US20230416223A1 - Niraparib Compositions - Google Patents
Niraparib Compositions Download PDFInfo
- Publication number
- US20230416223A1 US20230416223A1 US18/310,238 US202318310238A US2023416223A1 US 20230416223 A1 US20230416223 A1 US 20230416223A1 US 202318310238 A US202318310238 A US 202318310238A US 2023416223 A1 US2023416223 A1 US 2023416223A1
- Authority
- US
- United States
- Prior art keywords
- composition
- crystalline form
- indazole
- piperidin
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- Niraparib is an orally active and potent poly (ADP-ribose) polymerase, or PARP, inhibitor.
- Niraparib and pharmaceutically acceptable salts thereof are disclosed in International Publication No. WO2007/113596 and European Patent No. EP2007733B1; International Publication No. WO2008/084261 and U.S. Pat. No. 8,071,623; and International Publication No. WO2009/087381 and U.S. Pat. No. 8,436,185.
- Methods of making niraparib and pharmaceutically acceptable salts thereof are disclosed in International Publication Nos. WO2014/088983 and WO2014/088984.
- Methods to treat cancer with niraparib and pharmaceutically acceptable salts thereof are disclosed in U.S. Provisional Patent Application Nos. 62/356,461, 62/402,427, 62/470,141, and PCT application PCT/US17/40039. The contents of each of the foregoing references are incorporated herein
- PARP is a family of proteins involved in many functions in a cell, including DNA repair, gene expression, cell cycle control, intracellular trafficking and energy metabolism. PARP proteins play key roles in single strand break repair through the base excision repair pathway. PARP inhibitors have shown activity as a monotherapy against tumors with existing DNA repair defects, such as BRCA1 and BRCA2, and as a combination therapy when administered together with anti-cancer agents that induce DNA damage.
- One embodiment provides a composition comprising crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- Another embodiment provides the composition wherein the crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- compositions where the crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide is characterized by at least one X-ray diffraction pattern reflection selected from a 2 ⁇ value of 9.5 ⁇ 0.2, 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 24.9 ⁇ 0.2, 25.6 ⁇ 0.2, 26.0 ⁇ 0.2, and 26.9 ⁇ 0.2.
- composition wherein the crystalline Form I is characterized by X-ray diffraction pattern reflections at 2 ⁇ values of 9.5 ⁇ 0.2 and 26.0 ⁇ 0.2.
- composition wherein the crystalline Form I is characterized by X-ray diffraction pattern reflections at 2 ⁇ values of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- compositions wherein the crystalline Form I are characterized by at least one X-ray diffraction pattern reflection selected from a 2 ⁇ value of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- composition wherein the crystalline Form I is characterized by at least two X-ray diffraction pattern reflections selected from a 2 ⁇ value of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- compositions wherein the crystalline Form I is characterized by at least three X-ray diffraction pattern reflections selected from a 2 ⁇ value of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- composition wherein the crystalline Form I is characterized by at least four X-ray diffraction pattern reflections selected from a 2 ⁇ value of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- composition wherein the crystalline Form I is characterized by a scanning differential calorimetry pattern substantially as shown in FIG. 2 .
- compositions wherein the crystalline Form I are characterized by a Raman spectroscopy pattern substantially as shown in FIG. 3 .
- composition wherein the crystalline Form I is characterized by an infrared spectroscopy pattern substantially as shown in FIG. 4 .
- composition wherein the crystalline Form I is characterized by a dynamic water vapor sorption pattern substantially as shown in FIG. 5 .
- composition wherein the presence of Form III is characterized by at least one X-ray diffraction pattern reflection selected from a 2 ⁇ value of 17.8 ⁇ 0.2, 19.0 ⁇ 0.2, or 22.8 ⁇ 0.2.
- compositions wherein substantially free of Form II and Form III means less than about 20% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- composition wherein substantially free of Form II and Form III means less than about 15% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- composition wherein substantially free of Form II and Form III means less than about 10% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- compositions wherein substantially free of Form II and Form III means less than about 8% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- composition wherein substantially free of Form II and Form III means less than about 6% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- composition wherein substantially free of Form II and Form III means less than about 4% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- compositions wherein substantially free of Form II and Form III means less than about 3% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- composition wherein substantially free of Form II and Form III means less than about 2% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- composition wherein substantially free of Form II and Form III means less than about 1% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- One embodiment provides a composition comprising crystalline Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide and crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- One embodiment provides a composition comprising crystalline Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- One embodiment provides a composition comprising crystalline Form II 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide and crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- crystalline Form II is characterized by at least one X-ray diffraction pattern reflection selected from a 2 ⁇ value of 9.7 ⁇ 0.3, 12.8 ⁇ 0.3, 17.9 ⁇ 0.3, 19.7 ⁇ 0.3, and 21.8 ⁇ 0.3.
- crystalline Form II has an X-ray powder diffraction pattern substantially as shown in FIG. 9 for Form II.
- One embodiment provides a composition comprising crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide and crystalline Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- One embodiment provides a composition comprising crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- One embodiment provides crystalline Form III characterized by at least one X-ray diffraction pattern reflection selected from a 2 ⁇ value of 17.8 ⁇ 0.2, 19.0 ⁇ 0.2, or 22.8 ⁇ 0.2.
- One embodiment provides crystalline Form III that has an X-ray powder diffraction pattern substantially as shown in FIG. 9 for Form III.
- One embodiment provides crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide that has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
- One embodiment provides crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide characterized by a dynamic water vapor sorption pattern substantially as shown in FIG. 8 .
- One embodiment provides crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide characterized by a scanning differential calorimetry pattern substantially as shown in FIG. 2 .
- One embodiment provides a method of making crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide, comprising dissolving a composition comprising Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide or Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide, or a mixture thereof, in a solvent having a water:organic solvent ratio of about 10:1 to about 400:1 (v/v), and crystallizing the crystalline Form I.
- Another embodiment provides the method wherein the water:organic solvent ratio is about 10:1 (v/v), about 50:1 (v/v), about 100:1 (v/v), about 200:1 (v/v), about 300:1 (v/v), or about 400:1 (v/v).
- the organic solvent is a polar solvent, a polar protic solvent, a polar aprotic solvent, an ether-containing solvent, or any combination thereof.
- compositions wherein the organic solvent is 2-propanol, acetone, methyl ethyl ketone, acetonitrile, acetic acid, formic acid, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof.
- the organic solvent is acetone, methyl ethyl ketone, acetonitrile, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof.
- Another embodiment provides the composition wherein the organic solvent is 2-propanol, acetic acid, formic acid, or any combination thereof.
- composition wherein the organic solvent and water is heated prior to crystallization.
- One embodiment provides a composition comprising crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide prepared by dissolving a composition comprising Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide or Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide, or a mixture thereof, in a solvent having a water:organic solvent ratio of about 10:1 to about 400:1 (v/v), and crystallizing the crystalline Form I.
- compositions wherein the water:organic solvent ratio is about 10:1 (v/v), about 50:1 (v/v), about 100:1 (v/v), about 200:1 (v/v), about 300:1 (v/v), or about 400:1 (v/v).
- organic solvent is a polar solvent, a polar protic solvent, a polar aprotic solvent, an ether-containing solvent, or any combination thereof.
- compositions wherein the organic solvent is 2-propanol, acetone, methyl ethyl ketone, acetonitrile, acetic acid, formic acid, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof.
- the organic solvent is acetone, methyl ethyl ketone, acetonitrile, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof.
- Another embodiment provides the composition wherein the organic solvent is 2-propanol, acetic acid, formic acid, or any combination thereof.
- composition wherein the organic solvent and water is heated prior to crystallization.
- a composition described herein is a pharmaceutical composition (e.g., a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient).
- a pharmaceutical composition comprising crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide, and at least one pharmaceutically acceptable excipient.
- Another embodiment provides the pharmaceutical composition wherein the composition is in an oral dosage form.
- Another embodiment provides the pharmaceutical composition wherein the oral dosage form is a tablet or capsule.
- One embodiment provides an article of manufacture comprising multiple unit doses of the pharmaceutical composition in a sealed container with written instructions for use.
- the article of manufacture comprising multiple unit doses of the pharmaceutical composition in a sealed container with written instructions for use further comprises an induction seal, desiccant, or any combination thereof.
- One embodiment provides a method for treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition comprising crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide, and at least one pharmaceutically acceptable excipient, wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric cancer, bladder cancer, lung cancer, bone cancer, colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epider
- One embodiment provides a method for treating cancer in a patient having been diagnosed with cancer comprising administering to said patient a therapeutically effective amount of the pharmaceutical comprising crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide, and at least one pharmaceutically acceptable excipient, wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric cancer, bladder cancer, lung cancer, bone cancer, colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epi
- Another embodiment provides the method wherein the cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, and combinations thereof. Another embodiment provides the method wherein the cancer is a recurrent cancer. Another embodiment provides the method wherein the subject is a human subject. Another embodiment provides the method wherein the human subject was previously treated with a chemotherapy. Another embodiment provides the method wherein the chemotherapy is a platinum-based chemotherapy. Another embodiment provides the method wherein the human subject had a complete or partial response to the chemotherapy. Another embodiment provides the method wherein the pharmaceutical composition is administered once per day, twice per day, three times per day, or four times per day. Another embodiment provides the method wherein the pharmaceutical composition is administered once per week, twice per week, three times per week, or four times per week.
- Another embodiment provides the method wherein the pharmaceutical composition is administered every other day. Another embodiment provides the method wherein the pharmaceutical composition is administered once per day. Another embodiment provides the method wherein the total dose of a the pharmaceutical composition administered within a 24 hour period is about 1 mg to about 1000 mg. Another embodiment provides the method wherein the total dose is about 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 600 mg, about 500 mg, about 400 mg, about 300 mg, about 200 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 40 mg, about 30 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg. Another embodiment provides the method wherein the pharmaceutical composition is administered once per day and the total daily dose is about 300 mg. Another embodiment provides the method wherein the administration is oral administration.
- FIG. 1 shows an exemplary X-ray powder diffraction pattern for crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- FIG. 2 shows an exemplary scanning differential calorimetry pattern for crystalline monohydrate Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide and crystalline anhydrous Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- FIG. 3 shows an exemplary Raman spectroscopy pattern for crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- FIG. 4 shows an exemplary infrared spectroscopy pattern for crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- FIG. 5 shows an exemplary dynamic water vapor sorption pattern for crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- FIG. 6 shows an overlay of exemplary X-ray powder diffraction patterns for crystalline Form I, and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- FIG. 7 shows an exemplary X-ray powder diffraction pattern for crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- FIG. 8 shows an exemplary dynamic water vapor sorption pattern for crystalline anhydrous Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- FIG. 9 shows an overlay of exemplary X-ray powder diffraction patterns for crystalline Form I, Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- cancer includes both solid tumors and hematological malignancies.
- Cancers include, but are not limited to, ovarian cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric cancer, bladder cancer, lung cancer (e.g., adenocarcinoma, NSCLC and SCLC), bone cancer (e.g., osteosarcoma), colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma (e.g., liposarcoma), bladder cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma), myeloid disorders (e.g., AML, CML, mye
- composition as in pharmaceutical composition, is intended to encompass a drug product comprising niraparib or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, and the other inert ingredient(s) (pharmaceutically acceptable excipients).
- pharmaceutical compositions are synonymous with “formulation” and “dosage form”.
- compositions of the invention include, but are not limited to, granules, tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, orally disintegrating tablets, pulsatile release tablets, timed release tablets, delayed release, controlled release, extended release and sustained release tablets), capsules (hard and soft or liquid filled soft gelatin capsules), pills, troches, sachets, powders, microcapsules, minitablets, tablets in capsules and microspheres, matrix composition and the like.
- the pharmaceutical composition refers to capsules.
- the pharmaceutical composition refers to hard gelatin capsules or IPMC based capsules.
- the pharmaceutical composition refers to hard gelatin capsules.
- “Diluents” increase bulk of the composition to facilitate compression or create sufficient bulk for homogenous blend for capsule filling.
- Such compounds include e.g., lactose, 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, compressible sugar, such as Di-Pac® (Amstar); mannitol, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, confectioner's sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin;
- an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of the niraparib being administered that would be expected to relieve to some extent one or more of the symptoms of the disease or condition being treated.
- the result of administration of niraparib disclosed herein is reduction and/or alleviation of the signs, symptoms, or causes of cancer.
- an “effective amount” for therapeutic uses is the amount of niraparib, including a formulation as disclosed herein required to provide a decrease or amelioration in disease symptoms without undue adverse side effects.
- therapeutically effective amount includes, for example, a prophylactically effective amount.
- an “an effective amount” or a “therapeutically effective amount” varies, in some embodiments, from subject to subject, due to variation in metabolism of the compound administered, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
- enhancing refers to an increase or prolongation of either the potency or duration of a desired effect of niraparib, or a diminution of any adverse symptomatology that is consequent upon the administration of the therapeutic agent.
- enhancing refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents that are used in combination with niraparib disclosed herein.
- An “enhancing-effective amount,” as used herein, refers to an amount of niraparib or other therapeutic agent which is adequate to enhance the effect of another therapeutic agent or niraparib in a desired system. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
- excipient means a pharmacologically inactive component such as a diluent, lubricant, surfactant, carrier, or the like. Excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of present invention.
- “Filling agents” or “fillers” include compounds such as lactose, lactose monohydrate, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
- “Lubricants” and “glidants” are compounds that prevent, reduce or inhibit adhesion or friction of materials.
- Exemplary lubricants include, e.g., 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-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol (e.g., PEG-4000) or a methoxypolyethylene glycol such as CarbowaxTM, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lau
- subject is used to mean an animal, preferably a mammal, including a human or non-human.
- patient and subject may be used interchangeably.
- a “therapeutically effective amount” or “effective amount” is that amount of a pharmaceutical agent to achieve a pharmacological effect.
- the term “therapeutically effective amount” includes, for example, a prophylactically effective amount.
- An “effective amount” of niraparib is an amount needed to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects.
- the effective amount of a niraparib will be selected by those skilled in the art depending on the particular patient and the disease. It is understood that “an effective amount” or a “therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of niraparib, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
- amelioration or lessening of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any decrease of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that is attributed to or associated with administration of the compound or composition.
- treat include alleviating, abating or ameliorating a disease or condition, for example cancer, symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
- weight percent As used herein, “weight percent,” “wt %,” “percent by weight,” “% by weight,” and variations thereof refer to the concentration of a substance as the weight of that substance divided by the total weight of the composition and multiplied by 100.
- the present invention relates to solid dosage forms of niraparib and pharmaceutically acceptable salts thereof (e.g., niraparib tosylate monohydrate), including solid forms having desirable characteristics favorable for pharmaceutical development.
- Niraparib has the following structure:
- Niraparib is an orally available, selective poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitor.
- Methods of administering niraparib to cancer patients are also described in WO2018/005818, which is hereby incorporated by reference in its entirety.
- niraparib tosylate monohydrate 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1) and it has the following chemical structure:
- Niraparib tosylate monohydrate drug substance is a white to off-white, non-hygroscopic crystalline solid.
- Niraparib solubility is pH independent below the pKa of 9.95, with an aqueous free base solubility of 0.7 mg/mL to 1.1 mg/mL across the physiological pH range.
