Magnesium stearate Extragranular phase (~ 2-6% of the total mass of the tablet core) Disintegrant approximately 0.1-2 croscarmellose sodium glidant/adsorbent/absorbent approximately 0.1-2 silica lubricating substance approximately 0.1-2 Magnesium stearate Total weight of tablet core — ~950-1050 mg ~1050-1150 mg ~1150-1250 mg * based on the total mass of the tablet core (sum of intragranular phase + extragranular phase)

In embodiments of the present invention, the tablet composition is any composition described in table. 3, containing approximately 478 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the tablet composition is composition 13. In some embodiments of the present invention, the tablet composition is composition 14. In some embodiments of the present invention, the tablet composition is composition 15.

- 39 044464

Table 3

Exemplary tablets containing 300 mg niraparib (Formulations 13-15)

Component Mass. %* Composition 13 Composition 14 Composition 15 Intragranular phase (~ 94-98% of the total mass of the tablet core) Active Agent approximately 40- 50 niraparib tosylate monohydrate Thinner 1 approximately 8- 14 lactose monohydrate Thinner 2 approximately 30- 40 microcrystalline cellulose Binder approximately 1-3 povidone Disintegrant approximately 0.1-2 crospovidone glidant/adsorbent/absorbent approximately 2-4 silica Extragranular phase (~ 2-6% of the total mass of the tablet core) Disintegrant approximately 0.1-2 crospovidone glidant/adsorbent/absorbent approximately 0.1-2 silica lubricating substance approximately 0.1-2 Magnesium stearate Total weight of tablet core — -950-1050 mg - 1050-1150 mg - 1150-1250 mg * based on the total mass of the tablet core (sum of intragranular phase + extragranular phase)

In embodiments of the present invention, the tablet composition is any composition described in table. 4, containing approximately 478 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the tablet composition is composition 16. In some embodiments of the present invention, the tablet composition is composition 17. In some embodiments of the present invention, the tablet composition is composition 18.

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Table 4

Illustrative tablets containing 300 mg niraparib (Formulations 16-18)____

Component Mass. %* Composition 16 Composition 17 Composition 18 Intragranular phase (~ 94-98% of the total mass of the tablet core) Active Agent approximately 40- 50 niraparib tosylate monohydrate Thinner 1 approximately 8- 14 anhydrous lactose Thinner 2 approximately 30- 40 microcrystalline cellulose Binder approximately 1-3 povidone Disintegrant approximately 0.1-2 crospovidone glidant / adsorbent / absorbent approximately 2-4 silica Extra granular phase (~ 2-6% of the total weight of the tablet core) Disintegrant approximately 0.1-2 croscarmellose sodium glidant / adsorbent / absorbent approximately 0.1-2 silica lubricating substance approximately 0.1-2 Magnesium stearate Total weight of tablet core — ~950-1050 mg ~1050-1150 mg ~1150-1250 mg * based on the total mass of the tablet core (sum of intragranular phase + extragranular phase)

In embodiments of the present invention, the tablet composition is any composition described in table. 5, containing approximately 18.7 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the tablet composition is composition 19. In some embodiments of the present invention, the tablet composition is composition 20. In some embodiments of the present invention, the tablet composition is composition 21.

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Table 5

Exemplary tablets containing 200 mg niraparib (Formulations 19-21)

Component Mass. %* Composition 19 Composition 20 Composition 21 Intragranular phase (~94-98 % of the total weight of the tablet core) Active Agent approximately 40- 50 niraparib tosylate monohydrate Thinner 1 approximately 8- 14 lactose monohydrate Thinner 2 approximately 30- 40 microcrystalline cellulose Binder approximately 1-3 — povidone Disintegrant approximately 0.1-2 crospovidone sliding substance/adsorbent/ approximately 2-4 silica absorbent lubricating substance approximately 0.1-2 Magnesium stearate Extragranular phase (~ 2-6% of the total mass of the tablet core) Disintegrant approximately 0.1-2 crospovidone sliding substance/adsorbent/ approximately 0.1-2 silica absorbent lubricating substance approximately 0.1-2 Magnesium stearate Total weight of tablet core — ~600-650 mg ~650-700 mg ~700-750 mg * based on the total mass of the tablet core (sum of intragranular phase + extragranular phase)

In embodiments of the present invention, the tablet composition is any composition described in table. 6, containing approximately 18.7 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the tablet composition is composition 22. In some embodiments of the present invention, the tablet composition is composition 23. In some embodiments of the present invention, the tablet composition is composition 24.

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Table 6

Illustrative tablets containing 200 mg niraparib (Formulations 22-24)____

Component Intragranular, Active Agent Thinner 1 Thinner 2 Binder Disintegrating agent glidant / adsorbent / absorbent Mass. %* h phase (~ 94-98 approximately 4050 approximately 814 approximately 3040 approximately 1-3 approximately 0.1-2 approximately 2-4 Composition 22 Composition 23 Composition 24 % of total tablet core weight) niraparib tosylate monohydrate anhydrous lactose microcrystalline cellulose povidone crospovidone silicon dioxide lubricating substance approximately 0.1-2 Magnesium stearate Extragranular phase (~ 2-6% of the total mass of the tablet core) Disintegrant approximately 0.1-2 croscarmellose sodium glidant/adsorbent/absorbent approximately 0.1-2 silica lubricating substance approximately 0.1-2 Magnesium stearate Total weight of tablet core — ~600-650 mg ~650-700 mg ~700-750 mg * based on the total weight of the tablet core (sum of intragranular phase + extragranular phase)

In embodiments of the present invention, the tablet composition is any composition described in table. 7, containing approximately 18.7 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the tablet composition is composition 25. In some embodiments of the present invention, the tablet composition is composition 26. In some embodiments of the present invention, the tablet composition is composition 27.

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Table 7

Exemplary tablets containing 200 mg niraparib (Formulations 25-27)

Component Mass. %* Composition 25 Composition 26 Composition 27 Intragranular phase (~ 94-98% of the total mass of the tablet core) Active Agent approximately 40- 50 niraparib tosylate monohydrate Thinner 1 approximately 8- 14 lactose monohydrate Thinner 2 approximately 30- 40 microcrystalline cellulose Binder approximately 1-3 povidone Disintegrant approximately 0.1-2 crospovidone glidant/adsorbent/absorbent approximately 2-4 silica Extragranular phase (~ 2-6% of the total mass of the tablet core) Disintegrant approximately 0.1-2 crospovidone glidant/adsorbent/absorbent approximately 0.1-2 silica lubricating substance approximately 0.1-2 Magnesium stearate Total weight of tablet core — ~600-650 mg ~650-700 mg ~700-750 mg * based on the total mass of the tablet core (sum of intragranular phase + extragranular phase)

In embodiments of the present invention, the tablet composition is any composition described in table. 8, containing approximately 18.7 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the tablet composition is composition 28. In some embodiments of the present invention, the tablet composition is composition 29. In some embodiments of the present invention, the tablet composition is composition 30.

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Table 8

Exemplary tablets containing 200 mg niraparib (Formulations 28-30)

Component Mass. %* Composition 28 Composition 29 Composition 30 Intragranular phase (~ 94-98% of the total mass of the tablet core) Active Agent approximately 40- 50 niraparib tosylate monohydrate Thinner 1 approximately 8- 14 anhydrous lactose Thinner 2 approximately 30- 40 microcrystalline cellulose Binder approximately 1-3 povidone Disintegrant approximately 0.1-2 crospovidone glidant / absorbent / adsorbent approximately 2-4 silica Extra granular phase (~ 2-6% of the total weight of the tablet core) Disintegrant approximately 0.1-2 croscarmellose sodium glidant / absorbent / adsorbent approximately 0.1-2 silica lubricating substance approximately 0.1-2 Magnesium stearate Total weight of tablet core — ~600-650 mg ~650-700 mg ~700-750 mg * based on the total mass of the tablet core (sum of intragranular phase + extragranular phase)

In embodiments of the present invention, the tablet composition is any composition described in table. 9, containing approximately 159.3 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the tablet composition is composition 31. In some embodiments of the present invention, the tablet composition is composition 32. In some embodiments of the present invention, the tablet composition is composition 33.

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Table 9

Illustrative tablets containing 100 mg niraparib (Dosage Forms 31-33)

Component Mass. %* Composition 31 Composition 32 Composition 33 Intragranular phase (~ 94-98% of the total mass of the tablet core) Active agent approximately 40- 50 niraparib tosylate monohydrate Thinner 1 Thinner 2 Binder Disintegrating agent glidant / absorbent / adsorbent lubricant Extragranular fa Disintegrating agent glidant/absorbent/adsorbent approximately 814 approximately 30- 40 approximately 1-3 approximately 0.1-2 approximately 2-4 approximately 0.1-2 per (~ 2-6% of approximately 0.1-2 approximately 0.1-2 lactose monohydrate microcrystalline cellulose povidone crospovidone silica Magnesium stearate total weight of the tablet core) crospovidone silica lubricating substance approximately 0.1-2 Magnesium stearate Total weight of tablet core — ~300-350 mg ~350-400 mg ~400-450 mg * based on the total mass of the tablet core (sum of intragranular phase + extragranular phase)

In embodiments of the present invention, the tablet composition is any composition described in table. 10, containing approximately 159.3 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the tablet composition is composition 34. In some embodiments of the present invention, the tablet composition is composition 35. In some embodiments of the present invention, the tablet composition is composition 36.

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Table 10

Exemplary tablets containing 100 mg niraparib (Formulations 34-36)

Component Mass. %* Composition 34 Composition 35 Composition 36 Intragranular phase (~ 94-98% of the total mass of the tablet core) Active agent approximately 40- 50 niraparib tosylate monohydrate Thinner 1 approximately 8- 14 anhydrous lactose Thinner 2 approximately 30- 40 microcrystalline cellulose Binder approximately 1-3 povidone Disintegrant sliding substance/absorbent/adsorbent lubricant substance Extragranular phase Disintegrating agent glidant/absorbent/adsorbent approximately 0.1-2 approximately 2-4 approximately 0.1-2 for (~ 2-6% of approximately 0.1-2 approximately 0.1-2 crospovidone silica Magnesium stearate total weight of the tablet core) croscarmellose sodium silica lubricating substance approximately 0.1-2 Magnesium stearate Total weight of tablet core — ~300-350 mg ~350-400 mg ~400-450 mg * based on the total mass of the tablet core (sum of intragranular phase + extragranular phase)

In embodiments of the present invention, the tablet composition is any composition described in table. 11, containing approximately 159.3 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the tablet composition is composition 37. In some embodiments of the present invention, the tablet composition is composition 38. In some embodiments of the present invention, the tablet composition is composition 39.

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Table 11

Exemplary tablets containing 100 mg niraparib (Formulations 35-39)

Component Mass. %* Composition 37 Composition 38 Composition 39 Intragranular phase (~ 94-98% of the total mass of the tablet core) Active Agent approximately 40- 50 niraparib tosylate monohydrate Thinner 1 approximately 8- 14 lactose monohydrate Thinner 2 approximately 30- 40 microcrystalline cellulose Binder approximately 1-3 povidone Disintegrant approximately 0.1-2 crospovidone glidant / absorbent / adsorbent approximately 2-4 silica Extragranular phase (~ 2-6% of the total mass of the tablet core) Disintegrant approximately 0.1-2 crospovidone glidant / absorbent / adsorbent approximately 0.1-2 silica lubricating substance approximately 0.1-2 Magnesium stearate Total weight of tablet core — ~300-350 mg ~350-400 mg ~400-450 mg * based on the total mass of the tablet core (sum of intragranular phase + extragranular phase)

In embodiments of the present invention, the tablet composition is any composition described in table. 12, containing approximately 159.3 mg of niraparib tosylate monohydrate. In some embodiments of the present invention, the tablet composition is composition 40. In some embodiments of the present invention, the tablet composition is composition 41. In some embodiments of the present invention, the tablet composition is composition 42.

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Table 12

Illustrative tablets containing 100 mg niraparib (Formulation 40-42)_____

Component Mass. %* Composition 40 Composition 41 Composition 42 Intragranular phase (~ 94-98% of the total mass of the tablet core) Active agent approximately 40- 50 niraparib tosylate monohydrate Thinner 1 approximately 8- 14 anhydrous lactose Thinner 2 approximately 30- 40 microcrystalline cellulose Binder approximately 1-3 povidone Disintegrant approximately 0.1-2 crospovidone glidant / absorbent / adsorbent approximately 2-4 silica Extra granular phase (~ 2-6% of the total weight of the tablet core) Disintegrant approximately 0.1-2 croscarmellose sodium glidant / absorbent / adsorbent approximately 0.1-2 silica lubricating substance approximately 0.1-2 Magnesium stearate Total weight of tablet core — ~300-350 mg ~350-400 mg ~400-450 mg * based on the total mass of the tablet core (sum of intragranular phase + extragranular phase)

In embodiments of the present invention, any excipient in compositions 1-42 described herein may vary. For example, the amount of diluent 2 can be varied (eg, about 7.5-15 wt.% or about 9-11 wt.%). Accordingly, each of the compositions 1a-42a contains diluent 2 in an amount of approximately 7.5-15 wt.%, and is otherwise identical to the corresponding compositions 1-42. Likewise, each of formulations 1b-42b contains diluent 2 in an amount of approximately 9-11% by weight and is otherwise identical to the corresponding formulations 1-42.

In other embodiments of the present invention, any tablet composition described herein (eg, any of formulations 1-42) further comprises a coating layer (eg, any coating described herein).

Disintegration

Disintegration is a measure of the quality of oral dosage forms such as tablets. In general, pharmacopoeia (eg USP, British Pharmacopoeia, Indian Pharmacopoeia) have their own set of standards and disintegration tests are defined within them. The pharmacopoeias of a number of international organizations have been agreed upon by the International Council of Harmonization (ICH) and are interchangeable. The disintegration test is used to determine the time required for a solid oral dosage form to completely disintegrate. Disintegration time can serve as a measure of quality. This is due to the fact that

- 49 044464 that, for example, disintegration is a rate-limiting step for the release of the active material that is part of the tablet. If the disintegration time is too long, this means that the active ingredient may in turn be released too slowly, which may affect the rate at which the active ingredient is delivered to the body after ingestion. Conversely, if the decay is too rapid, the opposite may be true.

The disintegration test is carried out using a disintegration test apparatus. Although there are slight differences between different pharmacopoeias, the basic design and operation of the device generally remain the same. A typical test is carried out as follows. The device consists of a basket made of transparent polyvinyl or other plastic. It usually contains tubes of equal diameter installed in the same basket, and a stainless steel mesh with the same mesh size is attached to each of the tubes. Small metal discs may be used to completely immerse the dosage form. The entire basket-tripod assembly can be moved by a reciprocating motor that is attached to the top of said basket-tripod assembly. The entire assembly is immersed in a vessel containing the medium in which the disintegration test will be performed. The vessel is equipped with a thermostat to regulate the temperature of the fluid to the desired temperature.

The disintegration test for each dosage form is given in the pharmacopoeia. There are several common tests for typical types of dosage forms. Some types of dosage forms and their disintegration tests are as follows: (1) Uncoated tablets - the test can use distilled water as a medium at a temperature of 37±2°C at 29-32 cycles per minute; the test is completed after 15 minutes. It is acceptable if at the end of the cycle there is no noticeable core (for at least 5 tablets or capsules) and if the mass does not stick to the dipping disc. (2) Coated tablets - the same test procedure can be adapted, but the test time is 30 min. (3) Enteric coated tablets/gastric acid resistant tablets - the test can be done first in distilled water (at room temperature for 5 min; USP) and without distilled water as per BP (UK Pharmacopoeia) and IP (Indian Pharmacopoeia). Pharmacopoeia)), then tested in 0.1 M HCL (up to 2 hours; BP) or in artificial gastric juice (1 hour; USP) followed by the addition of phosphate buffer, pH 6.8 (1 hour; BP) or in artificial intestines juice without enzymes (1 hour; USP). (4) Chewable tablets - not subject to disintegration test (BP and IP), 4 hours (USP). Here are some examples to illustrate.

The illustrative disintegration test uses the USP <701> standard test apparatus. One tablet is placed in six cells of the device to determine disintegration, in the lower part of which there is a stainless steel mesh. A magnetic sensor is placed on top of the tablet. The basket with cells is immersed in a bath with a controlled water temperature of 37°C. The basket moves up and down in the bath, 29 to 32 cycles per minute. Once the tablet has completely disintegrated, a sensor on the top of the tablet comes into contact with the mesh. The sensor automatically records the time the tablet disintegrates.

In some embodiments of the present invention, the disintegration time of the tablet is from about 30 seconds to about 300 seconds. In some embodiments of the present invention, the disintegration time of the tablet is from about 30 seconds to about 200 seconds. In some embodiments of the present invention, the disintegration time of the tablet is from about 30 seconds to about 150 seconds. In some embodiments, the disintegration time of said tablet is about 30 seconds, about 40 seconds, about 50 seconds, about 60 seconds, about 70 seconds, about 80 seconds, about 90 seconds, about 100 seconds, about 1 second, about 120 seconds , approximately 130 s, approximately 140 s, approximately 150 s, approximately 160 s, approximately 170 s, approximately 180 s, approximately 190 s, approximately 200 s, approximately 210 s, approximately 220 s, approximately 230 s, approximately 240 s, approximately 250 s, approximately 260 s, approximately 270 s, approximately 280 s, approximately 290 s or approximately 300 s.

Stability

In some embodiments of the present invention, the pharmaceutical composition described herein is stable in particle size distribution for at least about: 30 days, 60 days, 90 days, 6 months, 1 year, 18 months, 2 years, 3 years, 4 years or 5 years, for example about 80%-100%, for example: 80%, 90%, 95% or 100% of the specified pharmaceutical composition is stable in terms of particle size distribution. In some embodiments of the present invention, the stable niraparib particles described herein in a solid oral dosage form will not demonstrate an increase in effective particle size of more than 50% over a period of about 3, 6, 9, 12, 24, or 36 months. storage at room temperature (about 15°C to about 25°C). In some embodiments of the present invention, stable niraparib particles described herein in a solid oral dosage form will not demonstrate an increase in effective particle size of more than 60% over a period of about 3, 6, 9, 12, 24, or 36 months. storage at room temperature (from about 15°C to about

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25°C). In some embodiments of the present invention, stable niraparib particles described herein in a solid oral dosage form will not demonstrate an increase in effective particle size of more than 70% over a period of about 3, 6, 9, 12, 24, or 36 months. storage at room temperature (about 15°C to about 25°C). In some embodiments of the present invention, stable niraparib particles described herein in a solid oral dosage form will not demonstrate an increase in effective particle size of more than 80% over a period of about 3, 6, 9, 12, 24, or 36 months. storage at room temperature (about 15°C to about 25°C). In some embodiments of the present invention, stable niraparib particles described herein in a solid oral dosage form will not demonstrate an increase in effective particle size of more than 90% over a period of about 3, 6, 9, 12, 24, or 36 months. storage at room temperature (about 15°C to about 25°C). In some embodiments of the present invention, stable niraparib particles described herein in a solid oral dosage form will not demonstrate an increase in effective particle size of more than 95% over a period of about 3, 6, 9, 12, 24, or 36 months. storage at room temperature (about 15°C to about 25°C).