- Methods for preparation of niraparib include those described in WO 2014/088983; WO 2014/088984; U.S. Pat. Nos. 8,071,623; 8,436,185; U.S. 62/489,415 filed Apr. 24, 2017; and Jones et al., J. Med. Chem., 52:7170-7185, 2009, each of which is incorporated by reference in its entirety.
- Niraparib prepared according to these methods can be used in the methods of preparation of the crystalline solid forms described herein.
- crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide can be prepared from solvent systems comprising water (e.g., as described in Example 1 and Example 2).
- Crystalline Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide can be produced under anhydrous conditions.
- Crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide can be produced from crystalline Form I under heating conditions (e.g., as described in Example 3).
- crystalline solid forms of 4-toluenesufonate salts of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide are provided herein.
- Crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide is the 4-toluenesulfonate salt and is a monohydrate.
- Crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide is also referred to by interchangeable terms such as: Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide; crystalline monohydrate Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide; crystalline Form I of niraparib tosylate monohydrate; crystalline Form I; or Form I.
- Exemplary X-ray powder diffraction data for Form I is provided in FIG. 1 and FIG. 6 .
- FIG. 1 and FIG. 6 Exemplary X-ray powder diffraction data for Form I is provided in FIG. 1 and FIG. 6 .
- FIG. 2 shows an exemplary scanning differential calorimetry pattern for crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- FIG. 3 shows an exemplary Raman spectroscopy pattern for crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- FIG. 4 shows an exemplary infrared spectroscopy pattern for crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- FIG. 5 shows an exemplary dynamic water vapor sorption pattern for crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- Crystalline Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide is the 4-toluenesulfonate salt and is a non-stoichiometric hydrate.
- Crystalline Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide is also referred to by interchangeable terms such as: Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide; crystalline Form II of niraparib; crystalline Form II; or Form II.
- Crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide is the 4-toluenesulfonate salt and is an anhydrous form.
- Exemplary X-ray powder diffraction data for Form III is provided in FIG. 6 and FIG. 7 .
- FIG. 2 shows an exemplary scanning differential calorimetry pattern for crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- FIG. 8 shows an exemplary dynamic water vapor sorption pattern for crystalline anhydrous Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- Crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide is also referred to by interchangeable terms such as: Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide; crystalline anhydrous Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide; crystalline Form III of niraparib; crystalline Form III; or Form III.
- FIG. 2 shows an exemplary scanning differential calorimetry pattern for crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phen
- Solid forms of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide described herein can have beneficial properties, including favorable properties for use in methods of treatment or in methods of manufacture of pharmaceutical formulations.
- a hydrochloride salt of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide has been shown to be highly hygroscopic.
- crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide is a non-hygroscopic solid form having suitable solubility properties, as well as favorable physical and chemical stability.
- compositions comprising crystalline Form I of niraparib tosylate monohydrate substantially free of Form II and Form III.
- compositions wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- compositions where the crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide is characterized by at least one X-ray diffraction pattern reflection selected from a 2 ⁇ value of 9.5 ⁇ 0.2, 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 24.9 ⁇ 0.2, 25.6 ⁇ 0.2, 26.0 ⁇ 0.2, and 26.9 ⁇ 0.2.
- composition wherein the crystalline Form I is characterized by X-ray diffraction pattern reflections at 2 ⁇ values of 9.5 ⁇ 0.2 and 26.0 ⁇ 0.2.
- composition wherein the crystalline Form I is characterized by X-ray diffraction pattern reflections at a 2 ⁇ values of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- compositions wherein the crystalline Form I are characterized by at least one X-ray diffraction pattern reflection selected from a 2 ⁇ value of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- composition wherein the crystalline Form I is characterized by at least two X-ray diffraction pattern reflections selected from a 2 ⁇ value of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- compositions wherein the crystalline Form I is characterized by at least three X-ray diffraction pattern reflections selected from a 2 ⁇ value of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- composition wherein the crystalline Form I is characterized by at least four X-ray diffraction pattern reflections selected from a 2 ⁇ value of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- composition wherein the crystalline Form I is characterized by a scanning differential calorimetry pattern substantially as shown in FIG. 2 .
- compositions wherein the crystalline Form I are characterized by a Raman spectroscopy pattern substantially as shown in FIG. 3 .
- composition wherein the crystalline Form I is characterized by an infrared spectroscopy pattern substantially as shown in FIG. 4 .
- composition wherein the crystalline Form I is characterized by a dynamic water vapor sorption pattern substantially as shown in FIG. 5 .
- One embodiment provides a composition comprising crystalline Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide and crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- One embodiment provides a composition comprising crystalline Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- compositions comprising comprising crystalline Form II 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide and crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- crystalline Form II is characterized by at least one X-ray diffraction pattern reflection selected from a 2 ⁇ value of 9.7 ⁇ 0.3, 12.8 ⁇ 0.3, 17.9 ⁇ 0.3, 19.7 ⁇ 0.3, and 21.8 ⁇ 0.3.
- crystalline Form II has an X-ray powder diffraction pattern substantially as shown in FIG. 9 for Form II.
- One embodiment provides a composition comprising crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide and crystalline Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- One embodiment provides a composition comprising crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- One embodiment provides crystalline Form III characterized by at least one X-ray diffraction pattern reflection selected from a 2 ⁇ value of 17.8 ⁇ 0.2, 19.0 ⁇ 0.2, or 22.8 ⁇ 0.2.
- One embodiment provides crystalline Form III that has an X-ray powder diffraction pattern substantially as shown in FIG. 9 for Form III.
- One embodiment provides crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide that has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
- One embodiment provides crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide characterized by a dynamic water vapor sorption pattern substantially as shown in FIG. 8 .
- One embodiment provides crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide characterized by a scanning differential calorimetry pattern substantially as shown in FIG. 2 .
- Niraparib is a selective poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitor which selectively kills tumor cells in vitro and in mouse xenograft models.
- PARP inhibition leads to irreparable double strand breaks (DSBs), use of the error-prone DNA repair pathway, resultant genomic instability, and ultimately cell death. Additionally, PARP trapped at genetic lesions as a result of the suppression of autoparlyation can contribute to cytotoxicity.
- PARP poly(ADP-ribose) polymerase
- ZEJULATM is indicated for the maintenance or treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer following a complete or partial response to platinum-based chemotherapy.
- Each ZEJULATM capsule contains 100 mg of niraparib (as tosylate monohydrate).
- the hard capsules have a white body with “100 mg” printed in black ink, and a purple cap with “Niraparib” printed in white ink.
- the recommended dose of ZEJULATM as monotherapy is three 100 mg capsules taken orally once daily, equivalent to a total daily dose of 300 mg.
- the oral composition containing niraparib or its pharmaceutically acceptable salts.
- the oral composition includes from about 20 wt % to about 60 wt % of niraparib for treatment of a disorder or condition such as cancer; and a pharmaceutically acceptable carrier, wherein the niraparib is distributed with substantial uniformity throughout the pharmaceutically acceptable carrier.
- the disorder or condition is cancer, for example, ovarian cancer.
- the niraparib is a pharmaceutically acceptable salt thereof.
- the pharmaceutically acceptable salt is niraparib tosylate monohydrate.
- the niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the pharmaceutical composition comprises about 50 mg to about 300 mg of niraparib tosylate monohydrate. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 300 mg of niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the pharmaceutical composition can comprise about 100 mg to about 200 mg of niraparib tosylate monohydrate.
- the pharmaceutical composition can comprise about 125 mg to about 175 mg of niraparib tosylate monohydrate.
- the formulation can comprise one or more components, including niraparib.
- the components can be combined to create a powder blend that is used to fill capsules.
- the powder blend can be filled into gelatin capsules, such as size 0 gelatin capsules.
- the niraparib may be present in the formulation as a pharmaceutically acceptable salt.
- the niraparib can be niraparib tosylate monohydrate.
- the formulation can comprise one or more diluents.
- the formulation can comprise lactose monohydrate.
- the formulation can comprise one or more lubricants.
- the formulation can comprise magnesium stearate.
- An exemplary niraparib formulation of the present invention comprises 100 mg of niraparib (based on free base, 1.000 mg niraparib anhydrous free base is equivalent to 1.594 mg niraparib tosylate monohydrate), 254.5 mg of lactose monohydrate and magnesium stearate.
- An exemplary niraparib formulation of the present invention comprises 100 mg of niraparib (based on free base, 1.000 mg niraparib anhydrous free base is equivalent to 1.594 mg niraparib tosylate monohydrate), 254.5 mg of lactose monohydrate, and magnesium stearate. It may also optionally comprisetartrazine.
- niraparib can be administered once, twice or three times daily in capsules using the manufacturing methods and compositions that have been described herein to achieve these results.
- the niraparib is present in an amount of from about 20-80 wt %, about 45-70 wt %, about 40-50 wt %, about 45-55 wt %, about 50-60 wt %, about 55-65 wt %, about 60-70 wt %, about 65-75 wt %, about 70-80 wt %, or about 40-60 wt %.
- the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the compositions described herein have a concentration of niraparib of 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 50%, or from about 45% to about 50% by weight of the composition.
- the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the compositions described herein have a concentration of niraparib of 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%, or from about 40% to about 45% by weight of the composition.
- the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the compositions described herein have a concentration of niraparib of 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 composition.
- the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the compositions described herein have a concentration of niraparib of from about 10% to about 35%, from about 50% 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%, or from about 30% to about 35% by weight of the composition.
- the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the compositions described herein have a concentration of niraparib of about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of the composition. In some embodiments, the compositions described herein have a concentration of niraparib tosylate monohydrate of about 19.16% by weight of the composition. In some embodiments, the compositions described herein have a concentration of niraparib tosylate monohydrate of about 38.32% by weight of the composition. In some embodiments, the compositions described herein have a concentration of niraparib tosylate monohydrate of about 57.48% by weight of the composition.
- the compositions described herein have a concentration of niraparib tosylate monohydrate of about 76.64% by weight of the composition.
- the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the compositions described herein have an amount of niraparib of from about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 25 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg,
- the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- compositions described herein can have an amount of niraparib tosylate monohydrate of from about 1 mg to about 1000 mg, for example, from about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 25 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850
- the compositions described herein have an amount of niraparib of 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, or 1000 mg.
- the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- compositions described herein can have an amount of niraparib tosylate monohydrate of 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, or 1000 mg.
- the compositions described herein have an amount of niraparib of 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, or about 500 mg.
- the compositions described herein can have an amount of niraparib tosylate monohydrate of 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, or about 500 mg.
- the compositions described herein have an amount of niraparib tosylate monohydrate of about 79.7 mg.
- the compositions described herein have an amount of niraparib tosylate monohydrate of about 159.4 mg.
- the compositions described herein have an amount of niraparib tosylate monohydrate of about 159.4 mg, wherein the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. In some embodiments, the compositions described herein have an amount of niraparib tosylate monohydrate of about 159.4 mg, wherein the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- the compositions described herein have an amount of niraparib tosylate monohydrate of about 159.4 mg, wherein the niraparib tosylate monohydrate is the crystalline Form I with an X-ray powder diffraction pattern substantially as shown in FIG. 1 . In some embodiments, the compositions described herein have an amount of niraparib tosylate monohydrate of about 318.8 mg. In some embodiments, the compositions described herein have an amount of niraparib tosylate monohydrate of about 478.2 mg. In some embodiments, the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the pharmaceutical composition disclosed herein comprises one or more pharmaceutically acceptable excipients.
- exemplary pharmaceutically acceptable excipients for the purposes of pharmaceutical compositions disclosed herein include, but are not limited to, binders, disintegrants, superdisintegrants, lubricants, diluents, fillers, flavors, glidants, sorbents, solubilizers, chelating agents, emulsifiers, thickening agents, dispersants, stabilizers, suspending agents, adsorbents, granulating agents, preservatives, buffers, coloring agents and sweeteners or combinations thereof.
- binders include microcrystalline cellulose, hydroxypropyl methylcellulose, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinylpolypyrrolidone, carboxymethylcellulose calcium, carboxymethylcellulose sodium, ceratonia , chitosan, cottonseed oil, dextrates, dextrin, ethylcellulose, gelatin, glucose, glyceryl behenate, galactomannan polysaccharide, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, 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, tocofersolan, zein, or combinations thereof.
- disintegrants examples include hydroxypropyl methylcellulose (HPMC), low substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium, sodium starch glycolate, lactose, magnesium aluminum silicate, methylcellulose, polacrilin potassium, sodium alginate, starch, or combinations thereof.
- HPMC hydroxypropyl methylcellulose
- L-HPC low substituted hydroxypropyl cellulose
- croscarmellose sodium sodium starch glycolate
- lactose lactose
- magnesium aluminum silicate magnesium aluminum silicate
- methylcellulose polacrilin potassium
- sodium alginate starch, or combinations thereof.
- Examples of a lubricant include stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, glycerin 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, potassium benzoate, magnesium stearate or combinations thereof.
- 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, sulfobutylether ⁇ -cyclodextrin, tragacanth, trehalose, xylitol, or combinations thereof.
- the pharmaceutically acceptable excipient is hydroxypropyl methylcellulose (HPMC). In some embodiments, the pharmaceutically acceptable excipient is low substituted hydroxypropyl cellulose (L-HPC). In some embodiments, the pharmaceutically acceptable excipient is lactose. In some embodiments, the pharmaceutically acceptable excipient is lactose monohydrate. In some embodiments, the pharmaceutically acceptable excipient is magnesium stearate. In some embodiments, the pharmaceutically acceptable excipient is lactose monohydrate and magnesium stearate.
- HPMC hydroxypropyl methylcellulose
- L-HPC low substituted hydroxypropyl cellulose
- the pharmaceutically acceptable excipient is lactose. In some embodiments, the pharmaceutically acceptable excipient is lactose monohydrate. In some embodiments, the pharmaceutically acceptable excipient is magnesium stearate. In some embodiments, the pharmaceutically acceptable excipient is lactose monohydrate and magnesium stearate.
- Various useful fillers or diluents include, but are not limited to calcium carbonate (BarcroftTM, MagGranTM, MillicarbTM, Pharma-CarbTM, PrecarbTM, SturcalTM, Vivapres CaTM) calcium phosphate, dibasic anhydrous (Emcompress AnhydrousTM, FujicalinTM), calcium phosphate, dibasic dihydrate (CalstarTM, Di-CafosTM, EmcompressTM), calcium phosphate tribasic (Tri-CafosTM TRI-TABTM), calcium sulphate (DestabTM, DrieriteTM, Snow WhiteTM, Cal-TabTM, CompactrolTM) cellulose powdered (ArbocelTM, ElcemaTM, SanacetTM), silicified microcrystailine cellulose, cellulose acetate, compressible sugar (Di-PacTM), confectioner's sugar, dextrates (CandexTM, EmdexTM) dextrin (AvedexTM
- a filler such as lactose monohydrate is present in an amount of about 5-90% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 5-80% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 5-70% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 5-60% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 5-50% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 5-40% by weight.
- a filler such as lactose monohydrate is present in an amount of about 25-40% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 40-90% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 40-80% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 40-70% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 40-60% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 40-50% by weight.
- a filler such as lactose monohydrate is present in an amount of about 40% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 50% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 60% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 70% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 80% by weight.
- a filler such as lactose monohydrate is present in an amount of from about 25 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 150 mg to about 1000 mg, from about 200 mg to about 1000 mg, from about 250 mg to about 1000 mg, from about 300 mg to about 1000 mg, from about 350 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 450 mg to about 1000 mg, or from about 500 mg to about 1000 mg.
- a filler such as lactose monohydrate can be present in an amount of from about 25 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 150 mg to about 1000 mg, from about 200 mg to about 1000 mg, from about 250 mg to about 1000 mg, from about 300 mg to about 1000 mg, from about 350 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 450 mg to about 1000 mg, or from about 500 mg to about 1000 mg.
- a filler such as lactose monohydrate is present in an amount of from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, or from about 500 mg to about 550 mg.
- a filler such as lactose monohydrate can be present in an amount of from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, or from about 500 mg to about 550 mg.
- a filler such as lactose monohydrate is present in an amount of about 15 mg, 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, or about 500 mg.
- a filler such as lactose monohydrate can be present in an amount of about 15 mg, 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, or about 500 mg.
- a filler such as lactose monohydrate is present in an amount of about 334.2 mg.
- a filler such as lactose monohydrate is present in an amount of about 254.5 mg. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 174.8 mg. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 95.1 mg. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 15.4 mg.
- Various useful disintegrants include, but are not limited to, alginic acid (ProtacidTM Satialgine H8TM), calcium phosphate, tribasic (TRI-TABTM), carboxymethylcellulose calcium (ECG 505TM), carboxymethylcellulose sodium (AkucellTM, FinnfixTM, Nymcel Tylose CBTM), colloidal silicon dioxide (AerosilTM, Cab-O_SiTM, Wacker HDKTM), croscarmellose sodium (Ac-Di-SolTM Pharmacel XLTM PrimelloseTM, SolutabTM, VivasolTM), crospovidone (Collison CLTM, Collison CL-MTM, Polyplasdone XLTM), docusate sodium, guar gum (MeyprodorTM, MeyprofmTM MeyproguarTM), low substituted hydroxypropyl cellulose, magnesium aluminum silicate (MagnabiteTM, NeusilinTM, PharmsorbTM, VeegumTM), methylcellulose (Met
- a disintegrant is optionally used in an amount of about 0-10% by weight. In some embodiments, a disintegrant is present in an amount of from about 0.1 mg to 0.5 mg, 0.5 mg to 1 mg, 1 mg to 2 mg, 2 mg to 2.5 mg, 2.5 mg to 5 mg, 5 mg to 7.5 mg, 7 mg to 9.5 mg, 9 mg to 11.5 mg, 11 mg to 13.5 mg, 13 mg to 15.5 mg, 15 mg to 17.5 mg, 17 to 19.5 mg, 19 mg to 21.5 mg, 21 mg to 23.5 mg, 23 mg to 25.5 mg, 25 mg to 27.5 mg, 27 mg to 30 mg, 29 mg to 31.5 mg, 31 mg to 33.5 mg, 33 mg to 35.5 mg, 35 mg to 37.5 mg, 37 mg to 40 mg, 40 mg to 45 mg, 45 mg to 50 mg, 50 mg to 55 mg, 55 mg to 60 mg, 60 mg to 65 mg, 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, 90 mg,
- a disintegrant is present in an amount 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 useful lubricants include, but are not limited to, calcium stearate (HyQualTM) glycerine monostearate (ImwitorTM 191 and 900, Kessco GMSSTM, 450 and 600, Myvaplex 600PTM MyvatexTM, Rita GMSTM, Stepan GMSTM, TeginTM, TeginTM 503 and 515, Tegin 4100TM, Tegin MTM Unimate GMSTM), glyceryl behenate (Compritol 888 ATOTM), glyceryl palmitostearate (Precirol ATO 5TM), hydrogenated castor oil (Castorwax MP 80TM, CroduretTM, Cutina HRTM, FancolTM Simulsol 1293TM), hydrogenated vegetable oil 0 type I (SterotexTM, Dynasan P60TM, HydrocoteTM Lipovol HS-KTM, Sterotex HMTM), magnesium lauryl sulphate, magnesium stearate, medium-chain t
- Suitable lubricants include, but are not limited to, 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 silica, and others as known in the art.
- a lubricant is magnesium stearate.
- a lubricant such as magnesium stearate is present in an amount of about 0.1-5% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.1-2% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.1-1% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.1-0.75% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.1-5% by weight.
- a lubricant such as magnesium stearate is present in an amount of about 0.2-5% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.2-2% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.2-1% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.2-0.75% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.3% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.4% by weight.
- a lubricant such as magnesium stearate is present in an amount of about 0.5% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.6% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.7% by weight.
- a lubricant is present in an amount of from about 0.01 mg to 0.05 mg, 0.05 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.25 mg, 0.25 mg to 0.5 mg, 0.5 mg to 0.75 mg, 0.7 mg to 0.95 mg, 0.9 mg to 1.15 mg, 1.1 mg to 1.35 mg, 1.3 mg to 1.5 mg, 1.5 mg to 1.75 mg, 1.75 to 1.95 mg, 1.9 mg to 2.15 mg, 2.1 mg to 2.35 mg, 2.3 mg to 2.55 mg, 2.5 mg to 2.75 mg, 2.7 mg to 3.0 mg, 2.9 mg to 3.15 mg, 3.1 mg to 3.35 mg, 3.3 mg to 3.5 mg, 3.5 mg to 3.75 mg, 3.7 mg to 4.0 mg, 4.0 mg to 4.5 mg, 4.5 mg to 5.0 mg, 5.0 mg to 5.5 mg, 5.5 mg to 6.0 mg, 6.0 mg to 6.5 mg, 6.5 mg to 7.0 mg, 7.0 mg to 7.5 mg, 7.5 mg to 8.0 mg,
- glidants include, but are not limited to, tribasic calcium phosphate (TRI-TABTM), calcium silicate, cellulose, powdered (SanacelTM, Solka-FloeTM), colloidal silicon dioxide (AerosilTM, Cab-O-Sil M-5PTM, Wacker HDKTM), magnesium silicate, magnesium trisilicate, starch (MelojelTM, MeritenaTM, Paygel 55TM, Perfectamyl D6PHTM, Pure-BindTM, Pure_CoteTM, Pure-DentTM, Pure-GelTM, Pure_SetTM, Purity 21TM, Purity 826TM, Tablet WhiteTM) and talc (Luzenac PharmaTM, Magsil OsmanthusTM, Magsil StarTM, SuperioreTM), or mixtures thereof.
- a glidant is optionally used in an amount of about 0-15% by weight. In some embodiments, a glidant is present in an amount of from about 0.1 mg to 0.5 mg, 0.5 mg to 1 mg, 1 mg to 2 mg, 2 mg to 2.5 mg, 2.5 mg to 5 mg, 5 mg to 7.5 mg, 7 mg to 9.5 mg, 9 mg to 11.5 mg, 11 mg to 13.5 mg, 13 mg to 15.5 mg, 15 mg to 17.5 mg, 17 to 19.5 mg, 19 mg to 21.5 mg, 21 mg to 23.5 mg, 23 mg to 25.5 mg, 25 mg to 27.5 mg, 27 mg to 30 mg, 29 mg to 31.5 mg, 31 mg to 33.5 mg, 33 mg to 35.5 mg, 35 mg to 37.5 mg, 37 mg to 40 mg, 40 mg to 45 mg, 45 mg to 50 mg, 50 mg to 55 mg, 55 mg to 60 mg, 60 mg to 65 mg, 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,
- a glidant is present in an amount 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.
- surfactants include, but are limited to both non-ionic and ionic surfactants suitable for use in pharmaceutical dosage forms.
- Ionic surfactants may include one or more of anionic, cationic or zwitterionic surfactants.
- Various useful surfactants include, but are not limited to, sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of olyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearyic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, or any other commercially available co-processed surfactant like SEPITRAP® 80 or SEPITRAP® 4000 and mixtures thereof.
- a surfactant is present in an amount 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.
- the pharmaceutical composition disclosed herein is stable 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% such as about: 80%, 90%, 95%, or 100% of the active pharmaceutical agent in the pharmaceutical composition is stable, e.g., as measured by High Performance Liquid Chromatography (HPLC).
- HPLC High Performance Liquid Chromatography
- 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 disclosed herein is stable for at least about: 30, 60, 90, 180, 360, 540, or 720 days, for example greater than 90 days, which can be measured by HPLC.
- about: 80%, 85%, 90%, 95%, or 100% (e.g., about 95%) of the crystalline Form I of niraparib tosylate monohydrate is stable for 30 days or more.
- the pharmaceutical composition is formulated into solid oral pharmaceutical dosage forms.
- Solid oral pharmaceutical dosage forms include, but are not limited to, tablets, capsules, powders, granules and sachets.
- the solid oral pharmaceutical dosage form can be a capsule.
- a therapeutically effective amount of niraparib administered to a subject via a solid dosage form is in the range of about 1 mg to about 1000 mg.
- the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- a therapeutically effective amount of niraparib administered to a subject via a solid dosage form is in the range of from about 50 mg to about 300 mg.
- a therapeutically effective amount of niraparib administered to a subject via a solid dosage form is in the range of from about 50 mg to about 300 mg, wherein the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the dosage form comprising niraparib as the crystalline Form I of niraparib tosylate monohydrate with an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- a niraparib formulation is administered as a solid dosage form at a concentration of about 50 mg to about 100 mg.
- the niraparib formulation is administered as a solid dosage form at concentration of about 100 mg to about 300 mg.
- a therapeutically effective amount of niraparib tosylate monohydrate crystalline Form I substantially free of Form II and Form III thereof administered to a subject via a solid dosage form can be from 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg
- a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form can be from about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 25 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850
- the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the solid oral dosage form can be administered one, two, or three times a day (b.i.d).
- a therapeutically effective amount of niraparib administered to a subject via a solid dosage form can be about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 25 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg,
- the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form is about 79.7 mg.
- a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form is about 159.4 mg.
- a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form is about 159.4 mg, wherein the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form is about 318.8 mg.
- a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form is about 478.2 mg.
- the solid oral dosage form can be administered one, two, or three times a day (b.i.d).
- Contemplated compositions of the present invention provide a therapeutically effective amount of niraparib over an interval of about 30 minutes to about 8 hours after administration, enabling, for example, once-a-day, twice-a-day, three times a day, and etc. administration if desired.
- the weight ratio of an active pharmaceutical ingredient e.g., niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III
- a non-active pharmaceutical ingredient e.g., lactose monohydrate
- the weight ratio of an active pharmaceutical ingredient 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.
- the weight ratio of an active pharmaceutical ingredient e.g., niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III
- a non-active pharmaceutical ingredient e.g., magnesium stearate
- the weight ratio of a non-active pharmaceutical ingredient (e.g., lactose monohydrate or magnesium stearate) to an active pharmaceutical ingredient (e.g., niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III) to is from about 3:2 to about 11:1, from about 3:1 to about 7:1, from about 1:1 to about 5:1, from about 9:2 to about 11:2, from about 4:2 to about 6:2, about 5:1, or about 2.5:1.
- the weight ratio of an active pharmaceutical ingredient e.g., niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III
- a non-active pharmaceutical ingredient e.g., lactose monohydrate or magnesium stearate
- the weight ratio of an active pharmaceutical ingredient e.g., niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III
- a non-active pharmaceutical ingredient e.g., lactose monohydrate or magnesium stearate
- the weight ratio of niraparib tosylate monohydrate to lactose monohydrate is about 38:61, for example, 38.32:61.18. In some embodiments, the weight ratio of niraparib tosylate monohydrate to magnesium stearate is about 77:1, for example, 76.64:1.
- the weight ratio of a first non-active pharmaceutical ingredient to a second non-active pharmaceutical ingredient is from about 5:1 to about 200:1, respectively, for example about 5:1, about 10:1, about 20:1, about 40:1, about 50:1, about 75:1, 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.
- the weight ratio of lactose monohydrate to magnesium stearate is about 120:1 to about 125:1. In some embodiments, the weight ratio of lactose monohydrate to magnesium stearate is about 122.36:1.
- any subject having cancer 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, gastric cancer, bladder cancer, lung cancer (e.g., adenocarcinoma, NSCLC and SCLC), bone cancer (e.g., osteosarcoma), colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma (e.g., liposarcoma), bladder cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma), myeloid disorders (e.g., AML, CML, myelody
- the methods of the invention treat subjects with ovarian cancer. In some embodiments, the methods of the invention treat subjects with epithelial ovarian cancer. In some embodiments, the methods of the invention treat subjects with fallopian tube cancer. In some embodiments, the methods of the invention treat subjects with primary peritoneal cancer.
- the methods of the invention treat subjects with recurrent ovarian cancer. In some embodiments, the methods of the invention treat subjects with recurrent epithelial ovarian cancer. In some embodiments, the methods of the invention treat subjects with recurrent fallopian tube cancer. In some embodiments, the methods of the invention treat subjects with recurrent primary peritoneal cancer.
- the methods of the invention treat subjects with recurrent ovarian cancer following a complete or partial response to a chemotherapy, such as a platinum-based chemotherapy. In some embodiments, the methods of the invention treat subjects with recurrent epithelial ovarian cancer following a complete or partial response to a chemotherapy, such as a platinum-based chemotherapy. In some embodiments, the methods of the invention treat subjects with recurrent fallopian tube cancer following a complete or partial response to a chemotherapy, such as a platinum-based chemotherapy. In some embodiments, the methods of the invention treat subjects with recurrent primary peritoneal cancer following a complete or partial response to a chemotherapy, such as a platinum-based chemotherapy.
- the methods of the invention treat subjects with recurrent ovarian cancer, recurrent epithelial ovarian cancer, recurrent fallopian tube cancer and/or recurrent primary peritoneal cancer following a complete or partial response to a platinum-based chemotherapy, wherein the subjects begin the treatment no later than 8 weeks after their most recent platinum-containing regimen.
- subjects can begin treatment with niraparib about 7 weeks after their most recent platinum-containing regimen.
- subjects can begin treatment with niraparib about 6 weeks after their most recent platinum-containing regimen.
- subjects can begin treatment with niraparib about 6 weeks after their most recent platinum-containing regimen.
- subjects can begin treatment with niraparib about 5 weeks after their most recent platinum-containing regimen.
- subjects can begin treatment with niraparib about 4 weeks after their most recent platinum-containing regimen.
- subjects can begin treatment with niraparib about 3 weeks after their most recent platinum-containing regimen.
- subjects can begin treatment with niraparib about 2 weeks after their most recent platinum-containing regimen.
- subjects can begin treatment with niraparib about 1 week after their most recent platinum-containing regimen.
- the methods of the invention treat subjects with prostate cancer
- the methods of the invention treat subjects with a pediatric cancer.
- pediatric cancers include, but are not limited to adrenocortical carcinoma, astrocytoma, atypical teratoid rhabdoid tumor, brain tumors, chondroblastoma, choroid plexus tumor, craniopharyngioma, desmoid tumor, dysembryplastic neuroepithelial tumor (DNT), ependymoma, fibrosarcoma, germ cell tumor of the brain, 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 lymphoma, Hodgkin lymphoma, non
- the methods of the invention treat subjects with a cancer with a dosage 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, or 1000 mg of niraparib once-daily, twice-daily, or thrice-daily.
- the methods of the invention treat subjects with a cancer with a dosage of 150 mg to 175 mg, 170 mg to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 to 295 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, or 370 mg to 400 mg of niraparib once-daily, twice-daily, or thrice-daily.