In some embodiments of the present invention, stable niraparib particles described herein in an oral dosage form will not demonstrate an increase in effective particle size of more than 50% over 3, 6, 9, 12, 24, or 36 months of storage at temperature from about 15°C to 30°C, from 15°C to 40°C, or from 15°C to 50°C. In some embodiments of the present invention, stable niraparib particles described herein in a solid oral dosage form will not exhibit an increase in effective particle size of more than 60% over 3, 6, 9, 12, 24, or 36 months of storage. at a temperature of from about 15°C to 30°C, from 15°C to 40°C, or from 15°C to 50°C. In some embodiments of the present invention, stable niraparib particles described herein in a solid oral dosage form will not exhibit an increase in effective particle size of more than 70% over 3, 6, 9, 12, 24, or 36 months of storage. at a temperature of from about 15°C to 30°C, from 15°C to 40°C, or from 15°C to 50°C. In some embodiments of the present invention, stable niraparib particles described herein in a solid oral dosage form will not exhibit an increase in effective particle size of more than 80% over 3, 6, 9, 12, 24, or 36 months of storage. at a temperature of from about 15°C to 30°C, from 15°C to 40°C, or from 15°C to 50°C. In some embodiments of the present invention, stable niraparib particles described herein in a solid oral dosage form will not exhibit an increase in effective particle size of more than 90% over 3, 6, 9, 12, 24, or 36 months of storage. at a temperature of from about 15°C to 30°C, from 15°C to 40°C, or from 15°C to 50°C. In some embodiments of the present invention, the stable particles of niraparib described herein in a solid oral dosage form will not demonstrate an increase in effective particle size of more than 95% over 3, 6, 9, 12, 24, or 36 months of storage. at a temperature of from about 15°C to 30°C, from 15°C to 40°C, or from 15°C to 50°C.

In some embodiments of the present invention, the pharmaceutical composition described herein is stable with respect to compound degradation for at least about 30 days, 60 days, 90 days, 6 months, 1 year, 18 months, 2 years, 3 years, 4 years or 5 years, for example, about 80-100%, for example, about 80%, 90%, 95% or 100% of the active pharmaceutical agent in the specified pharmaceutical composition is stable. Stability can be measured using high performance liquid chromatography (HPLC). In some embodiments of the present invention, about 80-100% (e.g., about 90-100% or 95-100%) of niraparib or a pharmaceutically acceptable salt thereof (e.g., niraparib tosylate monohydrate) in the pharmaceutical composition described herein is stable in for at least about 30, 60, 90, 180, 360, 540 or 720 days, for example more than 90 days. In some embodiments of the present invention, about 80%, 85%, 90%, 95%, or 100% (e.g., about 95%) of niraparib or a pharmaceutically acceptable salt thereof (e.g., niraparib tosylate monohydrate) is stable with respect to degradation of the compound within 30 days or more. In each case, stability can be measured using HPLC or other method known in the art. Methods for assessing chemical stability during storage of solid dosage forms are described in the literature. See, for example, S. T. Colgan, T. J. Watson, R. D. Whipple, R. Nosal, J. V. Beaman, D. De Antonis, The Application of Science and Risk Based Concepts to Drug Substance Stability Strategies J. Pharm. Innov. 7:205-2013 (2012); Waterman KC, Carella AJ, Gumkowski MJ, et al., Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms. Pharm Res 2007; 24(4):780-90; and S. T. Colgan, R. J. Timpano, D. Diaz, M. Roberts, R. Weaver, K. Ryan, K. Fields, G. Scrivens, Opportunities for Lean

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Stability Strategies J. Pharm. Innov. 9:259-271 (2014).

In some embodiments of the present invention, the pharmaceutical dosage forms described herein are stable with respect to degradation of the compound (e.g., less than 30% degradation, less than 25% degradation, less than 20% degradation, less than 15% degradation, less than 10% degradation, less than 8% degradation, less than 5% degradation, less than 3% degradation, less than 2% degradation, or less than 5% degradation) over a period of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 3 months, at least about 4 months, at least about 5 months, at least at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 24 months, or at least about 36 months under storage conditions (eg, room temperature). In some embodiments of the present invention, the dosage forms described herein are stable with respect to degradation of the compound over a period of at least about 1 week. In some embodiments of the present invention, the dosage forms described herein are stable with respect to degradation of the compound over a period of at least about 1 month. In some embodiments of the present invention, the dosage forms described herein are stable with respect to compound degradation over a period of at least about 3 months. In some embodiments of the present invention, the dosage forms described herein are stable with respect to compound degradation over a period of at least about 6 months. In some embodiments of the present invention, the dosage forms described herein are stable with respect to compound degradation over a period of at least about 9 months. In some embodiments of the present invention, the dosage forms described herein are stable with respect to compound degradation over a period of at least about 12 months.

Methods for assessing the chemical stability of solid dosage forms during storage, including under conditions of accelerated aging, are described in the literature. See, for example, S. T. Colgan, T. J. Watson, R. D. Whipple, R. Nosal, J. V. Beaman, D. De Antonis, The Application of Science and Risk Based Concepts to Drug Substance Stability Strategies J. Pharm. Innov. 7:205-2013 (2012); Waterman KC, Carella AJ, Gumkowski MJ, et al., Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms. Pharm Res 2007; 24(4):780-90; and S. T. Colgan, R. J. Timpano, D. Diaz, M. Roberts, R. Weaver, K. Ryan, K. Fields, G. Scrivens, Opportunities for Lean Stability Strategies J. Pharm. Innov. 9:259-271 (2014). The chemical stability of solid dosage forms during storage may also be determined according to the requirements of the International Council for the Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) or the World Health Organization (WHO).

Depending on the region of the world in which the pharmaceutical composition is intended for use and/or storage, stability studies may be conducted in accordance with the climatic conditions of that country. Generally, the world can be divided into five different zones: temperate zone, Mediterranean/subtropical zone, hot-dry zone, hot-humid zone/tropical zone, and hot-humidity zone. Those skilled in the art can determine suitable test conditions for a particular climate zone.

One aspect of the present disclosure relates to a composition comprising a tablet comprising: an effective amount of niraparib to inhibit poly(ADP-ribose) polymerase (PARP) when administered to a subject in need thereof; wherein said tablet is characterized by at least one of the following: a) said tablet contains less than 0.2 wt.% of any degradation product of niraparib; b) said tablet contains less than 0.2% by weight of any individual degradation product of niraparib after storage for 1 month at 40°C and 75% relative humidity (r.h.); and c) said tablet contains less than 0.2% by weight of any degradation product of niraparib after storage for 2 months at 40°C and 75% relative humidity (r.h.).

In some embodiments of the present invention, said tablet contains less than 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt. %, 0.05 wt%, 0.04 wt%, 0.03 wt%, 0.02 wt%, 0.01 wt%, 0.005 wt% or 0.001 wt% of any individual degradation product niraparib. In some embodiments of the present invention, the tablet contains less than 0.2 wt%, 0.1 wt%, 0.09 wt%, 0.08 wt%, 0.07 wt%, 0.06 wt% , 0.05 wt%, 0.04 wt%, 0.03 wt%, 0.02 wt%, 0.01 wt%, 0.005 wt%, or 0.001 wt% of any individual niraparib degradation product after khra

- 52 044464 for 1 month at a temperature of 40°C and a relative humidity of 75% (r.h.). In some embodiments of the present invention, said tablet contains less than 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt. %, 0.05 wt%, 0.04 wt%, 0.03 wt%, 0.02 wt%, 0.01 wt%, 0.005 wt% or 0.001 wt% of any individual degradation product niraparib after storage for 2 months at 40°C and 75% relative humidity (r.h.).

In some embodiments of the present invention, said tablet contains about 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt. %, 0.05 wt%, 0.04 wt%, 0.03 wt%, 0.02 wt%, 0.01 wt%, 0.005 wt% or 0.001 wt% of any individual degradation product niraparib. In some embodiments of the present invention, the tablet contains about 0.2 wt%, 0.1 wt%, 0.09 wt%, 0.08 wt%, 0.07 wt%, 0.06 wt% , 0.05 wt%, 0.04 wt%, 0.03 wt%, 0.02 wt%, 0.01 wt%, 0.005 wt%, or 0.001 wt% of any individual niraparib degradation product after storage for 1 month at 40°C and 75% relative humidity (r.h.). In some embodiments of the present invention, said tablet contains about 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt. %, 0.05 wt%, 0.04 wt%, 0.03 wt%, 0.02 wt%, 0.01 wt%, 0.005 wt% or 0.001 wt% of any individual degradation product niraparib after storage for 2 months at 40°C and 75% relative humidity (r.h.).

In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt.%, 0.05 wt.%, 0.04 wt.%, 0.03 wt.%, 0.02 wt.%, 0.01 wt.%, 0.005 wt.% or 0.001 wt.% of one or more degradation products, for example, one or more degradation products of niraparib, after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at a temperature of 5 °C. In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt.%, 0.05 wt.%, 0.04 wt.%, 0.03 wt.%, 0.02 wt.%, 0.01 wt.%, 0.005 wt.% or 0.001 wt.% of one or more degradation products, for example, one or more degradation products of niraparib, after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at a temperature of 25 °C and relative humidity 60% (r.h.). In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt.%, 0.05 wt.%, 0.04 wt.%, 0.03 wt.%, 0.02 wt.%, 0.01 wt.%, 0.005 wt.% or 0.001 wt.% of one or more degradation products, for example, one or more degradation products of niraparib, after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at a temperature of 30 °C and relative humidity 65% (r.h.). In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt.%, 0.05 wt.%, 0.04 wt.%, 0.03 wt.%, 0.02 wt.%, 0.01 wt.%, 0.005 wt.% or 0.001 wt.% of one or more degradation products, for example, one or more degradation products of niraparib, after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at a temperature of 40 °C and relative humidity 75% (r.h.).

In some embodiments of the present invention, the amount of one or more total niraparib impurity or degradation product is about 0.01 mg to 0.05 mg, 0.05 mg to 0.1 mg, 0.1 mg to 0.2 mg , from 0.2 mg to 0.25 mg, from 0.25 mg to 0.5 mg, from 0.5 mg to 0.75 mg, from 0.7 mg to 0.95 mg, from 0.9 mg up to 1.15 mg, from 1.1 mg to 1.35 mg, from 1.3 mg to 1.5 mg, from 1.5 mg to 1.75 mg, from 1.75 mg to 1.95 mg, from 1.9 mg to 2.15 mg, from 2.1 mg to 2.35 mg, from 2.3 mg to 2.55 mg, from 2.5 mg to 2.75 mg, from 2.7 mg to 3.0 mg, from 2.9 mg to 3.15 mg, from 3.1 mg to 3.35 mg, from 3.3 mg to 3.5 mg, from 3.5 mg to 3.75 mg, from 3.7 mg to 4.0 mg, from 4.0 mg to 4.5 mg, from 4.5 mg to 5.0 mg, from 5.0 mg to 5.5 mg, from 5.5 mg to 6 .0 mg, from 6.0 mg to 6.5 mg, from 6.5 mg to 7.0 mg, from 7.0 mg to 7.5 mg, from 7.5 mg to 8.0 mg, from 8 .0 mg to 8.5 mg, from 8.5 mg to 9.0 mg, from 9.0 mg to 9.5 mg or from 9.5 mg to 10.0 mg. In some embodiments of the present invention, the amount of one or more total niraparib impurity or degradation product is about or less than about 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.25 mg, 0.5 mg , 0.7 mg, 0.9 mg, 1.1 mg, 1.3 mg, 1.5 mg, 1.7 mg, 1.9 mg, 2 mg, 2.3 mg, 2.5 mg, 2 .75 mg, 3.0 mg, 3.1 mg, 3.3 mg, 3.5 mg, 3.7 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6 .0 mg, 6.5 mg,

- 53 044464

7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, or 10.0 mg.

In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt.%, 0.05 wt.%, 0.04 wt.%, 0.03 wt.%, 0.02 wt.%, 0.01 wt.%, 0.005 wt.% or 0.001 wt.% of one or more degradation products after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at a temperature of 5°C. In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt.%, 0.05 wt.%, 0.04 wt.%, 0.03 wt.%, 0.02 wt.%, 0.01 wt.%, 0.005 wt.% or 0.001 wt.% of one or more degradation products after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at a temperature of 25°C and a relative humidity of 60% (rel. ow.). In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt.%, 0.05 wt.%, 0.04 wt.%, 0.03 wt.%, 0.02 wt.%, 0.01 wt.%, 0.005 wt.% or 0.001 wt.% of one or more degradation products after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at a temperature of 30°C and a relative humidity of 65% (rel. ow.). In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt.%, 0.05 wt.%, 0.04 wt.%, 0.03 wt.%, 0.02 wt.%, 0.01 wt.%, 0.005 wt.% or 0.001 wt.% of one or more degradation products after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at a temperature of 40°C and a relative humidity of 75% (rel. ow.).

In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.05 wt.%, 0.025 wt.% or 0.001 wt. .% of one degradation product after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at 5°C. In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.05 wt.%, 0.025 wt.% or 0.001 wt. .% of one degradation product after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at 25°C and 60% relative humidity (r.h.). In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.05 wt.%, 0.025 wt.% or 0.001 wt. .% of one degradation product after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at 30°C and 65% relative humidity (r.h.). In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.05 wt.%, 0.025 wt.% or 0.001 wt. .% of one degradation product after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at 40°C and 75% relative humidity (r.h.).

In some embodiments, the present invention provides an oral dosage form comprising niraparib and a pharmaceutically acceptable nosie

- 54 044464 body, wherein the specified dosage form demonstrates the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt.%, 1.2 wt.%, 1.1 wt.%, 1 ,0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.%, 0.5 wt.%, 0.4 wt.%, 0, 3 wt%, 0.2 wt%, 0.1 wt%, 0.05 wt%, 0.025 wt%, or 0.001 wt% total degradation products, including niraparib degradation products, after storage for 1 month , 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at 5°C. In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.05 wt.%, 0.025 wt.% or 0.001 wt. .% of total degradation products, including niraparib degradation products, after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at 25°C and 60% relative humidity (r.h. ). In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.05 wt.%, 0.025 wt.% or 0.001 wt. .% total degradation products, including niraparib degradation products, after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at 30°C and 65% relative humidity (r.h. ). In some embodiments, the present invention relates to an oral dosage form containing niraparib and a pharmaceutically acceptable carrier, wherein the dosage form exhibits the formation of less than 1.5 wt.%, 1.4 wt.%, 1.3 wt. %, 1.2 wt.%, 1.1 wt.%, 1.0 wt.%, 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.% , 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.05 wt.%, 0.025 wt.% or 0.001 wt. .% of total degradation products, including niraparib degradation products, after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 24 months or 36 months at 40°C and 70% relative humidity (r.h. ).

In some embodiments of the present invention, the composition contains less than 10% by weight water. In some embodiments of the present invention, the composition contains less than 10 wt.% water after storage for 1 month at a temperature of 40°C and 75% relative humidity (RH). In some embodiments of the present invention, the composition contains less than 10 wt.% water after storage for 2 months at a temperature of 40°C and 75% relative humidity (RH).

In some embodiments of the present invention, the composition contains less than 30 wt%, 25 wt%, 20 wt%, 15 wt%, 10 wt%, 9 wt%, 8 wt%, 7 wt%, 6 wt%, 5 wt%, 4 wt%, 3 wt%, 2 wt%, 1 wt%, 0.5 wt% or 0.1 wt% water. In some embodiments of the present invention, the composition contains about 30 wt%, 25 wt%, 20 wt%, 15 wt%, 10 wt%, 9 wt%, 8 wt%, 7 wt%, 6 wt%, 5 wt%, 4 wt%, 3 wt%, 2 wt%, 1 wt%, 0.5 wt% or 0.1 wt% water. In some embodiments of the present invention, the composition contains less than 30 wt%, 25 wt%, 20 wt%, 15 wt%, 10 wt%, 9 wt%, 8 wt%, 7 wt%, 6 wt%, 5 wt%, 4 wt%, 3 wt%, 2 wt%, 1 wt%, 0.5 wt% or 0.1 wt% water after storage for 1 month at a temperature of 40°C and a relative humidity of 75% (r.h.). In some embodiments of the present invention, the composition contains about 30 wt%, 25 wt%, 20 wt%, 15 wt%, 10 wt%, 9 wt%, 8 wt%, 7 wt%, 6 wt%, 5 wt%, 4 wt%, 3 wt%, 2 wt%, 1 wt%, 0.5 wt% or 0.1 wt% water after storage for 1 month at a temperature of 40°C and a relative humidity of 75% (r.h.). In some embodiments of the present invention, the composition contains less than 30 wt%, 25 wt%, 20 wt%, 15 wt%, 10 wt%, 9 wt%, 8 wt%, 7 wt%, 6 wt%, 5 wt%, 4 wt%, 3 wt%, 2 wt%, 2 wt%, 0.5 wt% or 0.1 wt% water after storage for 2 months at a temperature of 40°C and a relative humidity of 75% (r.h.). In some embodiments of the present invention, the composition contains about 30 wt%, 25 wt%, 20 wt%, 15 wt%, 10 wt%, 9 wt%, 8 wt%, 7 wt%, 6 wt%, 5 wt%, 4 wt%, 3 wt%, 2 wt%, 2 wt%, 0.5 wt% or 0.1 wt% water after storage for 2 months at a temperature of 40°C and a relative humidity of 75% (r.h.). In some embodiments of the present invention, the composition contains less than 30 wt%, 25 wt%, 20 wt%, 15 wt%, 10 wt%, 9 wt%, 8 wt%, 7 wt%, 6 wt%, 5 wt%, 4 wt%, 3 wt%, 2 wt%, 36 wt%, 0.5 wt% or 0.1 wt% water after storage for 3 months , 6 months, 9 months, 12 months, 24 months or 36 months at a temperature of 40°C and a relative humidity of 75% (r.h.). In some embodiments of the present invention, the composition contains about 30 wt%, 25 wt%, 20 wt%, 15 wt%, 10 wt%, 9 wt%, 8 wt%, 7 wt%, 6 wt%, 5 wt%, 4 wt%, 3 wt%, 2 wt%, 36 wt%, 0.5 wt% or 0.1 wt% water after storage for 3 months , 6 months, 9 months, 12 months, 24 months or 36 months at a temperature of 40°C and a relative humidity of 75% (r.h.).

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Pills

In some embodiments of the present invention, said pharmaceutical composition is formulated into solid pharmaceutical dosage forms for oral administration. Solid pharmaceutical dosage forms for oral administration include, but are not limited to, tablets, capsules, powders, granules and sachets. For example, said solid pharmaceutical dosage form for oral administration may be a tablet.