- the methods of the invention treat subjects with a cancer with a dosage of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg.
- the methods of the invention treat subjects with a cancer with a dosage of from 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg,
- the methods of the invention treat subjects with a cancer with a dosage of from about 5 mg to 7.5 mg, 7 mg to 9.5 mg, 9 mg to 11.5 mg, 11 mg to 13.5 mg, 13 mg to 15.5 mg, 15 mg to 17.5 mg, 17 to 19.5 mg, 19 mg to 21.5 mg, 21 mg to 23/5 mg, 23 mg to 25.5 mg, 25 mg to 27.5 mg, 27 mg to 30 mg, 30 mg to 35 mg, 35 mg to 40 mg, 40 mg to 45 mg, 45 mg to 50 mg, 50 mg to 55 mg, 55 mg to 60 mg, 60 to 65 mg, 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 of niraparib once-daily, twice-daily, or thrice-daily.
- the recommended dose of the niraparib capsule formulations described herein as monotherapy is three 100 mg capsules taken orally once daily, equivalent to a total daily dose of 300 mg. Patients may be encouraged to take their dose at approximately the same time each day. Bedtime administration may be a potential method for managing nausea.
- doses of 1 to 1000 mg of niraparib may be administered for treatment of subjects, and methods and compositions described herein may comprise once-daily, twice-daily, or thrice-daily administration of a dose of 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, 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, or 1000 mg once-daily, twice-daily, or thrice-daily.
- the dose of niraparib is from 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg,
- the methods of the invention treat subjects with a cancer with a dosage 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, or 1000 mg of niraparib once-daily, twice-daily, or thrice-daily.
- a total daily dose of niraparib of 1 mg to 1000 mg, for example, or 50 to 300 mg is administered.
- the daily dose of niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the daily dosage wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the total daily dose of niraparib administered exceeds 100 mg per day. In some embodiments, the total daily dose of niraparib administered exceeds 200 mg per day.
- the total daily dose of niraparib administered exceeds 300 mg per day. In some embodiments, the total daily dose of niraparib administered exceeds 400 mg per day. In some embodiments, the total daily dose of niraparib administered exceeds 500 mg per day.
- the total daily dose of niraparib administered does not exceed 500 mg per day.
- the daily dose of niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the daily dosage wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the total daily dose of niraparib administered does not exceed 300 mg per day.
- the total daily dose of niraparib administered does not exceed 100 mg per day.
- the total daily dose of niraparib administered does not exceed 50 mg per day.
- the total daily dose of niraparib is from 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg,
- the total daily dose of niraparib 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, or 1000 mg.
- the daily dose of niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III.
- Another embodiment provides the daily dosage wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- a therapeutically effective dose of niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III 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, or 1000 mg per day.
- the amount of niraparib administered daily is from 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg,
- the amount of niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III is administered one time daily is 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850
- the amount of naraparib administered one time daily is 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, or 1000 mg.
- the amount of niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III is administered two times daily is 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850
- the amount of niraparib administered two times daily is 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, or 1000 mg.
- the amount of niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III is administered three times daily is 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850
- the amount of niraparib administered three times daily is 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, or 1000 mg.
- the niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III is present at a dose from about 1 mg to about 1000 mg, including, but not limited to, 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
- the niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III is present at a dose from 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, 35 mg to 140 mg, 70 mg to 140 mg, 80 mg to 135 mg, 10 mg to 25 mg, 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 150 mg, 150 mg to 200 mg, 10 mg to 35 mg, 35 mg to 70 mg, 70 mg to 105 mg, 105 mg to 140 mg, 140 mg to 175 mg, or 175 mg to 200 mg, 35 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg, 190 mg
- a composition disclosed herein is administered to an individual in need thereof once. In some embodiments, a composition disclosed herein is administered to an individual in need thereof more than once. In some embodiments, a first administration of a composition disclosed herein is followed by a second administration of a composition disclosed herein. In some embodiments, a first administration of a composition disclosed herein is followed by a second and third administration of a composition disclosed herein. In some embodiments, a first administration of a composition disclosed herein is followed by a second, third, and fourth administration of a composition disclosed herein. In some embodiments, a first administration of a composition disclosed herein is followed by a second, third, fourth, and fifth administration of a composition disclosed herein. In some embodiments, a first administration of a composition disclosed herein is followed by a drug holiday.
- a composition disclosed herein is administered once to an individual in need thereof with a mild acute condition. In some embodiments, a composition disclosed herein is administered more than once to an individual in need thereof with a moderate or severe acute condition.
- the administration of niraparib may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
- the niraparib composition is administered at predetermined time intervals over an extended period of time. In some embodiments, the niraparib composition is administered once every day. In some embodiments, the niraparib composition is administered every other day. In some embodiments, the niraparib composition is administered over 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 moths, 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.
- the niraparib composition is administered in doses having a dose-to-dose niraparib concentration variation of less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%.
- the administration of the niraparib may be given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
- the length of the drug holiday can vary between 2 days and 1 year, including by way of example 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.
- a first or second dose reduction during a drug holiday may be from 10%-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%.
- a first or second dose reduction during a drug holiday may be a dose reduced from 5 mg to 1 mg, 10 mg to 5 mg, 20 mg to 10 mg, 25 mg to 10 mg, 50 mg to 25 mg, 75 mg to 50 mg, 75 mg to 25 mg, 100 mg to 50 mg, 150 mg to 75 mg, 100 mg to 25 mg, 200 mg to 100 mg, 200 to 50 mg, 250 mg to 100 mg, 300 mg to 50 mg, 300 mg to 100 mg, 300 mg to 200 mg, 400 mg to 50 mg, 400 mg to 100 mg, 400 mg to 200 mg, 500 mg to 50 mg, 500 mg to 100 mg, 500 mg to 250 mg, 1000 mg to 50 mg, 1000 mg to 100 mg, or 1000 mg to 500 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg.
- a maintenance niraparib dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is optionally reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.
- the Rigaku Smart-Lab X-ray diffraction system was configured for reflection Bragg-Brentano geometry using a line source X-ray beam.
- the x-ray source is a Cu Long Fine Focus tube that was operated at 40 kV and 44 ma. That source provides an incident beam profile at the sample that changes from a narrow line at high angles to a broad rectangle at low angles. Beam conditioning slits are used on the line X-ray source to ensure that the maximum beam size is less than 10 mm both along the line and normal to the line.
- the Bragg-Brentano geometry is a para-focusing geometry controlled by passive divergence and receiving slits with the sample itself acting as the focusing component for the optics.
- the inherent resolution of Bragg-Brentano geometry is governed in part by the diffractometer radius and the width of the receiving slit used. Typically, the Rigaku Smart-Lab is operated to give peak widths of 0.1° 2 ⁇ or less.
- the axial divergence of the X-ray beam is controlled by 5.0-degree Soller slits in both the incident and diffracted beam paths.
- Powder samples were prepared in a low background Si holder using light manual pressure to keep the sample surfaces flat and level with the reference surface of the sample holder. Each sample was analyzed from 2 to 40 °2 ⁇ using a continuous scan of 6 °2 ⁇ per minute with an effective step size of 0.02 °2 ⁇ . Unless otherwise noted, XPRD studies were performed at room temperature and room humidity.
- DSC analyses were carried out using a TA Instruments Q2000 instrument.
- the instrument temperature calibration was performed using indium.
- the DSC cell was kept under a nitrogen purge of ⁇ 50 mL per minute during each analysis.
- the sample was placed in a standard, crimped, aluminum pan and was heated from 25° C. to 350° C. at a rate of 10° C. per minute.
- a batch of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide tosylate which is a mixture of Form I, Form II and Form III is dissolved in water:DMSO/200:1 to reach a concentration of about 0.15 M.
- the resulting mixture is heated until dissolution occurs and is then cooled to about 25° C. overnight.
- the resulting solid is collected, dried and analyzed by x-ray powder diffraction, differential scanning calorimetry, Raman spectroscopy, infrared spectroscopy, dynamic water vapor sorption, or any combination thereof, to determine the presence of Form II or Form III.
- FIG. 6 provides an overlay comparison of the x-ray powder diffraction patterns for Form I and Form III.
- FIG. 9 provides an overlay comparison of the x-ray powder diffraction patterns for Form I, Form II and Form III.
- FIGS. 1 and 6 provide the X-ray powder diffraction pattern for crystalline Form I monohydrate of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- Table 2 provides a listing of the reflections.
- FIG. 2 shows an exemplary scanning differential calorimetry pattern for crystalline monohydrate Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- the DSC curve of the monohydrate exhibits an endotherm at approximately 154° C. which is likely due to dehydration followed by an endotherm at approximately 231° C. which is likely due to melting.
- FIG. 5 shows an exemplary dynamic water vapor sorption pattern for crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- the DVS curve of the monohydrate indicates the monohydrate is not hygroscopic. After the experiment the samples were analyzed by XRPD. The monohydrate remained unchanged.
- FIG. 2 shows an exemplary scanning differential calorimetry pattern for crystalline anhydrous Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- the DSC curve of the anhydrate exhibits an endotherm at approximately 230° C. which is likely due to melting.
- composition comprising crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- composition of paragraph [00133], wherein the crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- composition of paragraph [00133] or [00134], wherein the crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide is characterized by at least one X-ray diffraction pattern reflection selected from a 2 ⁇ value of 9.5 ⁇ 0.2, 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 24.9 ⁇ 0.2, 25.6 ⁇ 0.2, 26.0 ⁇ 0.2, and 26.9 ⁇ 0.2.
- composition of paragraph [00136], wherein the crystalline Form I is further characterized by X-ray diffraction pattern reflections at 2 ⁇ value of 9.5 ⁇ 0.2 and 26.0 ⁇ 0.2.
- composition of paragraph [00136] or [00137], wherein the crystalline Form I is further characterized by X-ray diffraction pattern reflections at a 2 ⁇ value of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- composition of paragraph [00136] or [00137], wherein the crystalline Form I is further characterized by at least two X-ray diffraction pattern reflections selected from a 2 ⁇ value of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- composition of paragraph [00136] or [00137], wherein the crystalline Form I is further characterized by at least three X-ray diffraction pattern reflections selected from a 2 ⁇ value of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- composition of paragraph [00136] or [00137], wherein the crystalline Form I is further characterized by at least four X-ray diffraction pattern reflections selected from a 2 ⁇ value of 12.4 ⁇ 0.2, 13.2 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.9 ⁇ 0.2.
- a composition comprising crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide, wherein the crystalline Form I is characterized by a scanning differential calorimetry pattern substantially as shown in FIG. 2 .
- composition of paragraph [00143], wherein the composition is the composition of any one of paragraphs [00133]-[00142].
- a composition comprising crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide, wherein the crystalline Form I is characterized by a Raman spectroscopy pattern substantially as shown in FIG. 3 .
- composition of paragraph [00145], wherein the composition is the composition of any one of paragraphs [00133]-[00144].
- a composition comprising crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide, wherein the crystalline Form I is characterized by a dynamic water vapor sorption pattern substantially as shown in FIG. 5 .
- composition of paragraph [00147], wherein the composition is the composition of any one of paragraphs [00133]-[00146].
- a composition comprising crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide, wherein the crystalline Form I is characterized by an infrared spectroscopy pattern substantially as shown in FIG. 4 .
- composition of paragraph [00149], wherein the composition is the composition of any one of paragraphs [00133]-[00148].
- composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 20% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 15% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 8% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 6% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 1% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- a composition comprising crystalline Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide and crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- a composition comprising crystalline Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- a composition comprising crystalline Form II 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide and crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- a composition comprising crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide and crystalline Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- a composition comprising crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide.
- composition of any one of paragraphs [00163]-[00167], wherein the crystalline Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
- the organic solvent is a polar solvent, a polar protic solvent, a polar aprotic solvent, an ether-containing solvent, or any combination thereof.
- a composition comprising crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide as described in any one of paragraphs 1-[00160], prepared by dissolving a composition comprising Form II of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide or Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide, or a mixture thereof, in a solvent having a water:organic solvent ratio of about 10:1 to about 400:1 (v/v), and crystallizing the crystalline Form I.
- composition of paragraph [00180], wherein the water:organic solvent ratio is about 10:1 (v/v), about 50:1 (v/v), about 100:1 (v/v), about 200:1 (v/v), about 300:1 (v/v), or about 400:1 (v/v).
- composition of paragraph [00180], wherein the organic solvent is a polar solvent, a polar protic solvent, a polar aprotic solvent, an ether-containing solvent, or any combination thereof.
- composition of paragraph [00180], wherein the organic solvent is 2-propanol, acetone, methyl ethyl ketone, acetonitrile, acetic acid, formic acid, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof.
- composition of paragraph [00180], wherein the organic solvent is acetone, methyl ethyl ketone, acetonitrile, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof.
- composition of paragraph [00180], wherein the organic solvent is 2-propanol, acetic acid, formic acid, or any combination thereof.
- composition of any one of paragraphs [00133]-[00172] and [00180]-[00186], wherein the composition is a pharmaceutical composition.
- a pharmaceutical composition comprising crystalline Form I of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide substantially free of Form II and Form III of 2- ⁇ 4-[(3S)-piperidin-3-yl]phenyl ⁇ -2H-indazole-7-carboxamide, and at least one pharmaceutically acceptable excipient.
- composition of any one of paragraphs [00133]-[00188], wherein the composition is in an oral dosage form.
- composition paragraph [00187] or [00188] wherein the composition is in unit dose form.
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Abstract
The present invention relates to compositions comprising the compound niraparib, in particular certain solid forms of niraparib.
Description
- This application claims the benefit of U.S. Provisional Application No. 62/477,411, filed Mar. 27, 2017, which is incorporated herein by reference in its entirety.
- Niraparib is an orally active and potent poly (ADP-ribose) polymerase, or PARP, inhibitor. Niraparib and pharmaceutically acceptable salts thereof, are disclosed in International Publication No. WO2007/113596 and European Patent No. EP2007733B1; International Publication No. WO2008/084261 and U.S. Pat. No. 8,071,623; and International Publication No. WO2009/087381 and U.S. Pat. No. 8,436,185. Methods of making niraparib and pharmaceutically acceptable salts thereof are disclosed in International Publication Nos. WO2014/088983 and WO2014/088984. Methods to treat cancer with niraparib and pharmaceutically acceptable salts thereof are disclosed in U.S. Provisional Patent Application Nos. 62/356,461, 62/402,427, 62/470,141, and PCT application PCT/US17/40039. The contents of each of the foregoing references are incorporated herein by reference in their entirety.
- PARP is a family of proteins involved in many functions in a cell, including DNA repair, gene expression, cell cycle control, intracellular trafficking and energy metabolism. PARP proteins play key roles in single strand break repair through the base excision repair pathway. PARP inhibitors have shown activity as a monotherapy against tumors with existing DNA repair defects, such as BRCA1 and BRCA2, and as a combination therapy when administered together with anti-cancer agents that induce DNA damage.
- Despite several advances in treatment of ovarian cancer, most patients eventually relapse, and subsequent responses to additional treatment are often limited in duration. Women with germline BRCA1 or BRCA2 mutations have an increased risk for developing high grade serous ovarian cancer (HGSOC), and their tumors appear to be particularly sensitive to treatment with a PARP inhibitor. In addition, published scientific literature indicates that patients with platinum sensitive HGSOC who do not have germline BRCA1 or BRCA2 mutations may also experience clinical benefit from treatment with a PARP inhibitor.
- It is estimated that 5% to 10% of women who are diagnosed with breast cancer, or more than 15,000 women each year, carry a germline mutation in either their BRCA1 or BRCA2 genes. The development of cancer in these women involves the dysfunction of a key DNA repair pathway known as homologous recombination. While cancer cells can maintain viability despite disruption of the homologous recombination pathway, they become particularly vulnerable to chemotherapy if an alternative DNA repair pathway is disrupted. This is known as synthetic lethality—a situation where the individual loss of either repair pathway is compatible with cell viability; but the simultaneous loss of both pathways results in cancer cell deaths. Since PARP inhibitors block DNA repair, in the context of cancer cells with the BRCA mutation, PARP inhibition results in synthetic lethality. For this reason, patients with germline mutations in a BRCA gene show marked clinical benefit that follows treatment with a PARP inhibitor.
- One embodiment provides a composition comprising crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Another embodiment provides the composition wherein the crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . Another embodiment provides the composition where the crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 9.5±0.2, 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 24.9±0.2, 25.6±0.2, 26.0±0.2, and 26.9±0.2. Another embodiment provides the composition wherein the crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is characterized by an X-ray diffraction pattern reflection at 2θ=24.9±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by X-ray diffraction pattern reflections at 2θ values of 9.5±0.2 and 26.0±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by X-ray diffraction pattern reflections at 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by at least two X-ray diffraction pattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by at least three X-ray diffraction pattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by at least four X-ray diffraction pattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by a scanning differential calorimetry pattern substantially as shown inFIG. 2 . Another embodiment provides the composition wherein the crystalline Form I is characterized by a Raman spectroscopy pattern substantially as shown inFIG. 3 . Another embodiment provides the composition wherein the crystalline Form I is characterized by an infrared spectroscopy pattern substantially as shown inFIG. 4 . Another embodiment provides the composition wherein the crystalline Form I is characterized by a dynamic water vapor sorption pattern substantially as shown inFIG. 5 . Another embodiment provides the composition wherein the presence of Form III is characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 17.8±0.2, 19.0±0.2, or 22.8±0.2. - Another embodiment provides the composition wherein substantially free of Form II and Form III means less than about 20% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III. Another embodiment provides the composition wherein substantially free of Form II and Form III means less than about 15% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III. Another embodiment provides the composition wherein substantially free of Form II and Form III means less than about 10% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III. Another embodiment provides the composition wherein substantially free of Form II and Form III means less than about 8% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III. Another embodiment provides the composition wherein substantially free of Form II and Form III means less than about 6% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III. Another embodiment provides the composition wherein substantially free of Form II and Form III means less than about 4% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III. Another embodiment provides the composition wherein substantially free of Form II and Form III means less than about 3% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III. Another embodiment provides the composition wherein substantially free of Form II and Form III means less than about 2% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III. Another embodiment provides the composition wherein substantially free of Form II and Form III means less than about 1% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- One embodiment provides a composition comprising crystalline Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide and crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. One embodiment provides a composition comprising crystalline Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. One embodiment provides a composition comprising crystalline Form II 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide and crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. In one embodiment, crystalline Form II is characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 9.7±0.3, 12.8±0.3, 17.9±0.3, 19.7±0.3, and 21.8±0.3. In one embodiment, crystalline Form II has an X-ray powder diffraction pattern substantially as shown in
FIG. 9 for Form II. - One embodiment provides a composition comprising crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide and crystalline Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. One embodiment provides a composition comprising crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. One embodiment provides crystalline Form III characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 17.8±0.2, 19.0±0.2, or 22.8±0.2. One embodiment provides crystalline Form III that has an X-ray powder diffraction pattern substantially as shown in
FIG. 9 for Form III. One embodiment provides crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide that has an X-ray powder diffraction pattern substantially as shown inFIG. 7 . One embodiment provides crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide characterized by a dynamic water vapor sorption pattern substantially as shown inFIG. 8 . One embodiment provides crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide characterized by a scanning differential calorimetry pattern substantially as shown inFIG. 2 . - One embodiment provides a method of making crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, comprising dissolving a composition comprising Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide or Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, or a mixture thereof, in a solvent having a water:organic solvent ratio of about 10:1 to about 400:1 (v/v), and crystallizing the crystalline Form I. Another embodiment provides the method wherein the water:organic solvent ratio is about 10:1 (v/v), about 50:1 (v/v), about 100:1 (v/v), about 200:1 (v/v), about 300:1 (v/v), or about 400:1 (v/v). Another embodiment provides the composition wherein the organic solvent is a polar solvent, a polar protic solvent, a polar aprotic solvent, an ether-containing solvent, or any combination thereof. Another embodiment provides the composition wherein the organic solvent is 2-propanol, acetone, methyl ethyl ketone, acetonitrile, acetic acid, formic acid, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof. Another embodiment provides the composition wherein the organic solvent is acetone, methyl ethyl ketone, acetonitrile, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof. Another embodiment provides the composition wherein the organic solvent is 2-propanol, acetic acid, formic acid, or any combination thereof. Another embodiment provides the composition wherein the organic solvent and water is heated prior to crystallization.
- One embodiment provides a composition comprising crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide prepared by dissolving a composition comprising Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide or Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, or a mixture thereof, in a solvent having a water:organic solvent ratio of about 10:1 to about 400:1 (v/v), and crystallizing the crystalline Form I. Another embodiment provides the composition wherein the water:organic solvent ratio is about 10:1 (v/v), about 50:1 (v/v), about 100:1 (v/v), about 200:1 (v/v), about 300:1 (v/v), or about 400:1 (v/v). Another embodiment provides the composition wherein the organic solvent is a polar solvent, a polar protic solvent, a polar aprotic solvent, an ether-containing solvent, or any combination thereof. Another embodiment provides the composition wherein the organic solvent is 2-propanol, acetone, methyl ethyl ketone, acetonitrile, acetic acid, formic acid, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof. Another embodiment provides the composition wherein the organic solvent is acetone, methyl ethyl ketone, acetonitrile, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof. Another embodiment provides the composition wherein the organic solvent is 2-propanol, acetic acid, formic acid, or any combination thereof. Another embodiment provides the composition wherein the organic solvent and water is heated prior to crystallization.
- In some embodiments, a composition described herein is a pharmaceutical composition (e.g., a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient). One embodiment provides a pharmaceutical composition comprising crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, and at least one pharmaceutically acceptable excipient. Another embodiment provides the pharmaceutical composition wherein the composition is in an oral dosage form. Another embodiment provides the pharmaceutical composition wherein the oral dosage form is a tablet or capsule. One embodiment provides an article of manufacture comprising multiple unit doses of the pharmaceutical composition in a sealed container with written instructions for use. In another embodiment, the article of manufacture comprising multiple unit doses of the pharmaceutical composition in a sealed container with written instructions for use, further comprises an induction seal, desiccant, or any combination thereof.
- One embodiment provides a method for treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition comprising crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, and at least one pharmaceutically acceptable excipient, wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric cancer, bladder cancer, lung cancer, bone cancer, colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, myeloma, lymphoma, and combinations thereof.
- One embodiment provides a method for treating cancer in a patient having been diagnosed with cancer comprising administering to said patient a therapeutically effective amount of the pharmaceutical comprising crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, and at least one pharmaceutically acceptable excipient, wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric cancer, bladder cancer, lung cancer, bone cancer, colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, myeloma, lymphoma, and combinations thereof. Another embodiment provides the method wherein the cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, and combinations thereof. Another embodiment provides the method wherein the cancer is a recurrent cancer. Another embodiment provides the method wherein the subject is a human subject. Another embodiment provides the method wherein the human subject was previously treated with a chemotherapy. Another embodiment provides the method wherein the chemotherapy is a platinum-based chemotherapy. Another embodiment provides the method wherein the human subject had a complete or partial response to the chemotherapy. Another embodiment provides the method wherein the pharmaceutical composition is administered once per day, twice per day, three times per day, or four times per day. Another embodiment provides the method wherein the pharmaceutical composition is administered once per week, twice per week, three times per week, or four times per week. Another embodiment provides the method wherein the pharmaceutical composition is administered every other day. Another embodiment provides the method wherein the pharmaceutical composition is administered once per day. Another embodiment provides the method wherein the total dose of a the pharmaceutical composition administered within a 24 hour period is about 1 mg to about 1000 mg. Another embodiment provides the method wherein the total dose is about 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 600 mg, about 500 mg, about 400 mg, about 300 mg, about 200 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 40 mg, about 30 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg. Another embodiment provides the method wherein the pharmaceutical composition is administered once per day and the total daily dose is about 300 mg. Another embodiment provides the method wherein the administration is oral administration.
- All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
- The features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
-
FIG. 1 shows an exemplary X-ray powder diffraction pattern for crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. -
FIG. 2 shows an exemplary scanning differential calorimetry pattern for crystalline monohydrate Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide and crystalline anhydrous Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. -
FIG. 3 shows an exemplary Raman spectroscopy pattern for crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. -
FIG. 4 shows an exemplary infrared spectroscopy pattern for crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. -
FIG. 5 shows an exemplary dynamic water vapor sorption pattern for crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. -
FIG. 6 shows an overlay of exemplary X-ray powder diffraction patterns for crystalline Form I, and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. -
FIG. 7 shows an exemplary X-ray powder diffraction pattern for crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. -
FIG. 8 shows an exemplary dynamic water vapor sorption pattern for crystalline anhydrous Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. -
FIG. 9 shows an overlay of exemplary X-ray powder diffraction patterns for crystalline Form I, Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. - The term “cancer” includes both solid tumors and hematological malignancies. Cancers include, but are not limited to, ovarian cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric cancer, bladder cancer, lung cancer (e.g., adenocarcinoma, NSCLC and SCLC), bone cancer (e.g., osteosarcoma), colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma (e.g., liposarcoma), bladder cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma), myeloid disorders (e.g., AML, CML, myelodysplastic syndrome and promyelocytic leukemia), and lymphoid disorders (e.g., leukemia, multiple myeloma, mantle cell lymphoma, ALL, CLL, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma).
- The term “composition”, as in pharmaceutical composition, is intended to encompass a drug product comprising niraparib or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, and the other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”. Pharmaceutical compositions of the invention include, but are not limited to, granules, tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, orally disintegrating tablets, pulsatile release tablets, timed release tablets, delayed release, controlled release, extended release and sustained release tablets), capsules (hard and soft or liquid filled soft gelatin capsules), pills, troches, sachets, powders, microcapsules, minitablets, tablets in capsules and microspheres, matrix composition and the like. In some embodiments, the pharmaceutical composition refers to capsules. In some embodiments, the pharmaceutical composition refers to hard gelatin capsules or IPMC based capsules. In some embodiments, the pharmaceutical composition refers to hard gelatin capsules.
- “Diluents” increase bulk of the composition to facilitate compression or create sufficient bulk for homogenous blend for capsule filling. Such compounds include e.g., lactose, 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, compressible sugar, such as Di-Pac® (Amstar); mannitol, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, confectioner's 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 can also be used.
- The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of the niraparib being administered that would be expected to relieve to some extent one or more of the symptoms of the disease or condition being treated. For example, the result of administration of niraparib disclosed herein is reduction and/or alleviation of the signs, symptoms, or causes of cancer. For example, an “effective amount” for therapeutic uses is the amount of niraparib, including a formulation as disclosed herein required to provide a decrease or amelioration in disease symptoms without undue adverse side effects. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. It is understood that an “an effective amount” or a “therapeutically effective amount” varies, in some embodiments, from subject to subject, due to variation in metabolism of the compound administered, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
- The terms “enhance” or “enhancing” refers to an increase or prolongation of either the potency or duration of a desired effect of niraparib, or a diminution of any adverse symptomatology that is consequent upon the administration of the therapeutic agent. Thus, in regard to enhancing the effect of niraparib disclosed herein, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents that are used in combination with niraparib disclosed herein. An “enhancing-effective amount,” as used herein, refers to an amount of niraparib or other therapeutic agent which is adequate to enhance the effect of another therapeutic agent or niraparib in a desired system. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
- The term “excipient” means a pharmacologically inactive component such as a diluent, lubricant, surfactant, carrier, or the like. Excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of present invention.
- “Filling agents” or “fillers” include compounds such as lactose, lactose monohydrate, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
- “Lubricants” and “glidants” are compounds that prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants include, e.g., 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-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol (e.g., PEG-4000) or a methoxypolyethylene 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®, a starch such as corn starch, silicone oil, a surfactant, and the like.
- The term “subject” is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably.
- A “therapeutically effective amount” or “effective amount” is that amount of a pharmaceutical agent to achieve a pharmacological effect. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. An “effective amount” of niraparib is an amount needed to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. The effective amount of a niraparib will be selected by those skilled in the art depending on the particular patient and the disease. It is understood that “an effective amount” or a “therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of niraparib, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. As used herein, amelioration or lessening of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any decrease of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that is attributed to or associated with administration of the compound or composition.
- The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating a disease or condition, for example cancer, symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
- As used herein, “weight percent,” “wt %,” “percent by weight,” “% by weight,” and variations thereof refer to the concentration of a substance as the weight of that substance divided by the total weight of the composition and multiplied by 100.
- Other objects, features, and advantages of the methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only.
- The present invention relates to solid dosage forms of niraparib and pharmaceutically acceptable salts thereof (e.g., niraparib tosylate monohydrate), including solid forms having desirable characteristics favorable for pharmaceutical development. Niraparib has the following structure:
- Niraparib is an orally available, selective poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitor. Niraparib displays
PARP 1 and 2 inhibition with IC50=3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC50=4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range (see Jones et al., Journal Medicinal Chemistry, 2009, 52, 7170-7185). Methods of administering niraparib to cancer patients are also described in WO2018/005818, which is hereby incorporated by reference in its entirety. - The chemical name for niraparib tosylate monohydrate is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1) and it has the following chemical structure:
- The empirical molecular formula for niraparib is C26H30N4O5S and its molecular weight is 510.61 g/mol. Niraparib tosylate monohydrate drug substance is a white to off-white, non-hygroscopic crystalline solid. Niraparib solubility is pH independent below the pKa of 9.95, with an aqueous free base solubility of 0.7 mg/mL to 1.1 mg/mL across the physiological pH range.
- Methods for preparation of niraparib include those described in WO 2014/088983; WO 2014/088984; U.S. Pat. Nos. 8,071,623; 8,436,185; U.S. 62/489,415 filed Apr. 24, 2017; and Jones et al., J. Med. Chem., 52:7170-7185, 2009, each of which is incorporated by reference in its entirety. Niraparib prepared according to these methods can be used in the methods of preparation of the crystalline solid forms described herein. For example, crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide can be prepared from solvent systems comprising water (e.g., as described in Example 1 and Example 2). Crystalline Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide can be produced under anhydrous conditions. Crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide can be produced from crystalline Form I under heating conditions (e.g., as described in Example 3).
- Provided herein are crystalline solid forms of 4-toluenesufonate salts of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. For example, provided herein are crystalline solid forms of 4-toluenesufonate salts of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide having 1:1 stoichiometry.