In some embodiments of the present invention, the therapeutically effective amount of niraparib or a pharmaceutically acceptable salt thereof administered to a subject via a solid dosage form is in the range of from about 1 mg to about 2000 mg. In some embodiments of the present invention, the therapeutically effective amount of niraparib or a pharmaceutically acceptable salt thereof administered to a subject via a solid dosage form is in the range of from about 1 mg to about 1000 mg. In some embodiments of the present invention, the therapeutically effective amount of niraparib or a pharmaceutically acceptable salt thereof administered to a subject via a solid dosage form is in the range of from about 50 mg to about 300 mg. In some embodiments of the present invention, the niraparib dosage form is administered as a solid dosage form at a concentration of from about 50 mg to about 100 mg. In some embodiments of the present invention, the niraparib dosage form is administered as a solid dosage form at a concentration of from about 100 mg to about 300 mg. For example, a therapeutically effective amount of niraparib or a pharmaceutically acceptable salt thereof administered to a subject via a solid dosage form may be from about 1 mg to 5 mg, from 5 mg to 10 mg, from 10 mg to 20 mg, from 20 mg to 25 mg. , from 35 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg to 175 mg, from 170 mg to 195 mg, from 190 mg to 215 mg, from 210 mg to 235 mg, from 230 mg to 255 mg, from 250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from 330 mg to 355 mg, from 350 mg to 375 mg, from 370 to 400 mg, from 400 to 450 mg, from 450 to 500 mg, from 500 mg to 550 mg, from 550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg or from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to

1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from

1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg to 1550 mg, from 1550 mg to

1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from

1800 mg to 1850 mg, 1850 mg to 1900 mg, 1900 mg to 1950 mg, or 1950 mg to 2000 mg. For example, a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form may be from about 1 mg to about 2000 mg, such as from about 1 mg to 5 mg, from 5 mg to 10 mg, from 10 mg to 20 mg, from 20 mg to 25 mg, from 25 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg , from 150 mg to 175 mg, from 170 mg to 195 mg, from 190 mg to 215 mg, from 210 mg to 235 mg, from 230 mg to

255 mg, from 250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from 330 mg to

355 mg, from 350 mg to 375 mg, from 370 mg to 400 mg, from 400 mg to 450 mg, from 450 mg to 500 mg, from 500 mg to

550 mg, from 550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to

800 mg, from 800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from

1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to

1500 mg, from 1500 mg to 1550 mg, from 1550 mg to 1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from

1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg to 1850 mg, from 1850 mg to 1900 mg, from 1900 mg to

1950 mg or from 1950 mg to 2000 mg. In some aspects of the present invention, the oral solid dosage form may be administered once (1 time per day), twice (2 times per day) or three times per day (3 times per day).

For example, a therapeutically effective amount of niraparib or a pharmaceutically acceptable salt thereof administered to a subject via a solid dosage form may be from about 1 mg to 5 mg, from 5 mg to 10 mg, from 10 mg to 20 mg, from 20 mg to 25 mg. , from 25 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg to 175 mg, from 170 mg to 195 mg, from 190 mg to 215 mg, from 210 mg to 235 mg, from 230 mg to 255 mg, from

250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from 330 mg to 355 mg, from

350 mg to 375 mg, from 370 to 400 mg, from 400 to 450 mg, from 450 to 500 mg, from 500 mg to 550 mg, from 550 mg to

600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to

850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg to 1550 mg , from 1550 mg to 1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg to 1850 mg, from 1850 mg to 1900 mg, from 1900 mg to 1950 mg or from 1950 mg to

- 56 044464

2000 mg. For example, a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form may be from about 1 mg to 5 mg, from 5 mg to 10 mg, from 10 mg to 20 mg, from 20 mg to 25 mg, from 25 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg to 175 mg, from 170 mg up to 195 mg, from 190 mg to 215 mg, from 210 mg to 235 mg, from 230 mg to 255 mg, from 250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from 330 mg to 355 mg, from 350 mg to 375 mg, from 370 to 400 mg, from 400 to 450 mg, from 450 to 500 mg, from 500 mg to 550 mg, from 550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to

1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from

1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg to 1550 mg, from 1550 mg to

1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from

1800 mg to 1850 mg, 1850 mg to 1900 mg, 1900 mg to 1950 mg, or 1950 mg to 2000 mg. In some aspects of the present invention, the oral solid dosage form may be administered once (1 time per day), twice (2 times per day) or three times per day (3 times per day).

For example, a therapeutically effective amount of niraparib or a pharmaceutically acceptable salt thereof administered to a subject via a solid dosage form may be about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg , from 25 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg to 175 mg, from 170 mg to 195 mg, from 190 mg to 215 mg, from 210 mg to 235 mg, from 230 mg to 255 mg, from 250 mg to

275 mg, from 270 mg to 300 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from 330 mg to 355 mg, from 350 mg to

375 mg, from 370 to 400 mg, from 400 to 450 mg, from 450 to 500 mg, from 500 mg to 550 mg, from 550 mg to 600 mg, from

600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to 850 mg, from

850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg to 1550 mg, from 1550 mg up to 1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg to 1850 mg, from 1850 mg to 1900 mg, from 1900 mg to 1950 mg or from 1950 mg to 2000 mg. For example, a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form may be about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 35 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg to 175 mg, from 170 mg up to 195 mg, from 190 mg to 215 mg, from 210 mg to 235 mg, from 230 mg to 255 mg, from 250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from 330 mg to 355 mg, from 350 mg to 375 mg, from 370 to 400 mg, from 400 to 450 mg, from 450 to 500 mg, from 500 mg to 550 mg, from 550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to

1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from

1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg to 1550 mg, from 1550 mg to

1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from

1800 mg to 1850 mg, 1850 mg to 1900 mg, 1900 mg to 1950 mg, or 1950 mg to 2000 mg. In some embodiments of the present invention, the therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form is about 159.4 mg. In some embodiments of the present invention, the therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form is about 318.8 mg. In some embodiments of the present invention, the therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form is about 478.0 mg. In some aspects of the present invention, the oral solid dosage form may be administered once (1 time per day), twice (2 times per day) or three times per day (3 times per day).

The compositions of the present invention provide a therapeutically effective amount of niraparib or a pharmaceutically acceptable salt thereof within a range of from about 30 minutes to about 8 hours after administration, allowing for administration, for example, once daily, twice daily, three times daily, etc. etc., if necessary.

In some embodiments of the present invention, the tablet is made using materials that include, but are not limited to, natural or synthetic gelatin, pectin, casein, collagen, protein, modified starch, polyvinylpyrrolidone, acrylic polymers, cellulose derivatives, or combinations thereof. In some embodiments, the tablet is formulated with preservatives, coloring and opacifying agents, flavoring and sweetening agents, sugars, gastric acid resistant agents, or combinations thereof. In some embodiments of the present invention,

- 57 044464 The filled tablet is coated. In some embodiments of the present invention, the coating covering the tablet includes, but is not limited to, immediate release coatings, barrier coatings, enteric or delayed release coatings, sustained release coatings, barrier coatings, barrier coatings, or combinations thereof. The term coating refers to the process by which an outer layer of coating material is applied to the surface of a dosage dosage form to provide it with certain advantages over the uncoated variety. This involves applying a coating, including sugar or polymer coatings, to the dosage form. Coating tablets provides the benefits of off-flavor masking, off-odor masking, physical and chemical protection, protecting the drug in the stomach, and controlling its release profile. Coating can be applied to a wide range of solid oral dosage forms such as particles, powders, granules, crystals, pellets and tablets. When the coating composition is applied to a batch of tablets in a coating apparatus, the surfaces of the tablets are coated with a polymer film.

Film coatings

In some embodiments of the present invention, said tablets may further comprise an optional film coating. In some embodiments of the present invention, the film coating contains water-soluble polymer(s) and does not affect the immediate release or change the durability of the composition.

In some embodiments of the present invention, said film coating comprises a polymer, pigment, plasticizer, flavoring agents, surfactants, adhesion promoters, carrier(s), and any combination thereof. In some embodiments of the present invention, said film coating comprises a polymer, a pigment, and a plasticizer.

In some embodiments of the present invention, said film coating comprises saccharide, polydextrose, maltodextrin, lactose, waxes, cellulose derivatives, cellulose ethers, acrylic polymers and copolymers, polyethylene glycols, polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and any combination thereof . In some embodiments of the present invention, said film coating comprises polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, and any combination thereof.

In some embodiments of the present invention, said film coating includes polyols such as glycerin, propylene glycol, macrogols, organic esters such as phthalate esters, dibutyl sebacetate, citric acid esters, triacetin, oils/glycerides such as castor oil, acetylated monoglycerides, fractionated coconut oil, and any combination thereof.

In some embodiments of the present invention, said film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, ferrous oxide, and any combination thereof.

In some embodiments of the present invention, the film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, FD&C Blue #2/indigo carmine aluminum varnish, and any combination thereof.

In some embodiments, the film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, FD&C Blue #1/FCF Blue Aluminum Varnish, and any combination thereof.

In some embodiments, said film coating comprises organic dyes and varnishes thereof, inorganic dyes, natural dyes, and any combination thereof.

In some embodiments of the present invention, said film coating comprises Opadry®, Opadry® II, Opadry® QX, Opadry® SGR, Opadry® AMB, Opadry® fx ^tm , Opadry® ns-g, Opadry® NS, Opadry® tm, Opalux® , Opadry® EZ and any combination thereof.

In some embodiments of the present invention, said film coating comprises a dispersion prepared using various solvents, such as water, alcohols, ketones, esters, chlorinated hydrocarbons, and any combinations thereof. In some embodiments of the present invention, the dispersion contains water and alcohols. In some embodiments of the present invention, said dispersion contains water.

In some embodiments of the present invention, said film coating comprises Opadry® II. In some embodiments of the present invention, said Opadry® II is present in an amount of from about 0.1 wt.% to about 10 wt.%. In some embodiments of the present invention, said Opadry® II is present in an amount of from about 0.1 wt.% to about 5 wt.%. In some embodiments of the present invention, said Opadry® II is present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about

- 58 044464

0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt .%, about 1.5 wt.%, about 2 wt.%, about 2.5 wt.%, about 3 wt.%, about 3.5 wt.%, about 4 wt.%, about 4.5 wt. .% or about 5 wt.%.

In some embodiments of the present invention, the tablet is crushed into particles that are sprinkled onto soft food and swallowed without chewing. In some embodiments of the present invention, the shape and size of said tablet also vary. In some embodiments of the present invention, the pharmaceutical composition described herein (eg, a tablet) is swallowed whole. In some embodiments of the present invention, the pharmaceutical composition described herein is not a film. In some embodiments of the present invention, the pharmaceutical composition described herein is not intended for buccal administration. In some embodiments of the present invention, the pharmaceutical composition described herein (eg, a tablet) dissolves in the stomach or intestines.

One aspect of the present disclosure relates to a composition comprising a tablet comprising: an effective amount of niraparib to inhibit poly(ADP-ribose) polymerase (PARP) when administered to a subject in need thereof; wherein said tablet is characterized by at least one of the following: a) a net weight of at least 200, 500 or 800 mg; b) a thickness of at least 4.0 mm; and c) friability less than 2%; wherein said effective amount of niraparib is from about 50 mg to about 350 mg based on niraparib free base.

In some embodiments of the present invention, the effective amount of niraparib is from about 75 mg to about 125 mg based on niraparib free base. In some embodiments, the effective amount of niraparib is about 50 mg, about 100 mg, or about 150 mg based on niraparib free base. In some embodiments of the present invention, said effective amount of niraparib is about 100 mg based on niraparib free base.

In some embodiments of the present invention, the net weight of a tablet described herein is at least 200 mg, at least 210 mg, at least 220 mg, at least 230 mg, at least 240 mg, at least 250 mg, at least 260 mg, at least 270 mg, at least 280 mg, at least 290 mg, at least 300 mg, at least 310 mg, at least 320 mg, at least 330 mg, at least at least 340 mg, at least 350 mg, at least 360 mg, at least 370 mg, at least 380 mg, at least 390 mg, at least 400 mg, at least 410 mg, at least 420 mg, at least 430 mg, at least 440 mg, at least 450 mg, at least 460 mg, at least 470 mg, at least 480 mg, at least 490 mg or at least 500 mg. In some embodiments of the present invention, the net weight of the tablet described herein is at least 300 mg.

In some embodiments of the present invention, the effective amount of niraparib is from about 175 mg to about 225 mg based on niraparib free base. In some embodiments, the effective amount of niraparib is about 150 mg, about 200 mg, or about 250 mg based on niraparib free base. In some embodiments of the present invention, said effective amount of niraparib is about 200 mg based on niraparib free base.

In some embodiments of the present invention, the net weight of a tablet described herein is at least 500 mg, at least 510 mg, at least 520 mg, at least 530 mg, at least 540 mg, at least 550 mg, at least

560 mg, at least 570 mg, at least 580 mg, at least 590 mg, at least

600 mg, at least 610 mg, at least 620 mg, at least 630 mg, at least

640 mg, at least 650, at least 660 mg, at least 670 mg, at least 680 mg, at least 690 mg, at least 700 mg, at least 710 mg, at least

720 mg, at least 730 mg, at least 740 mg, at least 750 mg, at least

760 mg, at least 770 mg, at least 780 mg, at least 790 mg or at least 800 mg. In some embodiments of the present invention, the net weight of said tablet is at least 600 mg.

In some embodiments of the present invention, the effective amount of niraparib is from about 275 mg to about 325 mg based on niraparib free base. In some embodiments, the effective amount of niraparib is about 250 mg, about 300 mg, or about 350 mg based on niraparib free base. In some embodiments of the present invention, said effective amount of niraparib is about 300 mg based on niraparib free base.

In some embodiments of the present invention, the net weight of a tablet described herein is at least 800 mg, at least 810 mg, at least

- 59 044464

820 mg, at least 830 mg, at least 840 mg, at least 850 mg, at least

860 mg, at least 870 mg, at least 880 mg, at least 890 mg, at least

900 mg, at least 910 mg, at least 920 mg, at least 930 mg, at least

940 mg, at least 950 mg, at least 960 mg, at least 970 mg, at least

980 mg, at least 990 mg, at least 1000 mg, at least 1010 mg, at least

1020 mg, at least 1030 mg, at least 1040 mg, at least 1050 mg, at least 1060 mg, at least 1070 mg, at least 1080 mg, at least 1090 mg, at least 1100 mg , at least 1110 mg, at least 1120 mg, at least 1130 mg, at least 1140 mg, at least 1150 mg, at least 1160 mg, at least 1170 mg, at least 1180 mg, according to at least 1190 mg or at least 1200 mg. In some embodiments of the present invention, the net weight of a tablet described herein is about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg or about 1200 mg. In some embodiments of the present invention, the net weight of said tablet is at least 1000 mg.

In some embodiments of the present invention, the thickness of said tablet is at least 4.0 mm, at least 4.1 mm, at least 4.2 mm, at least 4.3 mm, at least 4.4 mm, at least 4.5 mm, at least 4.6 mm, at least 4.7 mm, less less less less less less less than

4.8

5.2

5.6

6.0

6.4

6.8

7.2

mm

4.9

5.3

5.7

6.1

6.5

6.9

7.3

mm

5.0

5.4

5.8

6.2

6.6

7.0

7.4

7.8 mm, mm, mm, mm, mm, mm, mm, mm, according to according to at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least at least 8.0 mm, at least 8.5 mm, at least 9.0 mm, at least 9.5

5.1

5.5

5.9

6.3

6.7

7.1

7.5

7.9 mm mm, mm, mm, mm, mm, mm, mm, mm, or at least 10 mm. In some embodiments of the present invention, the thickness of the tablet is about 4.5 mm, about 4.6 mm, about 4.7 mm, about 4.8 mm, about 4.9 mm, about 5.0 mm, about 5.1 mm, approximately 5.2 mm, approximately 5.3 mm, approximately 5.4 mm, approximately 5.5 mm, approximately 5.6 mm, approximately 5.7 mm, approximately 5.8 mm, approximately 5.9 mm, approximately 6.0 mm, approximately 6.1 mm, approximately 6.2 mm, approximately 6.3 mm, approximately 6.4 mm, approximately 6.5 mm, approximately 6.6 mm, approximately 6.7 mm, approximately 6 ,8, approximately 6.9 mm, approximately 7.0 mm, approximately 7.1 mm, approximately 7.2 mm, approximately 7.3 mm, approximately 7.4 mm, approximately 7.5 mm, approximately 7.6 mm , about 7.7 mm, about 7.8 mm, about 7.9 mm, about 8.0 mm, about 8.5 mm, about 9.0 mm, about 9.5 mm or about 10 mm.

In some embodiments of the present invention, the friability of a tablet described herein is less than 2%, less than 1.9%, less than 1.8%, less than 1.7%, less than 1.6%, less than 1.5%, less 1.4%, less than 1.3%, less than 1.2%, less than 1.1%, less than 1.0%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0, 6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2% or less than 0.1%.

In some embodiments of the present invention, the net weight of a tablet described herein is in the range of 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to mg, 35 mg to 50 mg, from 50 mg to 75 mg, from 70

130

230

330

500

750 mg mg mg mg mg to to to to to

155

255

355

550

800 mg, mg, mg, mg, mg, from from from from from

150

250

350

550 mg mg mg mg to to to to

175

275

375

600 mg, mg, mg, mg, from from from from

170

270

370

600 mg mg mg mg mg to to to to to to 95 mg, from 90 mg to 115 mg, from 110

195

300

400

650 mg, mg, mg, mg, from from from from

190

290

400

650 mg mg mg mg to to to to

215

315

450

700 mg, mg, mg, mg, from 210 from 310 from 450 from 700 mg mg mg mg mg to to to to to to

135

235

335

500

750

800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950

1000 mg up to

1250 mg, from

1450 mg up

1700 mg, from

1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200

1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to 1400 mg, from 1400

1500 mg, from 1500 mg to 1550 mg, from 1550 mg to 1600 mg, from 1600 mg to 1650 mg to mg, from mg to mg, from

1000 mg, mg, mg, mg, mg, mg,

1200 mg 1450 mg, 1650 mg from from from from from from to from to

1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg from 18 to 1850 mg, from 1850 mg to 1900 mg, from 1900 mg to 1950 mg or from 1950 mg to 2000 mg. For example, the net weight of a tablet described herein may range from about 50 mg to about 150 mg, from about 75 mg to about 125 mg, from about 90 mg to about 110 mg, from about 93 mg to about 107 mg, from about 94 mg to about 106 mg or from about 95 mg to about 105 mg. In other cases, the net weight of the tablet described herein ranges from about 850 mg to 900 mg, from about 900 mg to about 950 mg, from about 950 mg to 1000 mg, from about 1000 mg to about 1050 mg, from about 1050 mg to about 1100 mg, from about 1100 mg to 1150 mg, from about

- 60 044464

1150 mg to 1200 mg, from about 1200 mg to 1250 mg, from about 1250 mg to 1300 mg, from about

1300 mg to 1350 mg, from about 1350 mg to 1400 mg, from about 1400 mg to 1450 mg, from about

1450 mg to 1500 mg, from about 1500 mg to 1550 mg, from about 1550 mg to 1600 mg, from about

1600 mg to 1650 mg, from about 1650 mg to about 1700 mg, from about 1700 to about 1750 mg, from about 1750 mg to 1800 mg, from about 1800 mg to about 1850 mg, from about 1850 mg to 1900 mg, from about 1900 mg to about 1950 mg or from about 1950 mg to 2000 mg.