- Provided herein is crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is the 4-toluenesulfonate salt and is a monohydrate. Crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is also referred to by interchangeable terms such as: Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide; crystalline monohydrate Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide; crystalline Form I of niraparib tosylate monohydrate; crystalline Form I; or Form I. Exemplary X-ray powder diffraction data for Form I is provided in
FIG. 1 andFIG. 6 .FIG. 2 shows an exemplary scanning differential calorimetry pattern for crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.FIG. 3 shows an exemplary Raman spectroscopy pattern for crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.FIG. 4 shows an exemplary infrared spectroscopy pattern for crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.FIG. 5 shows an exemplary dynamic water vapor sorption pattern for crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. - Provided herein is crystalline Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Crystalline Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is the 4-toluenesulfonate salt and is a non-stoichiometric hydrate. Crystalline Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is also referred to by interchangeable terms such as: Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide; crystalline Form II of niraparib; crystalline Form II; or Form II.
- Provided herein is crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is the 4-toluenesulfonate salt and is an anhydrous form. Exemplary X-ray powder diffraction data for Form III is provided in
FIG. 6 andFIG. 7 .FIG. 2 shows an exemplary scanning differential calorimetry pattern for crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.FIG. 8 shows an exemplary dynamic water vapor sorption pattern for crystalline anhydrous Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is also referred to by interchangeable terms such as: Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide; crystalline anhydrous Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide; crystalline Form III of niraparib; crystalline Form III; or Form III.FIG. 2 shows an exemplary scanning differential calorimetry pattern for crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. - Solid forms of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide described herein can have beneficial properties, including favorable properties for use in methods of treatment or in methods of manufacture of pharmaceutical formulations. For example, a hydrochloride salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide has been shown to be highly hygroscopic. By contrast, crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is a non-hygroscopic solid form having suitable solubility properties, as well as favorable physical and chemical stability.
- One embodiment provides a composition comprising crystalline Form I of niraparib tosylate monohydrate substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . Another embodiment provides the composition where the crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 9.5±0.2, 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 24.9±0.2, 25.6±0.2, 26.0±0.2, and 26.9±0.2. Another embodiment provides the composition wherein the crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is characterized by an X-ray diffraction pattern reflection at 2θ=24.9±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by X-ray diffraction pattern reflections at 2θ values of 9.5±0.2 and 26.0±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by X-ray diffraction pattern reflections at a 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by at least two X-ray diffraction pattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by at least three X-ray diffraction pattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by at least four X-ray diffraction pattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2. Another embodiment provides the composition wherein the crystalline Form I is characterized by a scanning differential calorimetry pattern substantially as shown inFIG. 2 . Another embodiment provides the composition wherein the crystalline Form I is characterized by a Raman spectroscopy pattern substantially as shown inFIG. 3 . Another embodiment provides the composition wherein the crystalline Form I is characterized by an infrared spectroscopy pattern substantially as shown inFIG. 4 . Another embodiment provides the composition wherein the crystalline Form I is characterized by a dynamic water vapor sorption pattern substantially as shown inFIG. 5 . - One embodiment provides a composition comprising crystalline Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide and crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. One embodiment provides a composition comprising crystalline Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. One embodiment provides a composition comprising comprising crystalline Form II 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide and crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. In one embodiment, crystalline Form II is characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 9.7±0.3, 12.8±0.3, 17.9±0.3, 19.7±0.3, and 21.8±0.3. In one embodiment, crystalline Form II has an X-ray powder diffraction pattern substantially as shown in
FIG. 9 for Form II. - One embodiment provides a composition comprising crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide and crystalline Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. One embodiment provides a composition comprising crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. One embodiment provides crystalline Form III characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 17.8±0.2, 19.0±0.2, or 22.8±0.2. One embodiment provides crystalline Form III that has an X-ray powder diffraction pattern substantially as shown in
FIG. 9 for Form III. One embodiment provides crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide that has an X-ray powder diffraction pattern substantially as shown inFIG. 7 . One embodiment provides crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide characterized by a dynamic water vapor sorption pattern substantially as shown inFIG. 8 . One embodiment provides crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide characterized by a scanning differential calorimetry pattern substantially as shown inFIG. 2 . - Niraparib is a selective poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitor which selectively kills tumor cells in vitro and in mouse xenograft models. PARP inhibition leads to irreparable double strand breaks (DSBs), use of the error-prone DNA repair pathway, resultant genomic instability, and ultimately cell death. Additionally, PARP trapped at genetic lesions as a result of the suppression of autoparlyation can contribute to cytotoxicity.
- ZEJULA™ is indicated for the maintenance or treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer following a complete or partial response to platinum-based chemotherapy. Each ZEJULA™ capsule contains 100 mg of niraparib (as tosylate monohydrate). The hard capsules have a white body with “100 mg” printed in black ink, and a purple cap with “Niraparib” printed in white ink. The recommended dose of ZEJULA™ as monotherapy is three 100 mg capsules taken orally once daily, equivalent to a total daily dose of 300 mg.
- Provided herein is an oral composition containing niraparib or its pharmaceutically acceptable salts. In some embodiments, the oral composition includes from about 20 wt % to about 60 wt % of niraparib for treatment of a disorder or condition such as cancer; and a pharmaceutically acceptable carrier, wherein the niraparib is distributed with substantial uniformity throughout the pharmaceutically acceptable carrier.
- In some embodiments, the disorder or condition is cancer, for example, ovarian cancer.
- In some embodiments, the niraparib is a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is niraparib tosylate monohydrate.
- In some embodiments, the niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . - In some embodiments, the pharmaceutical composition comprises about 50 mg to about 300 mg of niraparib tosylate monohydrate. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 300 mg of niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . - For example, the pharmaceutical composition can comprise about 100 mg to about 200 mg of niraparib tosylate monohydrate. For example, the pharmaceutical composition can comprise about 125 mg to about 175 mg of niraparib tosylate monohydrate.
- The formulation can comprise one or more components, including niraparib. The components can be combined to create a powder blend that is used to fill capsules. For example, the powder blend can be filled into gelatin capsules, such as size 0 gelatin capsules.
- The niraparib may be present in the formulation as a pharmaceutically acceptable salt. For example, the niraparib can be niraparib tosylate monohydrate.
- The formulation can comprise one or more diluents. For example, the formulation can comprise lactose monohydrate.
- The formulation can comprise one or more lubricants. For example, For example, the formulation can comprise magnesium stearate.
- An exemplary niraparib formulation of the present invention comprises 100 mg of niraparib (based on free base, 1.000 mg niraparib anhydrous free base is equivalent to 1.594 mg niraparib tosylate monohydrate), 254.5 mg of lactose monohydrate and magnesium stearate. An exemplary niraparib formulation of the present invention comprises 100 mg of niraparib (based on free base, 1.000 mg niraparib anhydrous free base is equivalent to 1.594 mg niraparib tosylate monohydrate), 254.5 mg of lactose monohydrate, and magnesium stearate. It may also optionally comprisetartrazine.
- By means of methods and compositions described herein, formulations can be made that achieve therapeutically effective pharmacokinetic profiles. For example, therapeutically effective doses of niraparib can be administered once, twice or three times daily in capsules using the manufacturing methods and compositions that have been described herein to achieve these results. In some embodiments, the niraparib is present in an amount of from about 20-80 wt %, about 45-70 wt %, about 40-50 wt %, about 45-55 wt %, about 50-60 wt %, about 55-65 wt %, about 60-70 wt %, about 65-75 wt %, about 70-80 wt %, or about 40-60 wt %. In some embodiments, the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . - In some embodiments, the compositions described herein have a concentration of niraparib of 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 50%, or from about 45% to about 50% by weight of the composition. In some embodiments, the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . - In some embodiments, the compositions described herein have a concentration of niraparib of 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%, or from about 40% to about 45% by weight of the composition. In some embodiments, the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . - In some embodiments, the compositions described herein have a concentration of niraparib of 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 composition. In some embodiments, the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . - In some embodiments, the compositions described herein have a concentration of niraparib of from about 10% to about 35%, from about 50% 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%, or from about 30% to about 35% by weight of the composition. In some embodiments, the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . - In some embodiments, the compositions described herein have a concentration of niraparib of about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of the composition. In some embodiments, the compositions described herein have a concentration of niraparib tosylate monohydrate of about 19.16% by weight of the composition. In some embodiments, the compositions described herein have a concentration of niraparib tosylate monohydrate of about 38.32% by weight of the composition. In some embodiments, the compositions described herein have a concentration of niraparib tosylate monohydrate of about 57.48% by weight of the composition. In some embodiments, the compositions described herein have a concentration of niraparib tosylate monohydrate of about 76.64% by weight of the composition. In some embodiments, the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . - In some embodiments, the compositions described herein have an amount of niraparib of from about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 25 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. In some embodiments, the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . For example, the compositions described herein can have an amount of niraparib tosylate monohydrate of from about 1 mg to about 1000 mg, for example, from about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 25 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. - In some embodiments, the compositions described herein have an amount of niraparib of 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, or 1000 mg. In some embodiments, the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . For example, the compositions described herein can have an amount of niraparib tosylate monohydrate of 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, or 1000 mg. - In some embodiments, the compositions described herein have an amount of niraparib of 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, or about 500 mg. For example, the compositions described herein can have an amount of niraparib tosylate monohydrate of 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, or about 500 mg. In some embodiments, the compositions described herein have an amount of niraparib tosylate monohydrate of about 79.7 mg. In some embodiments, the compositions described herein have an amount of niraparib tosylate monohydrate of about 159.4 mg.
- In some embodiments, the compositions described herein have an amount of niraparib tosylate monohydrate of about 159.4 mg, wherein the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. In some embodiments, the compositions described herein have an amount of niraparib tosylate monohydrate of about 159.4 mg, wherein the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. In some embodiments, the compositions described herein have an amount of niraparib tosylate monohydrate of about 159.4 mg, wherein the niraparib tosylate monohydrate is the crystalline Form I with an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . In some embodiments, the compositions described herein have an amount of niraparib tosylate monohydrate of about 318.8 mg. In some embodiments, the compositions described herein have an amount of niraparib tosylate monohydrate of about 478.2 mg. In some embodiments, the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown inFIG. 1 . - In some aspects, the pharmaceutical composition disclosed herein comprises one or more pharmaceutically acceptable excipients. Exemplary pharmaceutically acceptable excipients for the purposes of pharmaceutical compositions disclosed herein include, but are not limited to, binders, disintegrants, superdisintegrants, lubricants, diluents, fillers, flavors, glidants, sorbents, solubilizers, chelating agents, emulsifiers, thickening agents, dispersants, stabilizers, suspending agents, adsorbents, granulating agents, preservatives, buffers, coloring agents and sweeteners or combinations thereof. Examples of binders include microcrystalline cellulose, hydroxypropyl methylcellulose, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinylpolypyrrolidone, carboxymethylcellulose calcium, carboxymethylcellulose sodium, ceratonia, chitosan, cottonseed oil, dextrates, dextrin, ethylcellulose, gelatin, glucose, glyceryl behenate, galactomannan polysaccharide, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, 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, tocofersolan, zein, or combinations thereof. Examples of disintegrants include hydroxypropyl methylcellulose (HPMC), low substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium, sodium starch glycolate, lactose, magnesium aluminum silicate, methylcellulose, polacrilin potassium, sodium alginate, starch, or combinations thereof. Examples of a lubricant include stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, glycerin 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, 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, sulfobutylether β-cyclodextrin, tragacanth, trehalose, xylitol, or combinations thereof. In some embodiments, the pharmaceutically acceptable excipient is hydroxypropyl methylcellulose (HPMC). In some embodiments, the pharmaceutically acceptable excipient is low substituted hydroxypropyl cellulose (L-HPC). In some embodiments, the pharmaceutically acceptable excipient is lactose. In some embodiments, the pharmaceutically acceptable excipient is lactose monohydrate. In some embodiments, the pharmaceutically acceptable excipient is magnesium stearate. In some embodiments, the pharmaceutically acceptable excipient is lactose monohydrate and magnesium stearate.
- Various useful fillers or diluents include, but are not limited to 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™), calcium phosphate tribasic (Tri-Cafos™ TRI-TAB™), calcium sulphate (Destab™, Drierite™, Snow White™, Cal-Tab™, Compactrol™) cellulose powdered (Arbocel™, Elcema™, Sanacet™), silicified microcrystailine cellulose, cellulose acetate, compressible sugar (Di-Pac™), confectioner's sugar, dextrates (Candex™, Emdex™) dextrin (Avedex™, Caloreen™, Primogran W™), dextrose (Caridex™, Dextrofin™, Tab fine D-IOO™), fructose (Fructofin™, 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™, Super-Tab™, 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™, Cow Coming 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.
- In some embodiments, a filler such as lactose monohydrate is present in an amount of about 5-90% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 5-80% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 5-70% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 5-60% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 5-50% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 5-40% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 5-30% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 25-90% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 25-80% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 25-70% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 25-60% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 25-50% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 25-40% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 40-90% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 40-80% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 40-70% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 40-60% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 40-50% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 40% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 50% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 60% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 70% by weight. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 80% by weight.
- In some embodiments, a filler such as lactose monohydrate is present in an amount of from about 25 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 150 mg to about 1000 mg, from about 200 mg to about 1000 mg, from about 250 mg to about 1000 mg, from about 300 mg to about 1000 mg, from about 350 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 450 mg to about 1000 mg, or from about 500 mg to about 1000 mg. For example, a filler such as lactose monohydrate can be present in an amount of from about 25 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 150 mg to about 1000 mg, from about 200 mg to about 1000 mg, from about 250 mg to about 1000 mg, from about 300 mg to about 1000 mg, from about 350 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 450 mg to about 1000 mg, or from about 500 mg to about 1000 mg.
- In some embodiments, a filler such as lactose monohydrate is present in an amount of from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, or from about 500 mg to about 550 mg. For example, a filler such as lactose monohydrate can be present in an amount of from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, or from about 500 mg to about 550 mg.
- In some embodiments, a filler such as lactose monohydrate is present in an amount of about 15 mg, 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, or about 500 mg. For example, a filler such as lactose monohydrate can be present in an amount of about 15 mg, 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, or about 500 mg. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 334.2 mg. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 254.5 mg. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 174.8 mg. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 95.1 mg. In some embodiments, a filler such as lactose monohydrate is present in an amount of about 15.4 mg.
- Various useful disintegrants include, but are not limited to, alginic acid (Protacid™ Satialgine H8™), calcium phosphate, tribasic (TRI-TAB™), carboxymethylcellulose calcium (ECG 505™), carboxymethylcellulose sodium (Akucell™, Finnfix™, Nymcel Tylose CB™), colloidal silicon dioxide (Aerosil™, Cab-O_Si™, Wacker HDK™), croscarmellose sodium (Ac-Di-Sol™ Pharmacel XL™ Primellose™, Solutab™, Vivasol™), crospovidone (Collison CL™, Collison CL-M™, Polyplasdone XL™), docusate sodium, guar gum (Meyprodor™, Meyprofm™ Meyproguar™), low substituted hydroxypropyl cellulose, 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™), sodium starch glycolate, polacrilin potassium (Amberlite IRP88™), silicified 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 pre-gelatinized 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, a disintegrant is optionally used in an amount of about 0-10% by weight. In some embodiments, a disintegrant is present in an amount of from about 0.1 mg to 0.5 mg, 0.5 mg to 1 mg, 1 mg to 2 mg, 2 mg to 2.5 mg, 2.5 mg to 5 mg, 5 mg to 7.5 mg, 7 mg to 9.5 mg, 9 mg to 11.5 mg, 11 mg to 13.5 mg, 13 mg to 15.5 mg, 15 mg to 17.5 mg, 17 to 19.5 mg, 19 mg to 21.5 mg, 21 mg to 23.5 mg, 23 mg to 25.5 mg, 25 mg to 27.5 mg, 27 mg to 30 mg, 29 mg to 31.5 mg, 31 mg to 33.5 mg, 33 mg to 35.5 mg, 35 mg to 37.5 mg, 37 mg to 40 mg, 40 mg to 45 mg, 45 mg to 50 mg, 50 mg to 55 mg, 55 mg to 60 mg, 60 mg to 65 mg, 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, a disintegrant is present in an amount 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 useful lubricants include, but are not limited to, calcium stearate (HyQual™) glycerine monostearate (Imwitor™ 191 and 900, Kessco GMSS™, 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™), hydrogenated vegetable oil 0 type I (Sterotex™, Dynasan P60™, Hydrocote™ Lipovol HS-K™, Sterotex HM™), magnesium lauryl sulphate, magnesium stearate, medium-chain triglycerides (Captex 300™, Labrafac CC™, Miglyol 810™, Neobee MS™, Nesatol™, Waglinol 3/9280™), poloxamer (Pluronic™, Synperonic™), polyethylene 5 glycol (Carbowax Sentry™ Lipo™, Lipoxol™, Lutrol E™, Pluriol E™), sodium benzoate (Antimol™), sodium chloride, sodium lauryl sulphate (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, 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 silica, and others as known in the art. In some embodiments a lubricant is magnesium stearate.
- In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.1-5% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.1-2% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.1-1% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.1-0.75% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.1-5% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.2-5% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.2-2% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.2-1% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.2-0.75% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.3% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.4% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.5% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.6% by weight. In some embodiments, a lubricant such as magnesium stearate is present in an amount of about 0.7% by weight. In some embodiments, a lubricant is present in an amount of from about 0.01 mg to 0.05 mg, 0.05 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.25 mg, 0.25 mg to 0.5 mg, 0.5 mg to 0.75 mg, 0.7 mg to 0.95 mg, 0.9 mg to 1.15 mg, 1.1 mg to 1.35 mg, 1.3 mg to 1.5 mg, 1.5 mg to 1.75 mg, 1.75 to 1.95 mg, 1.9 mg to 2.15 mg, 2.1 mg to 2.35 mg, 2.3 mg to 2.55 mg, 2.5 mg to 2.75 mg, 2.7 mg to 3.0 mg, 2.9 mg to 3.15 mg, 3.1 mg to 3.35 mg, 3.3 mg to 3.5 mg, 3.5 mg to 3.75 mg, 3.7 mg to 4.0 mg, 4.0 mg to 4.5 mg, 4.5 mg to 5.0 mg, 5.0 mg to 5.5 mg, 5.5 mg to 6.0 mg, 6.0 mg to 6.5 mg, 6.5 mg to 7.0 mg, 7.0 mg to 7.5 mg, 7.5 mg to 8.0 mg, 8.0 mg to 8.5 mg, 8.5 mg to 9.0 mg, 9.0 mg to 9.5 mg, or 9.5 mg to 10.0 mg. In some embodiments, a lubricant is present in an amount of 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, 2.0 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, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, or 10.0 mg.
- Various useful glidants include, but are not limited to, tribasic calcium phosphate (TRI-TAB™), calcium silicate, cellulose, powdered (Sanacel™, Solka-Floe™), colloidal silicon dioxide (Aerosil™, Cab-O-Sil M-5P™, Wacker HDK™), magnesium silicate, magnesium trisilicate, starch (Melojel™, Meritena™, Paygel 55™, Perfectamyl D6PH™, Pure-Bind™, Pure_Cote™, 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, a glidant is optionally used in an amount of about 0-15% by weight. In some embodiments, a glidant is present in an amount of from about 0.1 mg to 0.5 mg, 0.5 mg to 1 mg, 1 mg to 2 mg, 2 mg to 2.5 mg, 2.5 mg to 5 mg, 5 mg to 7.5 mg, 7 mg to 9.5 mg, 9 mg to 11.5 mg, 11 mg to 13.5 mg, 13 mg to 15.5 mg, 15 mg to 17.5 mg, 17 to 19.5 mg, 19 mg to 21.5 mg, 21 mg to 23.5 mg, 23 mg to 25.5 mg, 25 mg to 27.5 mg, 27 mg to 30 mg, 29 mg to 31.5 mg, 31 mg to 33.5 mg, 33 mg to 35.5 mg, 35 mg to 37.5 mg, 37 mg to 40 mg, 40 mg to 45 mg, 45 mg to 50 mg, 50 mg to 55 mg, 55 mg to 60 mg, 60 mg to 65 mg, 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, a glidant is present in an amount 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 limited to both non-ionic and ionic surfactants suitable for use in pharmaceutical dosage forms. Ionic surfactants may include one or more of anionic, cationic or zwitterionic surfactants. Various useful surfactants include, but are not limited to, sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of olyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearyic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, or any other commercially available co-processed surfactant like SEPITRAP® 80 or SEPITRAP® 4000 and mixtures thereof. In some embodiments, surfactant is optionally used in an amount of about 0-5% by weight. In some embodiments, a surfactant is present in an amount of from about 0.1 mg to 0.5 mg, 0.5 mg to 1 mg, 1 mg to 2 mg, 2 mg to 2.5 mg, 2.5 mg to 5 mg, 5 mg to 7.5 mg, 7 mg to 9.5 mg, 9 mg to 11.5 mg, 11 mg to 13.5 mg, 13 mg to 15.5 mg, 15 mg to 17.5 mg, 17 to 19.5 mg, 19 mg to 21.5 mg, 21 mg to 23.5 mg, 23 mg to 25.5 mg, 25 mg to 27.5 mg, 27 mg to 30 mg, 29 mg to 31.5 mg, 31 mg to 33.5 mg, 33 mg to 35.5 mg, 35 mg to 37.5 mg, 37 mg to 40 mg, 40 mg to 45 mg, 45 mg to 50 mg, 50 mg to 55 mg, 55 mg to 60 mg, 60 mg to 65 mg, 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, a surfactant is present in an amount 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.
- In some embodiments, the pharmaceutical composition disclosed herein is stable 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% such as about: 80%, 90%, 95%, or 100% of the active pharmaceutical agent in the pharmaceutical composition is stable, e.g., as measured by High Performance Liquid Chromatography (HPLC). In some embodiments, 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 disclosed herein is stable for at least about: 30, 60, 90, 180, 360, 540, or 720 days, for example greater than 90 days, which can be measured by HPLC. In some embodiments, about: 80%, 85%, 90%, 95%, or 100% (e.g., about 95%) of the crystalline Form I of niraparib tosylate monohydrate is stable for 30 days or more.
- In some embodiments, the pharmaceutical formulations described herein are stable with respect to compound degradation (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 any 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 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 (e.g., room temperature). In some embodiments, the formulations described herein are stable with respect to compound degradation over a period of at least about 1 week. In some embodiments, the formulations described herein are stable with respect to compound degradation over a period of at least about 1 month. In some embodiments, the formulations described herein are stable with respect to compound degradation over a period of at least about 3 months. In some embodiments, the formulations described herein are stable with respect to compound degradation over a period of at least about 6 months. In some embodiments, the formulations described herein are stable with respect to compound degradation over a period of at least about 9 months. In some embodiments, the formulations described herein are stable with respect to compound degradation over a period of at least about 12 months.
- Methods for assessing the chemical storage stability of solid dosage forms under accelerated aging conditions have been described in the literature. See, e.g., 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 K C, Carella A J, Gumkowski M J, 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).
- In some embodiments, the pharmaceutical composition is formulated into solid oral pharmaceutical dosage forms. Solid oral pharmaceutical dosage forms include, but are not limited to, tablets, capsules, powders, granules and sachets. For example, the solid oral pharmaceutical dosage form can be a capsule.
- In some embodiments, a therapeutically effective amount of niraparib administered to a subject via a solid dosage form is in the range of about 1 mg to about 1000 mg. In some embodiments, the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . In some embodiments, a therapeutically effective amount of niraparib 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, a therapeutically effective amount of niraparib administered to a subject via a solid dosage form is in the range of from about 50 mg to about 300 mg, wherein the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the dosage form comprising niraparib as the crystalline Form I of niraparib tosylate monohydrate with an X-ray powder diffraction pattern substantially as shown inFIG. 1 . In some embodiments, a niraparib formulation is administered as a solid dosage form at a concentration of about 50 mg to about 100 mg. In some embodiments, the niraparib formulation is administered as a solid dosage form at concentration of about 100 mg to about 300 mg. For example, a therapeutically effective amount of niraparib tosylate monohydrate crystalline Form I substantially free of Form II and Form III thereof administered to a subject via a solid dosage form can be from 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. For example, a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form can be from about 1 mg to about 1000 mg, for example, from 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. In some aspects, the solid oral dosage form can be administered one, two, or three times a day (b.i.d). - For example, a therapeutically effective amount of niraparib administered to a subject via a solid dosage form can be from about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 25 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. For example, a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form can be from about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 25 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. In some embodiments, the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . In some aspects, the solid oral dosage form can be administered one, two, or three times a day (b.i.d). - For example, a therapeutically effective amount of niraparib administered to a subject via a solid dosage form can be about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 25 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. For example, a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form can 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. In some embodiments, the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the composition wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . In some embodiments, a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form is about 79.7 mg. In some embodiments, a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form is about 159.4 mg. In some embodiments, a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form is about 159.4 mg, wherein the niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. In some embodiments, a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form is about 318.8 mg. In some embodiments, a therapeutically effective amount of niraparib tosylate monohydrate administered to a subject via a solid dosage form is about 478.2 mg. In some aspects, the solid oral dosage form can be administered one, two, or three times a day (b.i.d). - Contemplated compositions of the present invention provide a therapeutically effective amount of niraparib over an interval of about 30 minutes to about 8 hours after administration, enabling, for example, once-a-day, twice-a-day, three times a day, and etc. administration if desired.
- In some embodiments, the weight ratio of an active pharmaceutical ingredient (e.g., niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III) to a non-active pharmaceutical ingredient (e.g., lactose monohydrate) 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, the weight ratio of an active pharmaceutical ingredient (e.g., niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III) to a non-active 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, the weight ratio of a non-active pharmaceutical ingredient (e.g., lactose monohydrate or magnesium stearate) to an active pharmaceutical ingredient (e.g., niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III) to is from about 3:2 to about 11:1, from about 3:1 to about 7:1, from about 1:1 to about 5:1, from about 9:2 to about 11:2, from about 4:2 to about 6:2, about 5:1, or about 2.5:1. In some embodiments, the weight ratio of an active pharmaceutical ingredient (e.g., niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III) to a non-active pharmaceutical ingredient (e.g., lactose monohydrate or magnesium stearate) is about 1:1.6. In some embodiments, the weight ratio of an active pharmaceutical ingredient (e.g., niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III) to a non-active pharmaceutical ingredient (e.g., lactose monohydrate or magnesium stearate) is about 1:2. In some embodiments, the weight ratio of niraparib tosylate monohydrate to lactose monohydrate is about 38:61, for example, 38.32:61.18. In some embodiments, the weight ratio of niraparib tosylate monohydrate to magnesium stearate is about 77:1, for example, 76.64:1.
- In some embodiments, the weight ratio of a first non-active pharmaceutical ingredient to a second non-active pharmaceutical ingredient is from about 5:1 to about 200:1, respectively, for example about 5:1, about 10:1, about 20:1, about 40:1, about 50:1, about 75:1, 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, the weight ratio of lactose monohydrate to magnesium stearate is about 120:1 to about 125:1. In some embodiments, the weight ratio of lactose monohydrate to magnesium stearate is about 122.36:1.
- Any subject having cancer, 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, gastric cancer, bladder cancer, lung cancer (e.g., adenocarcinoma, NSCLC and SCLC), bone cancer (e.g., osteosarcoma), colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma (e.g., liposarcoma), bladder cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma), myeloid disorders (e.g., AML, CML, myelodysplastic syndrome and promyelocytic leukemia), and lymphoid disorders (e.g., leukemia, multiple myeloma, mantle cell lymphoma, ALL, CLL, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma) may be treated with compounds and methods described herein.
- In some embodiments, the methods of the invention treat subjects with ovarian cancer. In some embodiments, the methods of the invention treat subjects with epithelial ovarian cancer. In some embodiments, the methods of the invention treat subjects with fallopian tube cancer. In some embodiments, the methods of the invention treat subjects with primary peritoneal cancer.
- In some embodiments, the methods of the invention treat subjects with recurrent ovarian cancer. In some embodiments, the methods of the invention treat subjects with recurrent epithelial ovarian cancer. In some embodiments, the methods of the invention treat subjects with recurrent fallopian tube cancer. In some embodiments, the methods of the invention treat subjects with recurrent primary peritoneal cancer.
- In some embodiments, the methods of the invention treat subjects with recurrent ovarian cancer following a complete or partial response to a chemotherapy, such as a platinum-based chemotherapy. In some embodiments, the methods of the invention treat subjects with recurrent epithelial ovarian cancer following a complete or partial response to a chemotherapy, such as a platinum-based chemotherapy. In some embodiments, the methods of the invention treat subjects with recurrent fallopian tube cancer following a complete or partial response to a chemotherapy, such as a platinum-based chemotherapy. In some embodiments, the methods of the invention treat subjects with recurrent primary peritoneal cancer following a complete or partial response to a chemotherapy, such as a platinum-based chemotherapy.
- In some embodiments, the methods of the invention treat subjects with recurrent ovarian cancer, recurrent epithelial ovarian cancer, recurrent fallopian tube cancer and/or recurrent primary peritoneal cancer following a complete or partial response to a platinum-based chemotherapy, wherein the subjects begin the treatment no later than 8 weeks after their most recent platinum-containing regimen. For example, subjects can begin treatment with niraparib about 7 weeks after their most recent platinum-containing regimen. For example, subjects can begin treatment with niraparib about 6 weeks after their most recent platinum-containing regimen. For example, subjects can begin treatment with niraparib about 6 weeks after their most recent platinum-containing regimen. For example, subjects can begin treatment with niraparib about 5 weeks after their most recent platinum-containing regimen. For example, subjects can begin treatment with niraparib about 4 weeks after their most recent platinum-containing regimen. For example, subjects can begin treatment with niraparib about 3 weeks after their most recent platinum-containing regimen. For example, subjects can begin treatment with niraparib about 2 weeks after their most recent platinum-containing regimen. For example, subjects can begin treatment with niraparib about 1 week after their most recent platinum-containing regimen.
- In some embodiments, the methods of the invention treat subjects with prostate cancer
- In some embodiments, the methods of the invention treat subjects with a pediatric cancer. Exemplary pediatric cancers include, but are not limited to adrenocortical carcinoma, astrocytoma, atypical teratoid rhabdoid tumor, brain tumors, chondroblastoma, choroid plexus tumor, craniopharyngioma, desmoid tumor, dysembryplastic neuroepithelial tumor (DNT), ependymoma, fibrosarcoma, germ cell tumor of the brain, 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 lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, malignant fibrous histiocytoma, melanoma, myelodysplastic syndrome, nephroblastoma, neuroblastoma, neurofibrosarcoma, osteosarcoma, pilocytic astrocytoma, retinoblastoma, rhabdoid tumor of the kidney, rhabdomyosarcoma, Ewing sarcoma, soft tissue sarcoma, synovial sarcoma, spinal cord tumor and Wilm's tumor.