In some embodiments of the present invention, the net weight of a tablet described herein is about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg , 200 mg, 225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg , 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg,

1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg , 1900 mg, 1950 mg or 2000 mg. For example, the net weight of a tablet described herein may be about 100 mg, about 98 mg, about 96 mg, about 94 mg, about 92 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, or about 50 mg . In other cases, the net weight of the tablet described herein ranges from about 1050 mg, 1040 mg, 1030 mg, 1020 mg, 1010 mg, about 1000 mg, about 990 mg, about 980 mg, about 970 mg, about 960 mg, about 950 mg or about 940 mg.

In some embodiments of the present invention, said niraparib comprises niraparib free base or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of niraparib is niraparib tosylate.

Said method may comprise administering said niraparib composition in 1, 2, 3 or 4 tablets one, two or three times a day; for example 1, 2 or 3 tablets.

In some embodiments of the present invention, the weight ratio of active pharmaceutical ingredient (e.g., niraparib or a pharmaceutically acceptable salt thereof, such as niraparib tosylate monohydrate) to inactive pharmaceutical ingredient (e.g., lactose monohydrate, lactose anhydrous, mannitol, or dibasic calcium phosphate) is from about 1 :10 to about 10:1, respectively, for example about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9 , about 1:10, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1 or about 2:1 . In some embodiments of the present invention, the weight ratio of active pharmaceutical ingredient (e.g., niraparib or a pharmaceutically acceptable salt thereof, such as niraparib tosylate monohydrate) to inactive pharmaceutical ingredient (e.g., microcrystalline cellulose, starch, polyethylene oxide, or hydroxypropyl methylcellulose (HPMC)) is from about 1 :10 to about 10:1, respectively, for example about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9 , about 1:10, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1 or about 2:1 . In some embodiments of the present invention, the weight ratio of active pharmaceutical ingredient (e.g., niraparib or a pharmaceutically acceptable salt thereof, such as niraparib tosylate monohydrate) to inactive pharmaceutical ingredient (e.g., povidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose) is from about 10:1 to about 100: 1, respectively, for example, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, or about 90:1. In some embodiments of the present invention, the weight ratio of active pharmaceutical ingredient (e.g., niraparib or a pharmaceutically acceptable salt thereof, such as niraparib tosylate monohydrate) to inactive pharmaceutical ingredient (e.g., magnesium stearate) is from about 10:1 to about 100:1, respectively. for example, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, or about 90:1. In some embodiments of the present invention, the weight ratio of inactive pharmaceutical ingredient to active pharmaceutical ingredient (e.g., niraparib or a pharmaceutically acceptable salt thereof, such as niraparib tosylate monohydrate) is from about 3:2 to about 11:1, from about 3:1 to about 7:1, about 1:1 to about 5:1, about 9:2 to about 11:2, about 4:2 to about 6:2, about 5:1, or about 2.5:1. In some embodiments of the present invention, the weight ratio of active pharmaceutical ingredient (eg, niraparib or a pharmaceutically acceptable salt thereof, such as niraparib tosylate monohydrate) to inactive pharmaceutical ingredient is about 1:1.6. In some embodiments of the present invention, the weight ratio of active pharmaceutical ingredient (eg, niraparib or a pharmaceutically acceptable salt thereof, such as niraparib tosylate monohydrate) to inactive pharmaceutical ingredient is about 1:2. In some embodiments of the present invention, the weight ratio of active pharmaceutical ingredient (eg, niraparib or a pharmaceutically acceptable salt thereof, such as niraparib tosylate monohydrate) to inactive pharmaceutical ingredient is about 1:1.1. In some embodiments of the infusion

- 61 044464 of the present invention, the weight ratio of active pharmaceutical ingredient (eg, niraparib or a pharmaceutically acceptable salt thereof, such as niraparib tosylate monohydrate) to inactive pharmaceutical ingredient is approximately 1:1. In some embodiments of the present invention, the weight ratio of niraparib or a pharmaceutically acceptable salt thereof, such as niraparib tosylate monohydrate, to lactose monohydrate is about 48:20, such as 47.8:20.4. In some embodiments of the present invention, the weight ratio of niraparib or its pharmaceutically acceptable salt, such as niraparib tosylate monohydrate, to lactose monohydrate is approximately 48:19, for example 47.8:19.4. In some embodiments of the present invention, the weight ratio of niraparib or a pharmaceutically acceptable salt thereof, such as niraparib tosylate monohydrate, to lactose monohydrate is about 48:18, for example, 47.8:17.9. In some embodiments, the weight ratio of niraparib or a pharmaceutically acceptable salt thereof, such as niraparib tosylate monohydrate, to magnesium stearate is about 48:1, such as 47.8:1.

In some embodiments of the present invention, the weight ratio of the first inactive pharmaceutical ingredient to the second inactive pharmaceutical ingredient is from about 1:1 to about 200:1, such as about 1:1, about 2:1, about 3:1, about 4 :1, about 5:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70 :1, about 75:1, about 80:1, about 90:1, about 100:1, about 110:1, about 120:1, about 130:1, about 140:1, about 150:1, about 160 :1, about 170:1, about 180:1, about 190:1, or about 200:1. In some embodiments of the present invention, the weight ratio of lactose monohydrate to magnesium stearate is from about 120:1 to about 125:1. In some embodiments of the present invention, the weight ratio of lactose monohydrate to magnesium stearate is about 122.36:1. In some embodiments of the present invention, the weight ratio of lactose monohydrate to magnesium stearate is about 20:1. In some embodiments of the present invention, the weight ratio of lactose monohydrate to magnesium stearate is about 10:1

Indications for treatment

Any subject suffering from cancer can be treated using the compounds and methods described herein, including breast cancer, ovarian cancer, cervical cancer, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, stomach cancer, bladder cancer, lung cancer (eg adenocarcinoma, NSCLC and SCLC), bone cancer (eg osteosarcoma), colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancer, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma (eg, liposarcoma), bladder cancer, liver cancer (eg, hepatocellular carcinoma) , kidney cancer (eg, renal cell carcinoma), myeloid disorders (eg, AML, CML, myelodysplastic syndrome, and promyelocytic leukemia), and lymphoid disorders (eg, leukemia, multiple myeloma, mantle cell lymphoma, ALL, CLL, B-cell lymphoma, T -cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma).

In some embodiments, the methods of the present invention treat subjects with ovarian cancer. In some embodiments, the methods of the present invention treat subjects with epithelial ovarian cancer. In some embodiments, the methods of the present invention treat subjects with fallopian tube cancer. In some embodiments, the methods of the present invention treat subjects with primary peritoneal cancer.

In some embodiments, the methods of the present invention treat subjects with recurrent ovarian cancer. In some embodiments, the methods of the present invention treat subjects with recurrent epithelial ovarian cancer. In some embodiments, the methods of the present invention treat subjects with recurrent fallopian tube cancer. In some embodiments, the methods of the present invention treat subjects with recurrent primary peritoneal cancer.

In some embodiments, the methods of the present invention treat subjects with recurrent ovarian cancer after a complete or partial response to chemotherapy, such as platinum-based chemotherapy. In some embodiments, the methods of the present invention treat subjects with recurrent epithelial ovarian cancer after a complete or partial response to chemotherapy, such as platinum-based chemotherapy. In some embodiments, the methods of the present invention treat subjects with recurrent fallopian tube cancer after a complete or partial response to chemotherapy, such as platinum-based chemotherapy. In some embodiments of the present invention, the methods of the present invention treat subjects with recurrent primary peritoneal cancer after a complete or partial response to

- 62 044464 chemotherapy, such as platinum-based chemotherapy.

In some embodiments of the present invention, the methods of the present invention treat subjects with recurrent ovarian cancer, recurrent epithelial ovarian cancer, recurrent fallopian tube cancer, and/or recurrent primary peritoneal cancer after a complete or partial response to platinum-based chemotherapy, where the subjects begin receiving treatment without later than 8 weeks after the last treatment regimen with platinum-containing drugs. For example, subjects may begin treatment with niraparib approximately 7 weeks after their last platinum-containing regimen. For example, subjects may begin treatment with niraparib approximately 6 weeks after their last platinum-containing regimen. For example, subjects may begin treatment with niraparib approximately 6 weeks after their last platinum-containing regimen. For example, subjects may begin treatment with niraparib approximately 5 weeks after their last platinum-containing regimen. For example, subjects may begin treatment with niraparib approximately 4 weeks after their last platinum-containing regimen. For example, subjects may begin treatment with niraparib approximately 3 weeks after their last platinum-containing regimen. For example, subjects may begin treatment with niraparib approximately 2 weeks after their last platinum-containing regimen. For example, subjects may begin treatment with niraparib approximately 1 week after their last platinum-containing regimen.

In some embodiments, the methods of the present invention treat subjects with prostate cancer.

In some embodiments, the methods of the present invention treat subjects with pediatric prostate cancer. Typical pediatric cancers include, but are not limited to, the following: adrenocortical carcinoma, astrocytoma, atypical teratoid rhabdoid tumor, brain tumors, chondroblastoma, choroid plexus tumor, craniopharyngioma, desmoid tumor, dysembryoplastic neuroepithelial tumor (DNT), ependymoma, fibrosarcoma, embryonal -cell brain tumor, glioblastoma multiforme, diffuse pontine glioma, low-grade glioma, gliomatosis cerebri, hepatoblastoma, histiocytosis, kidney tumor, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), liposarcoma, liver cancer, Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant fibrous histiocytoma, melanoma, myelodysplastic syndrome, nephroblastoma, neuroblastoma, neurofibrosarcoma, osteosarcoma, pilocytic astrocytoma, retinoblastoma, renal rhabdoid tumor, rhabdomyosarcoma, sarcoma Inga, soft tissue sarcoma, synovial sarcoma, spinal cord tumor and Wilm's tumor.

In some embodiments of the present invention, the methods of the present invention treat subjects suffering from cancer with a dosage of niraparib or a pharmaceutically acceptable salt thereof of 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg or 2000 mg, once daily, twice daily day or three times a day. In some embodiments of the present invention, the methods of the present invention treat patients suffering from cancer with a dosage of niraparib or a pharmaceutically acceptable salt thereof of 150 mg to 175 mg, 170 mg to 195 mg, 190 mg to 215 mg, 210 mg up to 235 mg, from 230 mg to 255 mg, from 250 mg to 275 mg, from 270 mg to 295 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from 330 mg to 355 mg, from 350 mg to 375 mg or 370 mg to 400 mg, once daily, twice daily or three times daily. In some embodiments of the present invention, the methods of the present invention treat patients suffering from cancer with a dosage of niraparib or a pharmaceutically acceptable salt thereof of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, mg, 27.5 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg , 90 mg, 95 mg or 100 mg, once daily, twice daily or three times daily.

In some embodiments of the present invention, the methods of the present invention treat patients suffering from cancer with a dosage of niraparib or a pharmaceutically acceptable salt thereof of about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, from 35 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg up to 175 mg, from 170 mg to 195 mg, from 190 mg to 215 mg, from 210 mg to 235 mg, from

230 mg to 255 mg, from 250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from

330 mg to 355 mg, from 350 mg to 375 mg, from 370 mg to 400 mg, from 400 mg to 450 mg, from 450 mg to 500 mg, from

500 mg to 550 mg, from 550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from

750 mg to 800 mg, from 800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to

- 63 044464 approximately 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg to 1550 mg, from 1550 mg to 1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg to 1850 mg, from 1850 mg to 1900 mg, from 1900 mg to 1950 mg or from 1950 mg to 2000 mg, once daily, twice daily or three times daily. In some embodiments of the present invention, the methods of the present invention treat patients suffering from cancer with a dosage of niraparib or a pharmaceutically acceptable salt thereof of about 5 mg to 7.5 mg, 7 mg to 9.5 mg, 9 mg to 11 .5 mg, from 11 mg to 13.5 mg, from 13 mg to 15.5 mg, from 15 mg to 17.5 mg, from 17 mg to 19.5 mg, from 19 mg to 21.5 mg, from 21 mg to 23.5 mg, from 23 mg to 25.5 mg, from 25 mg to 27.5 mg, from 27 mg to 30 mg, from 30 mg to 35 mg, from 35 mg to 40 mg, from 40 mg up to 45 mg, from 45 mg to 50 mg, from 50 mg to 55 mg, from 55 mg to 60 mg, from 60 mg to 65 mg, from 65 mg to 70 mg, from 70 mg to 75 mg, from 75 mg to 80 mg, 80 mg to 85 mg, 85 mg to 90 mg, 90 mg to 95 mg, or 95 mg to 100 mg, once daily, twice daily, or three times daily.

Introduction of the composition

One of the recommended dosages of niraparib described herein (eg, as monotherapy) is three 100 mg doses taken orally once daily, equivalent to a total daily dose of 300 mg. Patients may be advised to take their dose at approximately the same time each day. Administration at bedtime may potentially help control nausea.

As described herein, doses of 1 to 2000 mg of niraparib or a pharmaceutically acceptable salt thereof may be administered to treat subjects, and the methods and compositions described herein may include once daily, twice daily, or three times daily administration. daily doses up to 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, from 250 mg to 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg , 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg or 2000 mg once daily, twice daily or three times daily. In some embodiments of the present invention, the dose of niraparib or a pharmaceutically acceptable salt thereof is from 1 mg to 5 mg, from 5 mg to 10 mg, from 10 mg to 20 mg, from 20 mg to 25 mg, from 35 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg to 175 mg, from 170 mg to 195 mg, from 190 mg to 215 mg, from 210 mg to 235 mg, from 230 mg to 255 mg, from 250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from 330 mg up to 355 mg, from 350 mg to

375 mg, from 370 mg to 400 mg, from 400 mg to 450 mg, from 450 mg to 500 mg, from 500 mg to 550 mg, from 550 mg to

600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to

850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg to 1550 mg , from 1550 mg to 1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg to 1850 mg, from 1850 mg to 1900 mg, 1900 mg to 1950 mg or 1950 mg to 2000 mg once daily, twice daily or three times daily. In some embodiments of the present invention, the methods of the present invention treat subjects suffering from cancer with a dosage of niraparib or a pharmaceutically acceptable salt thereof of 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 1θ0 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg or 2000 mg, once daily, twice daily day or three times a day.

In some embodiments of the present invention, the total daily dose of niraparib or a pharmaceutically acceptable salt thereof is from 1 mg to 2000 mg. In some embodiments of the present invention, a total daily dose of niraparib or a pharmaceutically acceptable salt thereof is administered, ranging from 1 mg to 1000 mg, for example, from 50 mg to 300 mg. In some embodiments of the present invention, the total daily dose of niraparib or a pharmaceutically acceptable salt thereof is greater than 100 mg per day. In some embodiments of the present invention, the total daily dose of niraparib or a pharmaceutically acceptable salt thereof is greater than 200 mg per day. In some embodiments of the present invention, the total daily dose of niraparib or a pharmaceutically acceptable salt thereof is greater than 300 mg per day. In some embodiments of the present invention, the total daily dose of niraparib or a pharmaceutically acceptable salt thereof is greater than 400 mg per day. In some embodiments of the present invention, the total daily dose of niraparib or a pharmaceutically acceptable salt thereof is greater than 500 mg per day.

In some embodiments of the present invention, the total daily dose of niraparib or a pharmaceutically acceptable salt thereof does not exceed 500 mg per day. In some embodiments of the present invention, the total daily dose of niraparib or a pharmaceutically acceptable salt thereof does not exceed 300 mg per day. In some embodiments of the present invention, the total daily

- 64 044464 the dose of niraparib or its pharmaceutically acceptable salt does not exceed 100 mg per day. In some embodiments of the present invention, the total daily dose of niraparib or a pharmaceutically acceptable salt thereof does not exceed 100 mg per day. In some embodiments of the present invention, the total daily dose of niraparib or a pharmaceutically acceptable salt thereof is about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 35 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg to 175 mg, from 170 mg to 195 mg , from 190 mg to 215 mg, from 210 mg to 235 mg, from 230 mg to 255 mg, from 250 mg to

275 mg, from 270 mg to 300 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from 330 mg to 355 mg, from 350 mg to

375 mg, from 370 mg to 400 mg, from 400 mg to 450 mg, from 450 mg to 500 mg, from 500 mg to 550 mg, from 550 mg to

600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to

850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg to 1550 mg , from 1550 mg to 1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg to 1850 mg, from 1850 mg to 1900 mg, from 1900 mg to 1950 mg or from 1950 mg to 2000 mg. The total daily dose of niraparib or a pharmaceutically acceptable salt thereof is approximately 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 to 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg , 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg, approximately 1350 mg, approximately 1400 mg, approximately 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg or about 2000 mg.

A therapeutically effective dose of niraparib or a pharmaceutically acceptable salt thereof may be about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg , 225 mg, from 250 to 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg, approximately 1350 mg, approximately 1400 mg, approximately 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg or about 2000 mg per day. In some embodiments of the present invention, the amount of niraparib or a pharmaceutically acceptable salt thereof administered daily is about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 35 mg up to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg to 175 mg, from 170 mg to 195 mg, from 190 mg to 215 mg, from 210 mg to 235 mg, from 230 mg to 255 mg, from

250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from 330 mg to 355 mg, from

350 mg to 375 mg, from 370 mg to 400 mg, from 400 mg to 450 mg, from 450 mg to 500 mg, from 500 mg to 550 mg, from

550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from

800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to

1300 mg, from 1300 mg to 1350 mg, from 1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from

1500 mg to 1550 mg, from 1550 mg to 1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to

1750 mg, from 1750 mg to 1800 mg, from 1800 mg to 1850 mg, from 1850 mg to 1900 mg, from 1900 mg to 1950 mg or from 1950 mg to 2000 mg per day.

In some embodiments of the present invention, the amount of niraparib or a pharmaceutically acceptable salt thereof administered once daily is from 1 mg to 5 mg, from 5 mg to 10 mg, from 10 mg to 20 mg, from 20 mg to 25 mg, from 35 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg to 175 mg, from 170 mg to 195 mg, from 190 mg to

215 mg, from 210 mg to 235 mg, from 230 mg to 255 mg, from 250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to

315 mg, from 310 mg to 335 mg, from 330 mg to 355 mg, from 350 mg to 375 mg, from 370 mg to 400 mg, from 400 mg to

450 mg, from 450 mg to 500 mg, from 500 mg to 550 mg, from 550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to

700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to

950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to

1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg to 1550 mg, from 1550 mg to 1600 mg, from

1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg to

1850 mg, from 1850 mg to 1900 mg, from 1900 mg to 1950 mg or from 1950 mg to 2000 mg. In some embodiments of the present invention, the amount of niraparib or a pharmaceutically acceptable salt thereof administered once daily is about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 to 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg,

- 65 044464 approximately 1300 mg, approximately 1350 mg, approximately 1400 mg, approximately 1450 mg, approximately 1500 mg, approximately 1550 mg, approximately 1600 mg, approximately 1650 mg, approximately 1700 mg, approximately 1750 mg, approximately 1800 mg, approximately 1850 mg , about 1900 mg, about 1950 mg, or about 2000 mg.

In some embodiments of the present invention, the amount of niraparib or a pharmaceutically acceptable salt thereof administered twice daily is from 1 mg to 5 mg, from 5 mg to 10 mg, from 10 mg to 20 mg, from 20 mg to 25 mg, from 35 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg to 175 mg, from 170 mg to 195 mg, from 190 mg to

215 mg, from 210 mg to 235 mg, from 230 mg to 255 mg, from 250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to

315 mg, from 310 mg to 335 mg, from 330 mg to 355 mg, from 350 mg to 375 mg, from 370 mg to 400 mg, from 400 mg to

450 mg, from 450 mg to 500 mg, from 500 mg to 550 mg, from 550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to

700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to

950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg to 1550 mg, from 1550 mg to 1600 mg, from 1600 mg to 1650 mg , from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg to 1850 mg, from 1850 mg to 1900 mg, from 1900 mg to 1950 mg or from 1950 mg to 2000 mg. In some embodiments of the present invention, the amount of niraparib or a pharmaceutically acceptable salt thereof administered twice daily is about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 to 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg , about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg or approximately 2000 mg.

In some embodiments of the present invention, the amount of niraparib or a pharmaceutically acceptable salt thereof administered three times daily is from 1 mg to 5 mg, from 5 mg to 10 mg, from 10 mg to 20 mg, from 20 mg to 25 mg, from 35 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg to 175 mg, from 170 mg to 195 mg, from 190 mg to

215 mg, from 210 mg to 235 mg, from 230 mg to 255 mg, from 250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to

315 mg, from 310 mg to 335 mg, from 330 mg to 355 mg, from 350 mg to 375 mg, from 370 mg to 400 mg, from 400 mg to

450 mg, from 450 mg to 500 mg, from 500 mg to 550 mg, from 550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to

700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to

950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to

1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg to 1550 mg, from 1550 mg to 1600 mg, from

1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg to

1850 mg, from 1850 mg to 1900 mg, from 1900 mg to 1950 mg or from 1950 mg to 2000 mg. In some embodiments of the present invention, the amount of niraparib or a pharmaceutically acceptable salt thereof administered three times daily is about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 to 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg , about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg or approximately 2000 mg.

In some embodiments of the present invention, the specified niraparib or a pharmaceutically acceptable salt thereof is present in a dose of from about 1 mg to about 2000 mg, including, but not limited to, the following: about 1 mg, 5 mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg,

19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 30.5 mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 34 mg, 34.5 mg, 35 mg, 35.5 mg, 36 mg, 36.5 mg, 37 mg, 37.5 mg, 38 mg, 38.5 mg, 39 mg, 39.5 mg, 40 mg, 40.5 mg, 41 mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 mg, 44 mg, 44.5 mg, 45 mg, 45.5 mg, 46 mg, 46.5 mg, 47 mg,

47.5 mg, 48 mg, 48.5 mg, 49 mg, 49.5 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg , 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 120.5 mg, 121 mg, 121.5 mg, 122 mg, 122.5 mg, 123 mg, 123.5 mg, 124 mg, 124, 5 mg, 125 mg, 125.5 mg, 126 mg, 126.5 mg, 127 mg, 127.5 mg, 128 mg, 128.5 mg, 129 mg, 129.5 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 225 mg, 250 mg to 275 mg, 300 mg , 325 mg, 350 mg 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg , 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, approximately 1650 mg, approximately 1700 mg, approximately 1750 mg, approximately 1800 mg, approximately 1850 mg, approximately

- 66 044464

1900 mg, approximately 1950 mg or approximately 2000 mg.

In some embodiments of the present invention, niraparib or a pharmaceutically acceptable salt thereof is present at a dose of about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 25 mg to 100 mg , from 35 mg to 140 mg, from 70 mg to 140 mg, from 80 mg to 135 mg, from 10 mg to 25 mg, from 25 mg to 50 mg, from 50 mg to 100 mg, from 100 mg to 150 mg, from 150 mg to 200 mg, from 10 mg to 35 mg, from 35 mg to 70 mg, from 70 mg to 105 mg, from 105 mg to 140 mg, from 140 mg to 175 mg or from 175 mg to 200 mg, from 35 mg to 50 mg, from 50 mg to 75 mg, from 70 mg to 95 mg, from 90 mg to 115 mg, from 110 mg to 135 mg, from 130 mg to 155 mg, from 150 mg to 175 mg, from 170 mg to 195 mg, from 190 mg to 215 mg, from 210 mg to 235 mg, from 230 mg to

255 mg, from 250 mg to 275 mg, from 270 mg to 300 mg, from 290 mg to 315 mg, from 310 mg to 335 mg, from 330 mg to

355 mg, from 350 mg to 375 mg, from 370 mg to 400 mg, from 400 mg to 450 mg, from 450 mg to 500 mg, from 500 mg to

550 mg, from 550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to

800 mg, from 800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, or from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to 1400 mg, from 1400 mg to 1450 mg, from 1450 mg to 1500 mg, from 1500 mg to 1550 mg, from 1550 mg to 1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg to 1850 mg , from 1850 mg to 1900 mg, from 1900 mg to 1950 mg or from 1950 mg to 2000 mg.

Frequency of administration

In some embodiments, a composition described herein is administered to an individual in need thereof once. In some embodiments, a composition described herein is administered to an individual in need thereof more than once. In some embodiments of the present invention, the first administration of a composition described herein is followed by a second administration of a composition described herein. In some embodiments of the present invention, the first administration of a composition described herein is followed by second and third administrations of a composition described herein. In some embodiments of the present invention, the first administration of a composition described herein is followed by second, third, and fourth administrations of the composition described herein. In some embodiments of the present invention, the first administration of a composition described herein is followed by a second, third, fourth, and fifth administration of a composition described herein. In some embodiments of the present invention, the first administration of a composition described herein is accompanied by a drug rest.

The number of times the composition is administered to an individual in need thereof depends on the judgment of the health care professional, the disorder, the severity of said disorder, and the individual's response to said composition. In some embodiments of the present invention, a composition described herein is administered once to an individual in need thereof with a mild acute condition. In some embodiments of the present invention, a composition described herein is administered once to an individual in need thereof with a moderate to severe acute condition. In the event that the patient's condition does not improve, at the doctor's discretion, niraparib may be administered continuously, that is, over an extended period of time, including throughout the patient's life, to improve or otherwise control or limit the symptoms of the patient's disease or condition.

In some embodiments of the present invention, the composition is administered at predetermined intervals over an extended period. In some embodiments of the present invention, the niraparib composition is administered once daily. In some embodiments of the present invention, the niraparib composition is administered every other day. In some embodiments of the present invention, the niraparib composition is administered for 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years , 8 years, 9 years, 10 years, 11 years or 12-15 years.

In some embodiments of the present invention, the niraparib composition is administered at doses having a dose-to-dose variation in niraparib concentration of less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%.

If the patient's condition actually improves, at the doctor's discretion, niraparib can be administered continuously; alternatively, the administered dose of drug can be temporarily reduced or temporarily suspended for a certain period of time (ie, drug rest). The length of time off medications can vary from 2 days to 1 year, including as examples only: 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days , 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days and 365 days. The first or second dose reduction during drug rest may range from 10 to 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50 %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100%. For example, the first or second dose reduction while off medication may be a reduced dose with

- 67 044464 mg to 1 mg, from 10 mg to 5 mg, from 20 mg to 10 mg, from 25 mg to 10 mg, from 50 mg to 25 mg, from 75 mg to 50 mg, from 75 mg to 25 mg, from 100 mg to 50 mg, from 150 mg to 75 mg, from 100 mg to 25 mg, from 200 mg to 100 mg, from 200 to 50 mg, from 250 mg to 100 mg, from 300 mg to 50 mg, from 300 mg to 100 mg, from 300 mg to 200 mg, from 400 mg to 50 mg, from 400 mg to 100 mg, from 400 mg to 200 mg, from 500 mg to 50 mg, from 500 mg to 100 mg, from 500 mg up to 250 mg, from 1000 mg to 50 mg, from 1000 mg to 100 mg or from 1000 mg to 500 mg, from 550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1000 mg, from 1000 mg to 1050 mg, from 1050 mg to 1100 mg, from 1100 mg to 1150 mg, from 1150 mg to 1200 mg, from 1200 mg to 1250 mg, from 1250 mg to 1300 mg, from 1300 mg to 1350 mg, from 1350 mg to 1400 mg, from 1400 mg to 1450 mg , from 1450 mg to 1500 mg, from 1500 mg to 1550 mg, from 1550 mg to 1600 mg, from 1600 mg to 1650 mg, from 1650 mg to 1700 mg, from 1700 mg to 1750 mg, from 1750 mg to 1800 mg, from 1800 mg to 1850 mg, from 1850 mg to 1900 mg, from 1900 mg to 1950 mg or from 1950 mg to 2000 mg. For example, the first or second dose reduction while off medication may be a dose reduced by 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg , 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg or 2000 mg.

After the patient's condition improves, a maintenance dose of niraparib is prescribed if necessary. Subsequently, the dose or frequency of administration, or both, depending on the symptoms, is not necessarily reduced to a level at which improvement of the disease, disorder or condition is maintained. In certain embodiments of the present invention, patients require periodic treatment on a long-term basis for any recurrence of symptoms.

Combination therapy

The tablet formulations of niraparib described herein may be useful as monotherapy or in combination therapy with the administration of one or more additional therapeutic agents or lines of therapy.

For example, the tablet composition described herein may be administered in combination with surgery, radiation therapy, chemotherapy, immunotherapy, an antiangiogenic agent, or an anti-inflammatory agent.

When a niraparib tablet composition is administered in combination with one or more other therapeutic agents (eg, those described herein), administration of said niraparib tablet composition may occur sequentially with the administration of said one or more other therapeutic agents. For example, administration of the niraparib tablet composition occurs prior to administration of said one or more other therapeutic agents. In embodiments of the present invention, administration of the niraparib tablet composition occurs after administration of said one or more other therapeutic agents. In other embodiments of the present invention, administration of the niraparib tablet composition occurs concurrently with the administration of said one or more other therapeutic agents.

In some embodiments of the present invention, the tablet composition described herein is administered in combination with one or more immune checkpoint inhibitors. In some embodiments of the present invention, the immune checkpoint inhibitor is an agent capable of inhibiting any of the following: PD-1 (e.g., inhibition by α-anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy), CTLA-4, TIM-3, TIGIT, LAG (for example, LAG-3), SEACAM (for example, SEACAM-1, -3 and/or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (eg, TGFR beta), B7-H1, B7 -H4 (VTCN1), OX-40, CD137, CD40, IDO or CSF-1R. In some embodiments, the immune checkpoint inhibitor is a small molecule, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or toxin. In some embodiments of the present invention, the immune checkpoint inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.

In some embodiments of the present invention, the immune checkpoint inhibitor is a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is a small molecule, nucleic acid, polypeptide (eg, an antibody, antibody conjugate, or antigen-binding fragment thereof), carbohydrate, lipid, metal, or toxin. In some embodiments, the PD-1 inhibitor is a PD-1 binding agent (eg, an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In some embodiments, the PD-1 binding agent is an antibody, an antibody conjugate, or an antigen binding fragment thereof. In some embodiments of the present invention, the PD-1 binding agent is TSR-042, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, PDR-001, tizelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ- 63723283, MGA012, BI-754091, IBI-308, camrelizumab (HR301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN-2034, CS1001, Sym- 021,

- 68 044464

SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimzumab (SVT-501), FAZ-053, SK-301, AK 104 or GLS-010. In some embodiments, the PD-1 inhibitor is a PD-L1 or PD-L2 binding agent, such as durvalimab, atezolizumab, avelumab, BGB-A333, SHR-1316, FAZ-053, CK-301, or millimolecule PD -L1, or their derivatives. In some embodiments, the anti-PD-1 agent is pembrolizumab. In some embodiments, the anti-PD-1 agent is nivolumab. In some embodiments of the present invention, the anti-PD-1 antibody agent is as described in international patent application publications WO 2014/179664, WO 2018/085468 or WO 2018/129559. In other embodiments of the present invention, the anti-PD-1 antibody agent is administered in accordance with the methods described in international patent application publications WO 2014/179664, WO 2018/085468 or WO 2018/129559. In some embodiments of the present invention, the anti-PD-1 agent is TSR-042.

In some embodiments of the present invention, the immune checkpoint inhibitor is a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is a small molecule, nucleic acid, polypeptide (eg, an antibody, antibody conjugate, or antigen-binding fragment thereof), carbohydrate, lipid, metal, or toxin. In some embodiments of the present invention, the TIM-3 inhibitor is a TIM-3 binding agent (eg, an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In some embodiments of the present invention, the TIM-3 binding agent is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. In some embodiments of the present invention, the TIM-3 binding agent is MBG453, LY3321367, Sym023, TSR-022, or a derivative thereof. In some embodiments of the present invention, the anti-TIM-3 antibody agent is as described in international patent application publications WO 2016/161270, WO 2018/085469 or WO 2018/129553. In some embodiments of the present invention, the anti-TIM-3 antibody agent is administered as described in International Patent Application Publications WO2016/161270, WO2018/085469, or WO2018/129553. In some embodiments of the present invention, the anti-TIM-3 antibody agent is TSR-022.

In some embodiments of the present invention, the immune checkpoint inhibitor is a LAG-3 inhibitor. In some embodiments, the anti-LAG-3 agent is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 agent is a small molecule, nucleic acid, polypeptide (eg, antibody), carbohydrate, lipid, metal, or toxin. In some embodiments of the present invention, the anti-LAG-3 agent is a small molecule. In some embodiments of the present invention, the anti-LAG-3 agent is a LAG-3 binding agent. In some embodiments, the anti-LAG-3 agent is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. In some embodiments of the present invention, the anti-LAG-3 agent is IMP321, relatlimab (BMS-986016), BI 754111, GSK2831781 (IMP-731), Novartis LAG525 (IMP701), REGN3767, MK-4280, MGD-013, GSK- 2831781, FS-118, XmAb22841, INCAGN2385, FS-18, ENUM-006, AVA-017, AM-0003, Avacta PD-L1/LAG-3 bispecific afamer, iOnctura anti-LAG3 antibody, Arcus anti-LAG-3 antibody , or Sym022, or TSR-033. In some embodiments of the present invention, the anti-LAG-3 antibody agent is as described in International Patent Application Publication WO 2016/126858 or International Patent Application PCT/US18/30027. In some embodiments, the anti-LAG-3 antibody agent is administered as described in International Patent Application Publication WO 2016/126858 or International Patent Application PCT/US 18/30027. In embodiments of the present invention, the anti-LAG-3 antibody agent is TSR-033.

In some embodiments, the niraparib tablet formulation is administered in combination with a PD-1 inhibitor (eg, TSR-042, pembrolizumab, or nivolumab). In some embodiments of the present invention, the niraparib tablet composition is administered in combination with a TIM-3 inhibitor (eg, TSR-022). In some embodiments of the present invention, the niraparib tablet composition is administered in combination with a LAG-3 inhibitor (eg, TSR-033). In some embodiments of the present invention, a tablet formulation of niraparib is administered in combination with a PD-1 inhibitor (eg, TSR-042, pembrolizumab, or nivolumab) and a TIM-3 inhibitor (eg, TSR-022). In some embodiments of the present invention, a tablet formulation of niraparib is administered in combination with a PD-1 inhibitor (eg, TSR-042, pembrolizumab, or nivolumab) and a LAG-3 inhibitor (eg, TSR-033). In some embodiments of the present invention, a tablet formulation of niraparib is administered in combination with a TIM-3 inhibitor (eg, TSR-022) and a LAG3 inhibitor (eg, TSR-033).

In some embodiments of the present invention, the tablet composition of Nira

- 69 044464 parib is administered in combination with a PD-1 inhibitor (eg TSR-042, pembrolizumab or nivolumab), a TIM-3 inhibitor (eg TSR-022) and a LAG-3 inhibitor (eg TSR-033).

In some embodiments of the present invention, the niraparib tablet composition is administered in combination with one or more chemotherapeutic agents.

In some embodiments of the present invention, the niraparib tablet composition is administered in combination with a platinum-based chemotherapy agent (eg, one or more of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin).

In some embodiments of the present invention, the niraparib tablet composition is administered in combination with a chemotherapeutic agent that is aminoglutethimide, amsacrine, anastrozole, asparaginase, BCG, bicalutamide, bleomycin, buserelin, busulfan, campothecin, capecitabine, carboplatin, carmustine, chlorabucil, cisplatin, cladribine , clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxy mesteron, flutamide, gemcitabine, genistein , goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, irononotecan, letrozole, leucovorin, leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mi totan, mitoxantrone, nilutamide, nocodazole , octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, suramin, tamoxifen, temozolomide, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine or vinorelbine.

In some embodiments of the present invention, the niraparib tablet composition is administered in combination with a second agent, which is a T regulatory cell (Treg) inhibitory agent; macrophage inhibitory agent; an agent that enhances an antigen-specific immune response; an agent that enhances an antigen-specific immune response; an antiangiogenic agent, a chemotherapeutic agent, or a combination thereof. In some embodiments of the present invention, the second agent is any second agent described in international application PCT/US 18/33437, the contents of which are incorporated herein by reference in their entirety.

In some embodiments of the present invention, the macrophage inhibitory agent is selected from the group consisting of an agent that inhibits macrophage recruitment (e.g., an anti-CCL2/CCR2 agent, an anti-P.6 agent, an anti-M-CSFR agent, and combinations thereof), an agent, preventing the survival of M2 macrophages, an agent that enhances Ml macrophages, an agent that converts M2 macrophages into M1 polarizing macrophages, an agent that inhibits macrophage activity, and combinations thereof. In some embodiments of the present invention, the macrophage recruitment inhibitory agent is selected from the group consisting of trabectedin, RS102895, PF-04136309, CNTO888, MLN1202, siltuximab, JNJ-28312141, GW2580, IMC-CS4 (LY3022855), emactuzumab, AMG820, pexidartinib , linifanib, OSI-930, CEP-32496, PLX7846, BLZ945, ARRY-382, JNJ-40346527, MCS110, PLX3397, PLX6134, PD-0360324, FPA008 and combinations thereof. In some embodiments of the present invention, the anti-M2 macrophage survival agent is selected from the group consisting of an MMP inhibitor, clodronate, zoledronic acid, dichloromethylene bisphosphonate, trabectedin, dasatinib, retinoic acid, attenuated bacteria (e.g., Shigella flexneri, Salmonella typhimurium, Listeria monocytogens, Chlamydia psittaci, Legionella pneumophild) and their combinations. In some embodiments of the present invention, the M1 macrophage enhancing agent or the M2 macrophage to M1 polarizing macrophage enhancing agent is selected from the group consisting of an anti-CD40 agent, an anti-IL-10R agent, a CD47 antagonist (e.g., Hu5f9-G4, cC-90002 and CD47-Fc fusion protein TTI-621), PolyI:C, LPS, monophosphoryl A, imiquimod, R-848, CpG-ODN, IFN-α, IFN-β, IFN-γ, GM-CSF, IL -12, IL-2, IL-15, Ta1, ibrutinib, EF-022 and combinations thereof. In some embodiments of the present invention, the macrophage inhibitory agent is selected from the group consisting of a STAT3 inhibitor, a STAT6 inhibitor, or an antitumor drug (e.g., the macrophage inhibitory agent is WP1066, sunitinib, sorafenib, STA-21, IS3 295 , S3IM2001, AS1517499, leflunomide, TMC-264, histidine-rich glycoprotein (FIRG), copper chelate (CuNG), 5,6-dimethylxanthenone-4-acetic acid (MDXAA), vadimezane (ASA404), cisplatin, silybin, proton inhibitor pump pantoprazole (PPZ) or CNI-1493 or combinations thereof). In some embodiments of the present invention, the macrophage inhibitory agent is an anti-IL-1a agent (eg, Xilonix).

In some embodiments of the present invention, the regulatory T cell (Treg) inhibitory agent is selected from the group consisting of a Treg ablation agent, an agent that inhibits Treg migration, an agent that inhibits Treg function, and combinations thereof. In some embodiments of the present invention, the Treg ablation agent is selected from the group consisting of cyclophosphamide, pa

- 70 044464 litaxel, imatinib, sunitinib, sorafenib, dasatinib, temozolomide, daclizumab, denileukindiftitox and their combinations. In some embodiments of the present invention, the Treg migration inhibitory agent is selected from the group consisting of AMD3100, mogamulizumab, casuarinin, fucoidan, and combinations thereof. In some embodiments, the Treg function inhibitory agent is selected from the group consisting of an anti-CTLA4 agent (e.g., ipilimumab, tremelimumab), an anti-OX40 agent, an anti-GITR agent, an adenosine receptor antagonist (e.g., caffeine, theophylline, theobromine and 8-phenylxanthines), P60 and their combinations.

In some embodiments of the present invention, the agent that enhances the antigen-specific immune response is selected from the group consisting of an anti-PD-1 agent, an α-PD-L1 agent, a GITR (glucocorticoid-induced TNFR-related protein) stimulating agent, an anti- CTLA4 agent, anti-TIM-3 agent, anti-LAG-3 agent, anti-IDO agent, tumor antigen presentation enhancing agent (eg, personalized cancer vaccine, autologous antigen presenting cell, autologous dendritic cells, artificial antigen presenting cell), chemokine agent signaling pathway, anti-VEGF agent, cytokine signal stimulating agent, and combinations thereof.

In some embodiments of the present invention, the GITR stimulating agent is selected from the group consisting of DTA-1, mGITRL, pGITRL, and combinations thereof. In some embodiments, the anti-CTLA4 agent is selected from the group consisting of ipilimumab, tremelimumab, and combinations thereof. In some embodiments of the present invention, the chemokine signaling pathway agent is selected from the group consisting of CXCL16, a CXCR6 chemokine receptor agonist (CD186), and combinations thereof. In some embodiments, the anti-VEGF agent is selected from the group consisting of bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, ponatinib, regorafenib, cabozantinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept, and combinations thereof. In some embodiments of the present invention, the cytokine signal stimulating agent is an interleukin or interferon. In some embodiments of the present invention, the interleukin is selected from the group consisting of IL-2, IL-1, IL-7, IL-15, IL-12, IL-18, and combinations thereof. In some embodiments of the present invention, the interferon is IFN-alpha.

In some embodiments of the present invention, the agent that enhances the antigen-specific immune response is selected from the group consisting of a flavonoid (e.g., flavonoid glycoside), lidocaine, lamotrigine, sulfamethoxazole, phenytoin, carbamazepine, sulfamethoxazole, phenytoin, allopurinol, paracetamol, mepivacaine, p-phenylenediamine , ciprofloxacin and moxifloxacin.

In some embodiments of the present invention, the antiangiogenic agent is TNP-470, platelet factor 4, thrombospondin-1, tissue inhibitors of metalloproteases (TIMP1 and TIMP2), prolactin, angiostatin, endostatin, soluble bFGF receptor, transforming growth factor beta, interferon alpha, soluble KDR and FLT-1 receptors, placental proliferin-related protein, and combinations thereof. In some embodiments, the antiangiogenic agent reduces the production of a proangiogenic factor, inhibits the interaction between a proangiogenic factor and a proangiogenic receptor, inhibits the function of a proangiogenic factor, inhibits the function of a proangiogenic factor receptor, reduces blood flow by destroying blood vessels, inhibits vascular sprouting, or any combination of these actions. In some embodiments of the present invention, the antiangiogenic agent is a small organic or inorganic molecule; saccharin; oligosaccharide; polysaccharide; carbohydrate; peptide; protein; peptide analog; peptide derivative; lipid; antibody; antibody fragment, peptidomimetic; nucleic acid; nucleic acid analogue; nucleic acid derivative; extract obtained from biological materials; naturally occurring or synthetic composition; metal; toxin; or any combination thereof. In some embodiments of the present invention, the antiangiogenic agent is selected from the group consisting of bevacizumab, itraconazole, carboxyamidotriazole, TNP-470, fumagillin, CM101, IL-12, platelet factor-4, suramin, SU5416, thrombospondin, angiostatic steroids, heparin derived from cartilage angiogenesis inhibitory factor, matrix metalloproteinase inhibitor, angiostatin, endostatin, 2methoxyestradiol, tecogalane, tetrathiomolybdate, thrombospondin, thalidomide, prolactin, aVe3 inhibitor, lenalidomide, linomide, ramucirumab, tasquinimod, ranibizumab, sorafenib, sunitinib, pazopanib, everolimus, tissue inhibitors of metalloproteinases ( TIMP1 and TIMP2), bFGF soluble receptor, transforming growth factor beta, interferon alpha, soluble KDR and FLT-1 receptors, placental proliferin-related protein, pazoranib, sunitinib, sorafenib, axinitib, ponatinib, cabozantinib, regorafenib, vandetanib, lenvatinib, semaxanib , SU6668, vatalanib, tivozanib, cediranib, protamine, heparin, steroids, ascorbic acid ethers, sulfated polysaccharide DS 4152, fumagillin, AGM 12470, neovastat, RO4929097, MRK-003, MK-0752, PF03084014, ME DI0639, curcumin, 3, 3'-diindolylmethane (DIM), resveratrol, 3,5-bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD) and epigallocatechin-3-gallate (EGCG), honokiol, OMP-21M18, navixizumab (OMP-305B83 ), Flt ₂ .n, CBO-P11, Je-11, V1 and any combination of them

- 71 044464 tion. In some embodiments of the present invention, the antiangiogenic agent inhibits the DLL4/Notch signaling pathway.

In some embodiments of the present invention, the angiogenesis inhibitor that inhibits the DLL4/Notch signaling pathway is a gamma secretase inhibitor (GSI), a siRNA, or a monoclonal antibody against a Notch receptor or ligand. In some embodiments of the present invention, the antiangiogenic agent is selected from the group consisting of RO4929097, MRK-003, MK-0752, PF03084014, MEDI0639, curcumin, 3,3'-diindolylmethane (DIM), resveratrol, 3,5-bis(2, 4difluorobenzylidene)-4-piperidone (DiFiD) and epigallocatechin-3-gallate (EGCG), honokiol and any combinations thereof.

In some embodiments of the present invention, the antiangiogenic agent inhibits the vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) pathway. In some embodiments of the present invention, the antiangiogenic agent is selected from the group consisting of an Akt inhibitor, calcineurin autoinhibitory peptide, ET-18OCH3, Go 6983, NG-nitro-L-arginine methyl ester, p21-activated kinase inhibitor, cPLA2a inhibitor, PI-103 , PP2, SB 203580, U0126, VEGFR tyrosine kinase inhibitor V, VIVEGFR2 kinase inhibitor, VEGFR2 kinase inhibitor III, ZM 336372 and any combination thereof.

In some embodiments, the antiangiogenic agent inhibits a VEGF family protein and/or a VEGFR family protein. In some embodiments, the VEGF family protein comprises VEGF-A, VEGF-B, VEGF-C, VEGF-D, PlGF (placental growth factor), VEGF-E (Orf-VEGF), Trimeresurus flavoviridis svVEGF, or any combination thereof. In some embodiments, the antiangiogenic agent is bevacizumab, ranibizumab, ORT-302, ziv-aflibercept, or any combination thereof. In some embodiments of the present invention, the antiangiogenic agent is Flt _2- n, CBO-P11, Je-11, V1, or any combination thereof. In some embodiments, the antiangiogenic agent is pazopanib, sunitinib, sorafenib, axitinib, ponatinib, cabozantinib, regorafenib, vandetanib, lenvatinib, semaxanib, SU6668, vatalanib, tivozanib, cediranib, or any combination thereof.

Methods for preparing niraparib formulations

Presented herein are methods for preparing tablet formulations of niraparib for the treatment of cancer. Also described herein are tablet formulations of niraparib containing niraparib tosylate monohydrate and at least one pharmaceutically acceptable excipient prepared by the methods described and oral therapeutic use of such formulation. In some embodiments of the present invention, the composition comprises niraparib; a first diluent selected from lactose monohydrate, lactose anhydrous, mannitol, dibasic calcium phosphate, magnesium stearate; a second diluent selected from microcrystalline cellulose, starch, polyethylene oxide and hydroxypropyl methylcellulose (HPMC); and a binder selected from povidone, hydroxypropylcellulose and hydroxypropylmethylcellulose. In some embodiments of the present invention, the composition contains the active ingredient niraparib tosylate (monohydrate) in an amount of from about 35 wt.% to about 60 wt.%. In some embodiments of the present invention, the composition contains the active ingredient niraparib tosylate (monohydrate) in an amount of from about 40% by weight to about 55% by weight. In some embodiments of the present invention, the composition contains the active ingredient niraparib tosylate (monohydrate) in an amount of from about 45 wt.% to about 50 wt.%. In some embodiments of the present invention, the composition contains the active ingredient niraparib tosylate (monohydrate) in an amount of from about 46 wt.% to about 48 wt.%.

In some embodiments of the present invention, the pharmaceutical composition of the present invention is prepared by mixing said niraparib with excipients. Mixing of the above components can preferably be carried out in a mixer, for example a drum mixer. Bulk density before compaction and bulk density after compaction can be determined in accordance with USP 24, Test 616 Bulk Density and Tapped Density.

In some embodiments of the present invention, the solid dosage forms of the present invention may be in the form of a powder (including sterile packaged powder, dispensed powder, or effervescent powder), capsules (including both soft and hard capsules, such as capsules made from animal gelatin origin or from plant-derived HPMC (or capsules with coated particles) or tablets. In some embodiments of the present disclosure, the pharmaceutical dosage form is in the form of a powder. In addition, the pharmaceutical compositions of the present invention can be administered in the form of a single capsule or in the form of multiple capsules. In some embodiments, said pharmaceutical composition is administered in one, or two, or three, or four capsules. In some embodiments, said solid dosage forms described herein are in the form of a tablet. In some embodiments, the present invention

- 72 044464 tenia, the pharmaceutical compositions described herein are administered in the form of a single tablet or in the form of several tablet dosage forms. In some embodiments, said pharmaceutical composition is administered in one, or two, or three, or four tablets.

In some embodiments of the present invention, solid dosage forms are prepared by mixing niraparib particles with one or more pharmaceutical excipients to form a master mixture composition. When these master mixture compositions are referred to as homogeneous, it is meant that the niraparib particles are uniformly distributed throughout the composition so that the composition can be readily divided into equally effective unit dosage forms, such as capsules or tablets. Individual dosage units may also contain film coatings that disintegrate upon oral administration or upon contact with solvents.

Non-limiting pharmaceutical techniques for preparing solid dosage forms include, alone or in combination, for example the following: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or anhydrous granulation, (5) wet or dry granulation or (6) melting. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, drying or fluidized bed coating (eg, Wurster method), tangential coating, surface spraying, tabletting, extrusion and the like.

The present invention should not be construed as limited to these particular conditions of combining the components, and it will be understood from this document that advantageous properties can be achieved under other conditions, if the components retain their essential properties and substantially homogeneity of the mixed components of the composition is achieved in some way in another way without any significant segregation.

In one embodiment of the present invention, to prepare the mixture, the components are weighed and placed in a mixing container. Mixing is carried out over a period of time to obtain a homogeneous mixture using suitable mixing equipment. Optionally, the mixture is passed through a sieve to remove any lumps. The sifted mixture can be returned to the mixing bowl and mixed for an additional period of time. The lubricant can then be added and the mixture mixed for an additional period of time.

In the pharmaceutical industry, grinding is often used to reduce the particle size of solid materials. Many types of mills are available, including pin, hammer, and jet mills. One of the most commonly used types of mills is the hammer mill. A hammer mill uses a high-speed rotor to which several fixed or oscillating hammers are attached. Hammers can be attached so that the cutting surface or head of the hammer contacts the material. As the material is fed into the mill, it is struck by the rotating hammers and broken down into smaller particles. Below the hammers there is a screen; smaller particles pass through the holes in this screen. The larger particles remain in the mill and continue to be broken down by hammers until the particles are small enough to pass through the holes in the screen. The material can be further sifted. In sieving, the material passes through a screen or series of screens to obtain the desired particle size.

Wet granulation

In some embodiments of the present invention, wet granulation is used to prepare the compositions described herein.

One aspect of the present invention relates to a method of preparing a composition containing a niraparib-containing tablet obtained by wet granulation, wherein the method comprises: a) preparing an intragranular phase, comprising i) combining niraparib, a first diluent (e.g., lactose monohydrate, lactose anhydrate, mannitol and dibasic calcium phosphate) and a second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide and hydroxypropyl methylcellulose (HPMC)) to obtain a composition containing niraparib, said first diluent and said second diluent; and ii) wet granulating said composition containing niraparib, said first diluent and said second diluent to produce granules; b) obtaining an extragranular phase, comprising iii) combining said granules with at least one pharmaceutically acceptable excipient to obtain a mixture; and (c) obtaining a tablet by compressing the mixture obtained in step iii).

Also described herein is a method of preparing a composition containing a niraparib-containing tablet obtained by wet granulation, wherein the method comprises: a) preparing an intragranular phase, comprising i) combining niraparib, lactose monohydrate and microcrystalline cellulose to produce a composition containing niraparib, lactose monohydrate and microcrystalline cellulose; and ii) wet granulation of said composition containing niraparib, lactose monohydrate and microcrystalline cellulose to obtain granules; b) obtaining an extragranular phase, comprising iii) combining said granules with at least

- 73 044464 with one pharmaceutically acceptable excipient to obtain a mixture; and c) obtaining a tablet by compressing the mixture obtained in step iii).

In some embodiments of the present invention, the wet granulation in step ii) further includes adding a binder. In some embodiments of the present invention, said binder is a liquid binder. In some embodiments of the present invention, said liquid binder is dissolved povidone. In some embodiments of the present invention, said liquid binder is dissolved starch, dissolved hydroxypropyl cellulose (HPC), dissolved hydroxypropyl methylcellulose (HPMC), or liquid polyethylene glycol (PEG). In some embodiments of the present invention, said liquid binder is a molten binder. In some embodiments of the present invention, said molten binder is a hydrophilic polyethylene glycol (PEG), a poloxamer, a hydrophobic fatty acid, a fatty alcohol, a wax, a hydrogenated vegetable oil, or a glyceride. In some embodiments of the present invention, said binder is a dry binder. In some embodiments of the present invention, said dry binder is hydroxypropyl cellulose (HPC). In some embodiments of the present invention, said dry binder is hydroxypropyl methylcellulose (HPMC). In some embodiments of the present invention, said dry binder is povidone (PVP) or starch. In some embodiments of the present invention, the wet granulation in step ii) further includes wet screening. In some embodiments of the present invention, the wet granulation in step ii) further includes drying and dry screening.

Moisture activated dry granulation

In some embodiments of the present invention, moisture-activated dry granulation is used to prepare the compositions described herein.

Another aspect of the present invention relates to a method of preparing a composition containing a tablet from a moisture-activated dry granulation containing niraparib, comprising: (a) preparing an intragranular phase, comprising i) combining niraparib, a first diluent (for example, lactose monohydrate, lactose anhydrate, mannitol and dibasic calcium phosphate) and a second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide and hydroxypropyl methylcellulose (HPMC)) to obtain a composition containing niraparib, said first diluent and said second diluent; ii) granulating said composition containing niraparib, said first diluent and said second diluent to produce granules; and (b) obtaining an extragranular phase, comprising iii) combining said granules with at least one pharmaceutically acceptable excipient to obtain a mixture; and (c) obtaining a tablet by compressing the mixture obtained in step iii). The present invention also relates to a method in which step i) of combining further includes combining with an adsorbent or absorbent.

Another aspect of the present invention relates to a method of preparing a composition containing a tablet from a moisture-activated dry granulation containing niraparib, comprising: (a) preparing an intragranular phase, comprising i) combining niraparib, lactose monohydrate and microcrystalline cellulose to obtain a composition containing niraparib, lactose monohydrate and microcrystalline cellulose; ii) granulating said composition containing niraparib, lactose monohydrate and microcrystalline cellulose to obtain granules; and (b) obtaining an extragranular phase, comprising iii) combining said granules with at least one pharmaceutically acceptable excipient to obtain a mixture; and (c) obtaining a tablet by compressing the mixture obtained in step iii).

In some embodiments of the present invention, granulation in step ii) further includes adding a binder. In some embodiments of the present invention, said binder is a liquid binder. In some embodiments of the present invention, said liquid binder is dissolved povidone. In some embodiments of the present invention, the liquid binder is water, dissolved starch, dissolved hydroxypropyl cellulose (HPC), dissolved hydroxypropyl methylcellulose (HPMC), or liquid polyethylene glycol (PEG). In some embodiments of the present invention, the composition further comprises a dry binder. In some embodiments, water is added to said dry binder-containing composition. In some embodiments of the present invention, granulation in step ii) further includes drying and dry screening. In some embodiments of the present invention, drying includes adding a glidant. In some embodiments of the present invention, said glidant is silica. In some embodiments of the present invention, said glidant is silica, tribasic calcium phosphate, calcium silicate, cellulose, magnesium silicate, magnesium trisilicate

- 74 044464 niya, starch, talc or mixtures thereof.

Dry granulation

In some embodiments of the present invention, dry granulation is used to prepare the compositions described herein.

Another aspect of the present invention relates to a method of preparing a composition containing a niraparib-containing tablet by dry granulation, comprising: a) preparing an intragranular phase, comprising i) combining niraparib, a first diluent (for example, lactose monohydrate, lactose anhydrous, mannitol and dibasic phosphate calcium) a second diluent (for example, microcrystalline cellulose, starch, polyethylene oxide and hydroxypropyl methylcellulose (HPMC)) and a lubricant (for example, magnesium stearate) to obtain a composition containing niraparib, said first diluent, said second diluent and said lubricant; and ii) dry granulating said composition containing niraparib, said first diluent, said second diluent and said lubricant to produce granules; b) obtaining an extragranular phase, comprising iii) combining said granules with at least one pharmaceutically acceptable excipient to obtain a mixture; and c) obtaining a tablet by compressing the mixture obtained in step iii).

In some embodiments of the present invention, the composition further comprises a dry binder. In some embodiments, water is added to said dry binder-containing composition. In some embodiments of the present invention, combining niraparib, said first diluent, said second diluent and said lubricant to form a composition comprising niraparib, said first diluent, said second diluent and said lubricant in step i) further comprises mixing said niraparib, said first a diluent, said second diluent and said lubricant. In some embodiments, the dry granulation in step ii) includes impact compaction and grinding. In some embodiments of the present invention, the thickness of the tape is from about 0.1 mm to about 3.5 mm. In some embodiments of the present invention, the thickness of the tape is about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm , about 0.8 mm, about 0.9 mm, about 1.0 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, approximately 1.7 mm, approximately 1.8 mm, approximately 1.9 mm, approximately 2.0 mm, approximately 2.1 mm, approximately 2.2 mm, approximately 2.3 mm, approximately 2, 4 mm, approximately 2.5 mm, approximately 2.6 mm, approximately 2.7 mm, approximately 2.8 mm, approximately 2.9 mm, approximately 3.0 mm, approximately 3.1 mm, approximately 3.2 mm , about 3.3 mm, about 3.4 mm, or about 3.5 mm.

Another aspect of the present invention relates to a method of preparing a composition containing a niraparib-containing tablet by dry granulation, comprising: a) preparing an intragranular phase, comprising i) combining niraparib, a diluent selected from mannitol and dibasic calcium phosphate, microcrystalline cellulose and magnesium stearate , producing a composition containing niraparib, a diluent selected from mannitol and dibasic calcium phosphate, microcrystalline cellulose and magnesium stearate; and ii) dry granulating said composition containing niraparib, a diluent selected from mannitol and dibasic calcium phosphate, microcrystalline cellulose and magnesium stearate to obtain granules; b) obtaining an extragranular phase, comprising iii) combining said granules with at least one pharmaceutically acceptable excipient to obtain a mixture; and c) obtaining a tablet by compressing the mixture obtained in step iii).

In some embodiments of the present invention, the composition further comprises a dry binder. In some embodiments, water is added to the dry binder-containing composition. In some embodiments of the present invention, combining niraparib, a diluent selected from mannitol and dicalcium phosphate, microcrystalline cellulose and magnesium stearate to form a composition comprising niraparib, a diluent selected from mannitol and dicalcium phosphate, microcrystalline cellulose and magnesium stearate in step i ) further comprises mixing said niraparib, a diluent selected from mannitol and dibasic calcium phosphate, microcrystalline cellulose and magnesium stearate. In some embodiments, the dry granulation in step ii) includes impact compaction and grinding. In some embodiments of the present invention, the thickness of the tape is from about 0.1 mm to about 2 mm.

In some embodiments of the present invention, said composition in step i) further comprises a glidant (eg, silica). In some embodiments of the present invention, said at least one pharmaceutically acceptable excipient for combining the granules with at least one pharmaceutically acceptable excipient to form a mixture in step iii) is a glidant (eg, silica). In some embodiments of the present invention, the at least one pharmaceutically acceptable excipient for combining granules according to

- 75 044464 with at least one pharmaceutically acceptable excipient to obtain a mixture in step iii) is a lubricant (for example, magnesium stearate). In some embodiments of the present invention, combining said granules with at least one pharmaceutically acceptable excipient to form a mixture in step iii) comprises mixing said granules with at least one pharmaceutically acceptable excipient. In some embodiments of the present invention, said composition in step i) is a mixture.

In some embodiments of the present invention, said composition in step i) further comprises silica. In some embodiments of the present invention, said at least one pharmaceutically acceptable excipient for combining the granules with at least one pharmaceutically acceptable excipient to form a mixture in step iii) is silica. In some embodiments of the present invention, said at least one pharmaceutically acceptable excipient for combining the granules with at least one pharmaceutically acceptable excipient to form a mixture in step iii) is magnesium stearate. In some embodiments of the present invention, combining said granules with at least one pharmaceutically acceptable excipient to form a mixture in step iii) comprises mixing said granules with at least one pharmaceutically acceptable excipient. In some embodiments of the present invention, said composition in step i) is a mixture.

In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 50% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 85% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 90% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 92.5% to about 97.5% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is approximately 95% by weight of the specified tablet composition.

In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 50% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 15% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 10% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2.5% to about 7.5% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is approximately 5% by weight of the specified tablet composition.

In some embodiments of the present invention, the bulk density of these granules before compaction is from about 0.10 to about 0.99 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.10 to about 0.90 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.10 to about 0.80 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.10 to about 0.70 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.10 to about 0.60 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.10 to about 0.50 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.10 to about 0.40 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.10 to about 0.30 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.10 to about 0.20 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of said granules is between

- 76 044464 approximately 0.20 to approximately 0.99 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.20 to about 0.90 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.20 to about 0.80 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.20 to about 0.70 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.20 to about 0.60 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.20 to about 0.50 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.20 to about 0.40 g/cm ³ . In some embodiments of the present invention, the bulk density before compaction of the granules is from about 0.20 to about 0.30 g/cm ³ .

In some embodiments of the present invention, the bulk density of said granules before compaction is about 0.10, about 0.11, about 0.12, about 0.13, about 0.14, about 0.15, about 0.16, about 0 .17, approximately 0.18, approximately 0.19, approximately 0.20, approximately 0.21, approximately 0.22, approximately 0.23, approximately 0.24, approximately 0.25, approximately 0.26, approximately 0 .27, approximately 0.28, approximately 0.29, approximately 0.30, approximately 0.31, approximately 0.32, approximately 0.33, approximately 0.34, approximately 0.35, approximately 0.36, approximately 0 .37, approximately 0.38, approximately 0.39, approximately 0.40, approximately 0.41, approximately 0.42, approximately 0.43, approximately 0.44, approximately 0.45, approximately 0.46, approximately 0 .47, approximately 0.48, approximately 0.49, approximately 0.50, approximately 0.51, approximately 0.52, approximately 0.53, approximately 0.54, approximately 0.55, approximately 0.56, approximately 0 .57, approximately 0.58, approximately 0.59, approximately 0.60, approximately 0.61, approximately 0.62, approximately 0.63, approximately 0.64, approximately 0.65, approximately 0.66, approximately 0 .67, approximately 0.68, approximately 0.69, approximately 0.70, approximately 0.71, approximately 0.72, approximately 0.73, approximately 0.74, approximately 0.75, approximately 0.76, approximately 0 .77, approximately 0.78, approximately 0.79, approximately 0.80, approximately 0.81, approximately 0.82, approximately 0.83, approximately 0.84, approximately 0.85, approximately 0.86, approximately 0 .87, approximately 0.88, approximately 0.89, approximately 0.90, approximately 0.91, approximately 0.92, approximately 0.93, approximately 0.94, approximately 0.95, approximately 0.96, approximately 0 .97, about 0.98, or about 0.99 g/cm ³ .

In some embodiments of the present invention, the bulk density of these granules after compaction is from about 0.10 to about 0.99 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.10 to about 0.90 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.10 to about 0.80 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.10 to about 0.70 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.10 to about 0.60 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.10 to about 0.50 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.10 to about 0.40 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.10 to about 0.30 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.10 to about 0.20 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.20 to about 0.99 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.20 to about 0.90 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.20 to about 0.80 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.20 to about 0.70 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.20 to about 0.60 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.20 to about 0.50 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.20 to about 0.40 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.20 to about 0.30 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.30 to about 0.99 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.30 to about 0.90 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.30 to about 0.80 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.30 to about

- 77 044464

0.70 g/ ^cm3 . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.30 to about 0.60 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.30 to about 0.50 g/cm ³ . In some embodiments of the present invention, the bulk density after compaction of the granules is from about 0.30 to about 0.40 g/cm ³ .

In some embodiments of the present invention, the bulk density after compaction of the granules is about 0.10, about 0.11, about 0.12, about 0.13, about 0.14, about 0.15, about 0.16, about 0 .17, approximately 0.18, approximately 0.19, approximately 0.20, approximately 0.21, approximately 0.22, approximately 0.23, approximately 0.24, approximately 0.25, approximately 0.26, approximately 0 .27, approximately 0.28, approximately 0.29, approximately 0.30, approximately 0.31, approximately 0.32, approximately 0.33, approximately 0.34, approximately 0.35, approximately 0.36, approximately 0 .37, approximately 0.38, approximately 0.39, approximately 0.40, approximately 0.41, approximately 0.42, approximately 0.43, approximately 0.44, approximately 0.45, approximately 0.46, approximately 0 .47, approximately 0.48, approximately 0.49, approximately 0.50, approximately 0.51, approximately 0.52, approximately 0.53, approximately 0.54, approximately 0.55, approximately 0.56, approximately 0 .57, approximately 0.58, approximately 0.59, approximately 0.60, approximately 0.61, approximately 0.62, approximately 0.63, approximately 0.64, approximately 0.65, approximately 0.66, approximately 0 .67, approximately 0.68, approximately 0.69, approximately 0.70, approximately 0.71, approximately 0.72, approximately 0.73, approximately 0.74, approximately 0.75, approximately 0.76, approximately 0 .77, approximately 0.78, approximately 0.79, approximately 0.80, approximately 0.81, approximately 0.82, approximately 0.83, approximately 0.84, approximately 0.85, approximately 0.86, approximately 0 .87, approximately 0.88, approximately 0.89, approximately 0.90, approximately 0.91, approximately 0.92, approximately 0.93, approximately 0.94, approximately 0.95, approximately 0.96, approximately 0 .97, about 0.98, or about 0.99 g/cm ³ .

Intragranular phase/extragranular phase distribution

Another aspect of the present invention relates to a method for preparing compositions with a specific distribution of intragranular phase and extragranular phase components. One aspect of the present invention relates to a method of preparing a composition containing a niraparib-containing tablet, comprising: a) preparing an intragranular phase, comprising i) combining niraparib and at least one pharmaceutically acceptable excipient to obtain a composition containing niraparib and at least one pharmaceutical acceptable excipient; and ii) granulating said composition containing niraparib and at least one pharmaceutically acceptable excipient to obtain granules; b) obtaining an extragranular phase, comprising iii) combining said granules with at least one pharmaceutically acceptable excipient to obtain a mixture; and c) obtaining a tablet by compressing the mixture obtained in step iii); wherein said tablet is characterized by at least one of the following: (1) the amount of components used to produce said intragranular phase is from about 50% to about 98% by weight of said tablet composition; and (2) the amount of components used to obtain said extragranular phase is from about 2% to about 50% by weight of said tablet composition.

In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 50% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 85% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 90% to about 98% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is from about 92.5% to about 97.5% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified intragranular phase is approximately 95% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 50% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 15% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2% to about 10% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is from about 2.5% to about 7.5% by weight of the specified tablet composition. In some embodiments of the present invention, the specified amount of components used to obtain the specified extragranular phase is approximately 5% by weight of the specified tablet composition.

- 78 044464

In some embodiments of the present invention, the at least one pharmaceutically acceptable excipient in step i) is a second diluent (eg, microcrystalline cellulose, starch, polyethylene oxide and hydroxypropyl methylcellulose (HPMC)). In some embodiments of the present invention, the at least one pharmaceutically acceptable excipient in step i) is a first diluent (eg, lactose monohydrate, lactose anhydrous, mannitol, or dibasic calcium phosphate). In some embodiments of the present invention, said at least one pharmaceutically acceptable excipient in step i) is a lubricant (eg, magnesium stearate). In some embodiments of the present invention, said at least one pharmaceutically acceptable excipient in step i) is a glidant (eg, silica).

In some embodiments of the present invention, said at least one pharmaceutically acceptable excipient in step i) is microcrystalline cellulose. In some embodiments of the present invention, the at least one pharmaceutically acceptable excipient in step i) is lactose monohydrate, lactose anhydrous, mannitol, or dibasic calcium phosphate. In some embodiments of the present invention, said at least one pharmaceutically acceptable excipient in step i) is magnesium stearate. In some embodiments of the present invention, said at least one pharmaceutically acceptable excipient in step i) is silica.

In some embodiments of the present invention, the granulation in step ii) is wet granulation. In some embodiments of the present invention, wet granulation further includes adding a binder. In some embodiments of the present invention, said binder is a liquid binder. In some embodiments of the present invention, said liquid binder is dissolved povidone. In some embodiments of the present invention, said liquid binder is dissolved starch, dissolved hydroxypropyl cellulose (HPC), dissolved hydroxypropyl methylcellulose (HPMC), or liquid polyethylene glycol (PEG). In some embodiments of the present invention, said liquid binder is a molten binder. In some embodiments of the present invention, said molten binder is a hydrophilic polyethylene glycol (PEG), a poloxamer, a hydrophobic fatty acid, a fatty alcohol, a wax, a hydrogenated vegetable oil, or a glyceride. In some embodiments of the present invention, said binder is a dry binder. In some embodiments of the present invention, said dry binder is hydroxypropyl cellulose (HPC). In some embodiments of the present invention, said dry binder is hydroxypropyl methylcellulose (HPMC). In some embodiments of the present invention, said dry binder is povidone (PVP) or starch. In some embodiments of the present invention, the wet granulation in step ii) further includes wet screening. In some embodiments of the present invention, the wet granulation in step ii) further includes drying and dry screening. In some embodiments of the present invention, drying includes adding a glidant. In some embodiments of the present invention, said glidant is silica.

In some embodiments of the present invention, the granulation in step ii) is dry granulation. In some embodiments of the present invention, said dry granulation includes impact compaction and grinding.

In some embodiments of the present invention, said at least one pharmaceutically acceptable excipient for combining the granules with at least one pharmaceutically acceptable excipient to form a mixture in step iii) is silica. In some embodiments of the present invention, said at least one pharmaceutically acceptable excipient for combining the granules with at least one pharmaceutically acceptable excipient to form a mixture in step iii) is magnesium stearate.

Coating of dosage form

The term coating refers to the process by which an outer layer of coating material is applied to the surface of a dosage dosage form to provide it with certain advantages over the uncoated variety. This involves applying a coating, including sugar or polymer coatings, to the dosage form. Coating tablets provides the benefits of off-flavor masking, off-odor masking, physical and chemical protection, improved handling safety of dosage forms, protection of the drug in chemically challenging environments (eg, the stomach), and control of its release profile. The coating can provide protection against moisture,

- 79 044464 improved appearance, increased mechanical integrity, improved swallowability, improved taste and/or masking of unpleasant odor. Coating can be applied to a wide range of solid oral dosage forms such as particles, powders, granules, crystals, pellets and tablets. When the coating composition is applied to a batch of tablets in a coating apparatus, the surfaces of the tablets are coated with a polymer film. In some embodiments of the present invention, the solid dosage form may contain polyvinyl alcohol (PVA) coating systems with polyethylene glycol (PEG/Macrogol) as a plasticizer. In some embodiments, the coating systems may contain: i) PVA, ii) HPMC with glycerol triacetate (triacetin) as a plasticizer, iii) ethylcellulose with a plasticizer, iv) Eudragit with a plasticizer, and v) acrylates. Commercial coating systems are also available in the art and can be used with any of the solid dosage forms described herein.

Dose uniformity

In some embodiments of the present invention, in the composition, the dose-to-dose variation in niraparib concentration is less than 50%. In some embodiments of the present invention, in the composition, the dose-to-dose variation in niraparib concentration is less than 40%. In some embodiments of the present invention, in the composition, the dose-to-dose variation in niraparib concentration is less than 30%. In some embodiments of the present invention, in the composition, the dose-to-dose variation in niraparib concentration is less than 20%. In some embodiments of the present invention, in the composition, the dose-to-dose variation in niraparib concentration is less than 10%. In some embodiments of the present invention, in the composition, the dose-to-dose variation in niraparib concentration is less than 5%. Specific standards for dosage uniformity can be found in: 1) Ph. Eur. 2.9.40. Uniformity of Dosage Units, 2) JP 6.02 Uniformity of Dosage Units, and 3) USP General Chapter Uniformity of Dosage Units, each of which is incorporated herein by reference.

In some embodiments of the present invention, the dose-to-dose variation in niraparib concentration is calculated based on 10 consecutive doses. In some embodiments of the present invention, the dose-to-dose variation in niraparib concentration is calculated based on 8 consecutive doses. In some embodiments of the present invention, the dose-to-dose variation in niraparib concentration is calculated based on 5 consecutive doses. In some embodiments of the present invention, the dose-to-dose variation in niraparib concentration is calculated based on 3 consecutive doses. In some embodiments of the present invention, the dose-to-dose variation in niraparib concentration is calculated based on 2 consecutive doses.

Kits/Production Items

If desired, niraparib can be provided in a kit. The kits contain a therapeutically effective dose of niraparib to treat diseases and conditions such as cancer. Dosage dosage forms may be packaged in blister packs for ease of daily administration and to improve compliance.

The present invention also provides kits for preventing, treating, or alleviating symptoms of a disease or disorder in a mammal. Typically, such kits will contain one or more niraparib compositions or devices described herein and instructions for use of the kit. The present disclosure also relates to the use of one or more compositions of niraparib for the preparation of medicaments for the treatment, attenuation, reduction or alleviation of symptoms of a disease, dysfunction or disorder in a mammal, such as a human, suspected of having or at risk of developing cancer.

In some embodiments of the present invention, the kit contains one or more additional containers, each of which contains one or more different materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user point of view for the application of the composition, described in this document. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; a label on the case, packaging, container, bottle and/or tube indicating the contents and/or instructions for use and a package insert with instructions for use. An optional set of instructions is included. In a further embodiment of the present invention, the label is on or associated with the container. In yet another further embodiment of the present invention, the label is on the container, with the letters, numbers or other symbols forming the label being affixed, molded or etched onto the container itself; a label is associated with a container if it is located inside a box or case that also contains the container, such as a package insert. In other embodiments of the present invention, a label is used to indicate that the contents are intended for a particular therapeutic use. In yet another embodiment of the present invention, the label also provides instructions for use of the contents, such as those described in

- 80 044464 methods in this document.

In certain embodiments of the present invention, these pharmaceutical compositions are presented in a package or dosing device that contains one or more unit dosage forms containing a compound described herein. In another embodiment of the present invention, said packaging comprises metal or plastic foil, for example a blister pack. In a further embodiment of the present invention, said package or dispensing device is accompanied by instructions for administration. In another further embodiment of the present invention, said package or dispensing device is also accompanied by a notice associated with the container in a form prescribed by a government agency regulating the receipt, use or sale of pharmaceuticals, wherein such notice reflects said agency's approval of said form of the drug for use in human or veterinary. In another embodiment of the present invention, such notice may, for example, be an FDA-approved label or an approved product insert. In another embodiment of the present invention, compositions containing a compound described herein, formulated in a compatible pharmaceutical carrier, are also prepared, placed in an appropriate container and labeled for the treatment of the specified condition.

Although preferred embodiments of the present invention are shown and described herein, those skilled in the art will appreciate that such embodiments are presented by way of example only. Those skilled in the art will appreciate that various variations, changes and substitutions can be made without departing from the present invention. It should be understood that in the practice of the present invention, various alternatives to the embodiments of the present invention described herein can be used. It is intended that the following claims define the scope of the present invention and that they cover methods and structures within the scope of these claims and their equivalents.

Examples

The following examples illustrate some embodiments and aspects of the present invention. It will be apparent to those skilled in the relevant art that various modifications, additions, substitutions and the like may be made without changing the spirit or scope of the present invention, and such modifications and changes are covered by the present invention as defined in the claims. The invention described herein is further illustrated by the following examples, which should not be construed as limiting in any way.

Example 1 Tablet formulations prepared by wet granulation.

The following compositions given in table. 13-14 were obtained by wet granulation as shown in FIG. 1.

Table 13

Composition 1 (300 mg niraparib)

Component Amount (mg) % Intragranular phase Niraparib tosylate monohydrate 478.0 47.8 Lactose monohydrate 203.5 20.4 Microcrystalline cellulose 203.5 20.4

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Crospovidone 40.0 4.0 Povidone 20.0 2.0 Purified water N/A Total (intragranular phase) 945.0 94.5 Extra granular phase Crospovidone 40.0 4.0 Silica 5.0 0.5 Magnesium stearate 10.00 1.0 Total (extragranular phase) 55.0 5.5

Table 14

Composition 2 (300 mg niraparib)

Component Amount (mg) % Intragranular phase Niraparib tosylate monohydrate 478.0 47.8 Lactose monohydrate 193.5 19.4 Microcrystalline cellulose 193.50 19.4 Croscarmellose 40.0 4.0 Hydroxypropyl cellulose 40.0 4.0 Purified water N/A Total (intragranular phase) 945.0 94.5 Extragranular phase Croscarmellose sodium 40.0 4.0 Silica 5.00 0.5 Magnesium stearate 10.00 1.0 Total (extragranular phase) 55.00 5.5

Example 2. Tablet formulations obtained using moisture-activated dry granulation.

The following compositions given in table. 15 were obtained using moisture-activated dry granulation as shown in FIG. 2.

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Table 15

Composition 3 (300 mg niraparib)

Component Amount (mg) % Intragranular phase Niraparib tosylate monohydrate 478.0 47.8 Lactose monohydrate 178.5 17.9 Microcrystalline cellulose 178.5 17.9 Crospovidone 40.0 4.0 Povidone 40.0 4.0 Purified water N/A Silica 25.0 2.5 Total (intragranular phase) 940.0 94.0 Extragranular phase Crospovidone 40.0 4.0 Silica 10.0 1.0 Magnesium stearate 10.00 1.0 Total (extragranular phase) 60.00 6.00

Example 3: Tablet formulations obtained by dry granulation The following formulations given in table. 16-18 were obtained by dry granulation as shown in FIG. 3.

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Table 16

Composition 4 (300 mg niraparib)

Component Amount (mg) % Intragranular phase Niraparib tosylate monohydrate 478.0 47.8 Microcrystalline cellulose 201.0 20.1 Dibasic phosphate calcium 201.0 20.1 Crospovidone 40.0 4.0 Povidone 20.0 2.0 Magnesium stearate 5.0 0.5 Total (intragranular phase) 945.0 94.5 Extragranular phase Crospovidone 40.0 4.0 Silica 5.0 0.5 Magnesium stearate 10.00 1.0 Total (extragranular phase) 55.0 5.5

Table 17

Composition 5 (300 mg niraparib)

Component Amount (mg) % Intragranular phase Niraparib tosylate monohydrate 478.0 47.8 Microcrystalline cellulose 201.0 20.1 Mannitol 201.0 20.1 Croscarmellose sodium 40.0 4.0 Hydroxypropyl cellulose 20.0 2.0 Magnesium stearate 5.0 0.5 Total (intragranular phase) 945.0 94.5 Extragranular phase Croscarmellose sodium 40.0 4.0 Silica 5.0 0.5 Magnesium stearate 10.00 1.0 Total (extragranular phase) 55.0 5.5

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Table 18

Composition 6 (300 mg niraparib)

Component Amount (mg) % Intragranular phase Niraparib tosylate monohydrate 478.0 47.8 Microcrystalline cellulose 201.0 20.1 Mannitol 201.0 20.1 Crospovidone 40.0 4.0 Povidone 20.0 2.0 Magnesium stearate 5.0 0.5 Total (intragranular 945.0 94.5 phase) Contributed granular phase Crospovidone 40.0 4.0 Silica 5.0 0.5 Magnesium stearate 10.00 1.0 Total (extragranular phase) 55.0 5.5

Example 4: Clinical trials.

The safety and effectiveness of niraparib as maintenance therapy was studied in a stage 3, randomized, double-blind, placebo-controlled (NOVA) trial in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. All patients had previously received at least two platinum-containing regimens and had a response (either complete or partial) to the most recent platinum-containing regimen.

Eligible patients were assigned to one of two groups based on test results for germline BRCA gene mutations. Women who were carriers of an inherited germline BRCA mutation were assigned to the germline BRCA mutation (gBRCAmut) cohort (n=203), and women who did not have an inherited germline BRCA mutation were assigned to the non-gBRCAmut cohort (n=350). In each cohort, patients were randomized using a 2:1 allocation of niraparib to placebo. Randomization occurred within 8 weeks of the last dose of the most recent platinum-containing regimen.

Randomization in each cohort was stratified by time to progression after penultimate platinum therapy (6 to <12 months and >12 months); the use of bevacizumab in combination with the penultimate or last treatment regimen with platinum-containing drugs (yes/no); and better response during the most recent platinum-containing regimen (complete response and partial response).

Patients began treatment in a 1/day cycle of 1 niraparib 300 mg or matching placebo administered every day in continuous 28-day cycles. Clinic visits occurred every cycle (4 weeks ± 3 days). Patients randomized to placebo were not allowed to switch to niraparib treatment at any time.

The primary endpoint, PFS (progression-free survival), was determined by central independent assessment according to RECIST (Response Evaluation Criteria in Solid Tumors, version 1.1) or clinical signs and symptoms and CA-125 elevation. PFS, as defined in the NOVA trial, was measured from the time of randomization (which occurred up to 2 months after completion of the last chemotherapy regimen) until disease progression or death.

Prior to tumor trial disclosure, patients randomized to the non-gBRCAmut cohort were tested for homologous recombination disorder (HRD) using the Myriad myChoice® HRD test, which assesses three independent biomarkers of tumor genomic instability:

- 85 044464 loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions. Tumors with homologous recombination disorders and somatic BRCA mutations were defined as HRD-positive (HRDpos).

The primary efficacy analysis for PFS was prospectively determined and assessed in the gBRCAmut cohort. The primary efficacy analysis for PFS was prospectively determined and assessed in the non-gBRCAmut cohort using a hierarchical testing design. In the first step, PFS was assessed in the cohort of patients with HRDpos tumors and, if significant, PFS was assessed in the entire non-gBRCAmut cohort.

Secondary efficacy endpoints included chemotherapy-free interval (CFI), time to first subsequent therapy (TFST), PFS after first subsequent therapy (PFS2), time to second subsequent therapy (TSST), and OS (overall survival).

In table Figure 19 shows results for the primary endpoint of PFS for each of the primary efficacy populations (gBRCAmut cohort, entire non-gBRCAmut cohort, and HRDpos group within the specified non-gBRCAmut cohort).

PFS was significantly longer for patients receiving niraparib compared with those receiving placebo in all three primary efficacy populations.

In the gBRCAmut cohort, median PFS from randomization was 21.0 months with niraparib and 5.5 months with placebo.

In the overall He-gBRCAmut cohort, median PFS from randomization was 9.3 months with niraparib and 3.9 months with placebo.

PFS was also significantly longer with niraparib than with placebo in the HRDpos arm in the non-gBRCAmut cohort, 12.9 months versus 3.8 months.

Table 19

Primary endpoints PFS

cohort gBJ?C4mut cohort negBJ?C4mut HRDpos* Nirapari b (N=138) Placeb o (N=65) Nirapari b (N=234) Placeb o (N=116) Nirapari b (N=106) Placeb o (N=56) Median PFS (95% W 21.0 (12.9, NR) 5.5 (3.8, 7.2) 9.3 (7.2, 11.2) 3.9 (3.7, 5.5) 12.9 (8.1, 15.9) 3.8 (3.5, 5.7) p value <0.0001 <0.0001 <0.0001 Relationships e risk (HR) (95% CI) 0.27 (0.173, 0.410) 0.45 (0.338, 0.607) 0.38 (0.243, 0.586)

*HRDpos represents a prospectively defined subset of the non-gBRCAmut cohort.

t Progression-free survival is defined as the time in months from the date of randomization to disease progression or death. Kaplan-Meier curves for the 2 treatment arms in the gBRCAmut cohort show early divergence of the curves, with the niraparib curve consistently above the placebo curve and the curves steadily separating throughout follow-up (Figure 4).

Kaplan-Meier curves for the 2 treatment groups in the overall non-gBRCAmut cohort show early divergence of the curves, with the niraparib curve consistently above the placebo curve and the curves steadily separating throughout the follow-up period (Fig. 5).

Secondary endpoints CFI and TFST demonstrated a consistent treatment effect in favor of the niraparib group in the gBRCAmut cohort. Median CFI was 22.8 months (95% CI: 17.9, NE) in the niraparib group versus 9.4 months (95% CI: 7.9, 10.6) in the placebo group with FIR (hazard ratio) 0.26 (95% CI: 0.166, 0.409) (p<0.0001). Median TFST was 21.0 months (95% CI: 17.5, NE) in the niraparib group versus 8.4 months (95% CI: 6.6, 10.6) in the placebo group with an HR of 0.31 ( 95% CI: 0.205, 0.481) (p<0.0001).

In the non-gBRCAmut cohort: Median CFI was 12.7 months (95% CI: 11.0, 14.7) in the niraparib group compared with 8.6 months (95% CI: 6.9, 10.0) in placebo group with HR 0.50 (95% CI: 0.370, 0.666) (p < 0.0001). Median TFST was 11.8 months (95% CI: 9.7, 13.1) in the niraparib group versus 7.2 months (95% CI: 5.7, 8.5) in the placebo group with HR 0. 55 (95% CI: 0.412, 0.721) (p<0.0001).

At the time of analysis, results for the secondary endpoints PFS2, OS and TSST were not mature enough to conduct evaluations. However, no adverse effects were observed for any of the endpoints at the end of data collection.

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Example 5. Stability of tablets under storage conditions.

The stability of the tablets described herein, such as the tablets described in Examples 1-3, was assessed when stored in HDPE vials in open containers under accelerated conditions, such as at a temperature of 40°C and 75% relative humidity (r.h.). ). Stability can be assessed, for example, over 1, 3, 6, 9, 12, 24 or 36 months.

Tablets corresponding to Formulations 1 - 6 were assessed for total impurities at 40°C and 75% relative humidity (RH) after storage for 0, 1 and 2 months, and the total impurities measured for each tablet were less than 0.2%.

Tablets corresponding to formulations 1-6 were also evaluated for water content at a temperature of 40°C and relative humidity 75% (r.h.) after storage for 0, 1 and 2 months, the results are shown in table. 20.

Table 20

Water content (%)

Content Content Content water after 0 water water Tablet months after 1 month after 2 months [%] (40 °C/75 rel. (40 °C/75 rel. ow.) [%] ow.) [%] Composition 1 5.0 7.2 6.0 Composition 2 4.3 6.4 5.7 Composition 3 7.7 7.6 7.0 Composition 4 4.3 6.4 6.0 Composition 5 3.4 5.1 4.1 Composition 6 4.2 6.0 4.9

Example 6. Clinical study of tablet compositions.

The study is a multicenter, open-label study in patients with advanced solid tumors and is a two-phase, random-sequence, single-crossover study to evaluate the relative bioavailability (BA) and bioequivalence (BE) of the tablet formulation of niraparib relative to the capsule formulation.

Niraparib will be provided as niraparib tosylate monohydrate in the amounts indicated, based on an equivalent amount of niraparib free base.

At the first stage of the study, pharmacokinetics (PK) are studied. During the PK phase, the patient may receive a single dose of the formulation (eg, one 300 mg tablet or three 100 mg capsules) followed by a 7-day (+1 day) washout/PK period for the phase 1 study and a 14-day (±4 -day) washout/PK period for the phase 2 study, followed by a dose of the alternative formulation also on an empty stomach, followed by a 7-day washout/PK period. Patients receiving tablets in the first stage of treatment will receive capsules in the second stage, and vice versa.

The following pharmacokinetic parameters will be assessed: area under the plasma concentration-time curve (AUC) from time 0 to time of last measured concentration (AUC _0-t ), area under the plasma concentration-time curve from time 0, extrapolated at infinity (AUC _0- ^), apparent total clearance (CL/F), C _max , tmax, terminal half-life (t _1/2 ), apparent final volume of distribution (Vz/F) and bioavailability/bioequivalence of the tablet formulation compared to the encapsulated formulation.

In some embodiments, the 90% confidence interval of the geometric least squares ratio of the PK parameter for a tablet formulation is about 80-125%, or about 90-110% of the same PK parameter for a capsule formulation, providing an equivalent administered dose of niraparib.

When patients complete the FC phase of the study (at least 7 days from the start of the FC 2 phase), they may be eligible to participate in the extension phase and continue to receive niraparib. Tumor assessment can be performed before the first dose of the additional step (pre-additional step).

The initial dose of niraparib in the extension phase may be based on the patient's baseline true body weight or platelet count. Patients with a baseline true body weight >77 kg and a platelet count at screening >150,000/µL (after completion of the PK step as part of screening in the additional step) will take one 300 mg tablet or 3 x 100 mg capsules at each dosing (1 once a day). Patients with initial true body weight <77 kg and/or amount

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Claims (17)

platelets when screening <150,000/μL, one 200 mg tablet or 2 100 mg capsules (once daily) will be taken at each dose. For patients whose initial dose is 200 mg once daily, an increase to 300 mg once daily is permitted after 2 cycles of therapy unless interruption or discontinuation of treatment is required during the first 2 cycles of the additional phase of therapy. If the patient begins the extension phase with a dose of 100 mg, a dose increase to 200 mg may be considered after 2 cycles of therapy, unless interruption or discontinuation of treatment is required during the first 2 cycles of the extension phase of therapy, and after approval of the sponsor . The patient can remain on the same formulation (tablet or capsule) throughout the additional phase. Patients will return for a follow-up visit on the first day of each treatment cycle (28±7 days) to receive the test drug and undergo a safety assessment. Visits will continue approximately every 4 weeks until treatment is stopped. The US prescribing information for niraparib allows dose interruption (up to 28 days) due to adverse events (AEs). In addition, due to AEs, a dose reduction to 200 mg once daily and then to 100 mg once daily is permitted. For example, in table. 21 provides illustrative dose modifications based on non-hematologic toxicity. Table 21 Niraparib dose reduction for non-hematologic toxicity Event Dose ¹ Initial dose 300 mg 1 time/day First dose reduction for treatment-related AEs or grade 3 or 4 SAEs per NCICCAE v.4.03 where prevention is not considered feasible 200 mg 1 time / day Second dose reduction for grade 3 or 4 AEs or SAEs per NCI-CTCAE v.4.03 where prevention is not considered feasible 100 mg 1 time/day Continued CTCAE grade 3 or 4 treatment-related AEs or SAEs >28 days Stop taking the study drug Abbreviations: AE=adverse event; CTCAE=Common Terminology Criteria for Adverse Events; NCI-CTCAE=National Cancer Institute CTCAE; SAE=serious adverse event; 1 r/day = once a day ^{, 1} dose should not be reduced to less than 100 mg per day. Example 7: Stability data. Stability data for exemplary niraparib formulations presented in 100 and 300 mg tablets are shown in Table. 22 and in fig. 6-9. As these data demonstrate, the dosage forms described herein may have the desired stability. Table 22 Stability data for niraparib tablets Batch number and dosage Storage conditions: Storage time (months) Corresponding figure Batch A 25°C/60% rel. ow. T = 6 Fig. 6 (100 mg) 40°C/75% rel. ow. T = 6 Fig. 7 Party B 25°C/60% rel. ow. T = 6 Fig. 8 (300 mg) 40°C/75% rel. ow. T = 6 Fig. 9 CLAIM 1. Polyadenosine diphosphate ribose polymerase (PARP) inhibition tablet containing the following components in mass percentage: (a) in the intragranular part: (i) 40-50% 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1); - 88 044464 (ii) 9-11% of the first diluent; (iii) 30-40% second diluent; (iv) 1-3% binder; (v) 0.1-2% disintegrant; (vi) 2-4% glidant or adsorbent or absorbent; and (vii) 0.1-2% lubricant; and (b) in the extragranular part: (i) 0.1-2% disintegrant; (ii) 0.1-2% glidant or adsorbent or absorbent; and (iii) 0.1-2% lubricant. 2. A tablet according to claim 1, characterized in that said first diluent is lactose monohydrate. 3. A tablet according to any one of claims 1, 2, characterized in that said second diluent is microcrystalline cellulose. 4. A tablet according to any one of claims 1-3, characterized in that said binder is povidone. 5. A tablet according to any one of claims 1 to 4, characterized in that said disintegrant of the intragranular part is crospovidone. 6. A tablet according to any one of claims 1 to 5, characterized in that said glidant, adsorbent or absorbent of the intragranular part is silicon dioxide. 7. A tablet according to any one of claims 1 to 6, characterized in that said lubricant of the intragranular part is magnesium stearate. 8. A tablet according to any one of claims 1 to 7, characterized in that said disintegrant of the extragranular part is crospovidone. 9. A tablet according to any one of claims 1 to 8, characterized in that said glidant, adsorbent or extragranular part absorbent is silicon dioxide. 10. A tablet according to any one of claims 1 to 9, characterized in that said extragranular lubricant is magnesium stearate. 11. Tablet according to claim 1, characterized in that: (i) the first intragranular portion diluent is lactose monohydrate; (ii) the second intragranular part diluent is microcrystalline cellulose; (iii) the intragranular portion binder is povidone; (iv) the intragranular disintegrant is crospovidone; (v) the glidant, adsorbent or absorbent of the intragranular portion is silica; (vi) the intragranular lubricant is magnesium stearate; (vii) the disintegrating agent of the extragranular part is crospovidone; (viii) the glidant, adsorbent or extragranular portion absorbent is silica; and (ix) the extragranular lubricant is magnesium stearate. 12. A tablet according to any one of claims 1 to 11, additionally containing a film coating. 13. A tablet according to claim 12, characterized in that the film coating is Opadry II. 14. Tablet according to any one of claims 1 to 13, characterized in that the amount of 2-{4-[(3S)-piperidin-3yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1 ) per tablet is 100 mg based on niraparib free base. 15. Tablet according to any one of claims 1 to 13, characterized in that the amount of 2-{4-[(3S)-piperidin-3yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1 ) per tablet is 200 mg based on niraparib free base. 16. Tablet according to any one of claims 1 to 13, characterized in that the amount of 2-{4-[(3S)-piperidin-3yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1 ) per tablet is 300 mg based on niraparib free base. 17. Tablet for polyadenosine diphosphate ribose polymerase (PARP) inhibition, containing the following components in mass percentage: (a) in the intragranular part: (i) 40-50% 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1); (ii) 9-11% of a first diluent selected from lactose monohydrate, lactose anhydrous, mannitol and dibasic calcium phosphate; (iii) 30-40% of a second diluent selected from microcrystalline cellulose, starch, polyethylene oxide and hydroxypropyl methylcellulose; (iv) 1-3% binder selected from povidone, hydroxypropylcellulose and hydroxypropylme -