- In some embodiments, the methods of the invention treat subjects with a cancer with a dosage 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, or 1000 mg of niraparib once-daily, twice-daily, or thrice-daily. In some embodiments, the methods of the invention treat subjects with a cancer with a dosage of 150 mg to 175 mg, 170 mg to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 to 295 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, or 370 mg to 400 mg of niraparib once-daily, twice-daily, or thrice-daily. In some embodiments, the methods of the invention treat subjects with a cancer with a dosage of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg. 17.5 mg, 20 mg, 22.5 mg, 25 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 of niraparib once-daily, twice-daily, or thrice-daily.
- In some embodiments, the methods of the invention treat subjects with a cancer with a dosage of from 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg of niraparib once-daily, twice-daily, or thrice-daily. In some embodiments, the methods of the invention treat subjects with a cancer with a dosage of from about 5 mg to 7.5 mg, 7 mg to 9.5 mg, 9 mg to 11.5 mg, 11 mg to 13.5 mg, 13 mg to 15.5 mg, 15 mg to 17.5 mg, 17 to 19.5 mg, 19 mg to 21.5 mg, 21 mg to 23/5 mg, 23 mg to 25.5 mg, 25 mg to 27.5 mg, 27 mg to 30 mg, 30 mg to 35 mg, 35 mg to 40 mg, 40 mg to 45 mg, 45 mg to 50 mg, 50 mg to 55 mg, 55 mg to 60 mg, 60 to 65 mg, 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 of niraparib once-daily, twice-daily, or thrice-daily.
- The recommended dose of the niraparib capsule formulations described herein as monotherapy is three 100 mg capsules taken orally once daily, equivalent to a total daily dose of 300 mg. Patients may be encouraged to take their dose at approximately the same time each day. Bedtime administration may be a potential method for managing nausea.
- As described herein, doses of 1 to 1000 mg of niraparib may be administered for treatment of subjects, and methods and compositions described herein may comprise once-daily, twice-daily, or thrice-daily administration of a dose of 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, 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, or 1000 mg once-daily, twice-daily, or thrice-daily. In some embodiments, the dose of niraparib is from 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg, once-daily, twice-daily, or thrice-daily. In some embodiments, the methods of the invention treat subjects with a cancer with a dosage 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, or 1000 mg of niraparib once-daily, twice-daily, or thrice-daily.
- In some embodiments, a total daily dose of niraparib of 1 mg to 1000 mg, for example, or 50 to 300 mg, is administered. In some embodiments, the daily dose of niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the daily dosage wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . In some embodiments, the total daily dose of niraparib administered exceeds 100 mg per day. In some embodiments, the total daily dose of niraparib administered exceeds 200 mg per day. In some embodiments, the total daily dose of niraparib administered exceeds 300 mg per day. In some embodiments, the total daily dose of niraparib administered exceeds 400 mg per day. In some embodiments, the total daily dose of niraparib administered exceeds 500 mg per day. - In some embodiments, the total daily dose of niraparib administered does not exceed 500 mg per day. In some embodiments, the daily dose of niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the daily dosage wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . In some embodiments, the total daily dose of niraparib administered does not exceed 300 mg per day. In some embodiments, the total daily dose of niraparib administered does not exceed 100 mg per day. In some embodiments, the total daily dose of niraparib administered does not exceed 50 mg per day. In some embodiments, the total daily dose of niraparib is from 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. the total daily dose of niraparib 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, or 1000 mg. In some embodiments, the daily dose of niraparib is niraparib tosylate monohydrate is a crystalline Form I substantially free of Form II and Form III. Another embodiment provides the daily dosage wherein the crystalline Form I of niraparib tosylate monohydrate has an X-ray powder diffraction pattern substantially as shown inFIG. 1 . - A therapeutically effective dose of niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III 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, or 1000 mg per day. In some embodiments, the amount of niraparib administered daily is from 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg per day.
- In some embodiments, the amount of niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III is administered one time daily is 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. In some embodiments, the amount of naraparib administered one time daily is 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, or 1000 mg.
- In some embodiments, the amount of niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III is administered two times daily is 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. In some embodiments, the amount of niraparib administered two times daily is 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, or 1000 mg.
- In some embodiments, the amount of niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III is administered three times daily is 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, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. In some embodiments, the amount of niraparib administered three times daily is 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, or 1000 mg.
- In some embodiments, the niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III is present at a dose from about 1 mg to about 1000 mg, including, but not limited to, 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, 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, or 1000 mg.
- In some embodiments, the niraparib tosylate monohydrate as a crystalline Form I substantially free of Form II and Form III is present at a dose from 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, 35 mg to 140 mg, 70 mg to 140 mg, 80 mg to 135 mg, 10 mg to 25 mg, 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 150 mg, 150 mg to 200 mg, 10 mg to 35 mg, 35 mg to 70 mg, 70 mg to 105 mg, 105 mg to 140 mg, 140 mg to 175 mg, or 175 mg to 200 mg, 35 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 300 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 400 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg.
- In some embodiments, a composition disclosed herein is administered to an individual in need thereof once. In some embodiments, a composition disclosed herein is administered to an individual in need thereof more than once. In some embodiments, a first administration of a composition disclosed herein is followed by a second administration of a composition disclosed herein. In some embodiments, a first administration of a composition disclosed herein is followed by a second and third administration of a composition disclosed herein. In some embodiments, a first administration of a composition disclosed herein is followed by a second, third, and fourth administration of a composition disclosed herein. In some embodiments, a first administration of a composition disclosed herein is followed by a second, third, fourth, and fifth administration of a composition disclosed herein. In some embodiments, a first administration of a composition disclosed herein is followed by a drug holiday.
- The number of times a composition is administered to an individual in need thereof depends on the discretion of a medical professional, the disorder, the severity of the disorder, and the individual's response to the formulation. In some embodiments, a composition disclosed herein is administered once to an individual in need thereof with a mild acute condition. In some embodiments, a composition disclosed herein is administered more than once to an individual in need thereof with a moderate or severe acute condition. In the case wherein the patient's condition does not improve, upon the doctor's discretion the administration of niraparib may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
- In some embodiments, the niraparib composition is administered at predetermined time intervals over an extended period of time. In some embodiments, the niraparib composition is administered once every day. In some embodiments, the niraparib composition is administered every other day. In some embodiments, the niraparib composition is administered over 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 moths, 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, the niraparib composition is administered in doses having a dose-to-dose niraparib concentration variation of less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%.
- In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the niraparib may be given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday can vary between 2 days and 1 year, including by way of example 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. A first or second dose reduction during a drug holiday may be from 10%-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, a first or second dose reduction during a drug holiday may be a dose reduced from 5 mg to 1 mg, 10 mg to 5 mg, 20 mg to 10 mg, 25 mg to 10 mg, 50 mg to 25 mg, 75 mg to 50 mg, 75 mg to 25 mg, 100 mg to 50 mg, 150 mg to 75 mg, 100 mg to 25 mg, 200 mg to 100 mg, 200 to 50 mg, 250 mg to 100 mg, 300 mg to 50 mg, 300 mg to 100 mg, 300 mg to 200 mg, 400 mg to 50 mg, 400 mg to 100 mg, 400 mg to 200 mg, 500 mg to 50 mg, 500 mg to 100 mg, 500 mg to 250 mg, 1000 mg to 50 mg, 1000 mg to 100 mg, or 1000 mg to 500 mg, 550 mg to 600 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 750 mg, 750 mg to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, or 950 mg to 1000 mg. For example, a first or second dose reduction during a drug holiday 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, or 1000 mg.
- Once improvement of the patient's condition has occurred, a maintenance niraparib dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is optionally reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.
- The following examples illustrate some embodiments and aspects of the invention. It will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be performed without altering the spirit or scope of the invention, and such modifications and variations are encompassed with invention as defined in the claims which follow. The invention disclosed herein is further illustrated by the following examples which in no way should be construed as being limiting.
- The Rigaku Smart-Lab X-ray diffraction system was configured for reflection Bragg-Brentano geometry using a line source X-ray beam. The x-ray source is a Cu Long Fine Focus tube that was operated at 40 kV and 44 ma. That source provides an incident beam profile at the sample that changes from a narrow line at high angles to a broad rectangle at low angles. Beam conditioning slits are used on the line X-ray source to ensure that the maximum beam size is less than 10 mm both along the line and normal to the line. The Bragg-Brentano geometry is a para-focusing geometry controlled by passive divergence and receiving slits with the sample itself acting as the focusing component for the optics. The inherent resolution of Bragg-Brentano geometry is governed in part by the diffractometer radius and the width of the receiving slit used. Typically, the Rigaku Smart-Lab is operated to give peak widths of 0.1° 2θ or less. The axial divergence of the X-ray beam is controlled by 5.0-degree Soller slits in both the incident and diffracted beam paths.
- Powder samples were prepared in a low background Si holder using light manual pressure to keep the sample surfaces flat and level with the reference surface of the sample holder. Each sample was analyzed from 2 to 40 °2θ using a continuous scan of 6 °2θ per minute with an effective step size of 0.02 °2θ. Unless otherwise noted, XPRD studies were performed at room temperature and room humidity.
- DSC analyses were carried out using a TA Instruments Q2000 instrument. The instrument temperature calibration was performed using indium. The DSC cell was kept under a nitrogen purge of ˜50 mL per minute during each analysis. The sample was placed in a standard, crimped, aluminum pan and was heated from 25° C. to 350° C. at a rate of 10° C. per minute.
- DVS analyses were carried out TA Instruments Q5000 Dynamic Vapor Sorption analyzer. The instrument was calibrated with standard weights and a sodium bromide standard for humidity. Samples were analyzed at 25° C. with a maximum equilibration time of 60 minutes in 10% relative humidity (RH) steps from 5 to 95% RH (adsorption cycle) and from 95 to 5% RH (desorption cycle).
- Slurry experiments designed to provide a range of water activities were carried out in solvent mixtures containing water and dimethylsulfoxide (Table 1). The anhydrate appears to be the preferred form at water activities of 0.11 or less and the monohydrate appears to be the preferred form at water activities of 0.22 or more. The amorphous halo observed in many of the patterns is due to solvent. The samples were analyzed while wet to avoid changes, such as the hydrate converting to the anhydrate, from drying.
-
TABLE 1 Solvent Water Time XRPD (% water in DMSO) activity (days) Result 0 0 2 anhydrate 9.8 0.11 2 anhydrate 17.2 0.22 2 hydrate 27.6 0.38 2 hydrate 43.3 0.60 2 hydrate 82.8 0.84 2 hydrate 100.0 1.00 2 hydrate - A batch of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate which is a mixture of Form I, Form II and Form III is dissolved in water:DMSO/200:1 to reach a concentration of about 0.15 M. The resulting mixture is heated until dissolution occurs and is then cooled to about 25° C. overnight. The resulting solid is collected, dried and analyzed by x-ray powder diffraction, differential scanning calorimetry, Raman spectroscopy, infrared spectroscopy, dynamic water vapor sorption, or any combination thereof, to determine the presence of Form II or Form III.
FIG. 6 provides an overlay comparison of the x-ray powder diffraction patterns for Form I and Form III.FIG. 9 provides an overlay comparison of the x-ray powder diffraction patterns for Form I, Form II and Form III. - Niraparib 4-toluenesulfonate monohydrate (3.01 g) was suspended in 110 mL of toluene, and the resulting mixture was heated to reflux for 2 hours, collecting toluene/water into a Dean-Stark trap. A small amount of water was observed in the trap. The slurry was allowed to cool to ambient temperature, vacuum filtered, and the solids air dried.
-
FIGS. 1 and 6 provide the X-ray powder diffraction pattern for crystalline Form I monohydrate of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Table 2 provides a listing of the reflections. -
TABLE 2 Pos. [°2Th.] d-spacing [Å] Height [cts] FWHM [°2Th.] 6.5879 13.40619 460.5 0.5288 6.985 12.64485 477.57 0.823 9.0602 9.75275 2868.98 0.4263 9.524 9.27879 78535.62 0.1109 11.7927 7.49835 1707.43 0.1243 12.355 7.15828 54936.48 0.1168 12.6092 7.01457 1188.76 0.0993 13.2213 6.69113 35563.92 0.1254 13.5062 6.55063 569.25 0.3698 13.8394 6.39368 6772.92 0.1125 13.9958 6.32258 6011.08 0.1324 14.1943 6.23457 16335.01 0.1248 14.6912 6.0248 24730.51 0.1255 14.858 5.95753 27991.59 0.1169 15.0707 5.87396 18385.48 0.1353 15.3794 5.75672 2780.53 0.1073 15.5881 5.68013 3779.59 0.1025 16.3332 5.42265 9823.46 0.1415 16.617 5.33067 2329.47 0.201 17.4264 5.08485 50122.63 0.1333 17.573 5.04276 8100.61 0.3643 17.8849 4.95552 2229.24 0.1546 18.427 4.81093 204163.1 0.1721 18.8482 4.70436 3012.17 0.1544 19.177 4.62444 14586.06 0.166 19.4706 4.55535 8731.12 0.1299 19.9266 4.45213 21822.89 0.1538 20.2412 4.38364 6045.22 0.1614 21.0044 4.22605 63640.16 0.1445 21.5548 4.11937 10560.25 0.1515 22.2131 3.99876 753.36 0.1605 22.9905 3.86526 4058.7 0.1646 23.1768 3.83462 7387.16 0.1302 23.6115 3.76499 6636.48 0.3093 23.8073 3.73447 3271.55 0.0929 24.2164 3.6723 21759.7 0.1697 24.4265 3.64119 6345.06 0.161 24.9128 3.5712 103096 0.1575 25.5764 3.48002 47498.83 0.1529 26.0348 3.41979 99687.98 0.1845 26.9234 3.3089 32700.42 0.1866 27.4696 3.24434 21472.77 0.1595 27.9243 3.19253 1792.33 0.1146 28.3295 3.14778 1967.85 0.8105 28.6335 3.11505 13930.93 0.1549 29.1807 3.05787 12702.19 0.1798 29.6703 3.00852 6677.41 0.4434 29.9963 2.97655 16868.65 0.1759 30.3008 2.94733 6812.67 0.1494 30.508 2.92779 14421.1 0.1956 31.0316 2.87957 5755.4 0.1828 31.5213 2.83594 5497.13 0.179 32.575 2.74657 498.46 0.1586 32.9187 2.71867 3851.61 0.2345 33.532 2.67034 2240.41 0.2865 33.8569 2.64546 1516.95 0.2802 34.4808 2.599 1196.67 0.1616 35.0202 2.5602 3988.39 0.2523 35.4178 2.53236 2443.9 0.1374 35.5372 2.52412 2795 0.2115 36.1608 2.48202 5523.84 0.2396 37.3996 2.4026 5344.49 0.2021 37.7359 2.38196 1623.87 0.2622 38.2141 2.35324 4115.75 0.203 38.55 2.33351 1414.01 0.1982 38.8559 2.31584 6323.46 0.1835 30.508 2.92779 14421.1 0.1956 31.0316 2.87957 5755.4 0.1828 -
FIG. 2 shows an exemplary scanning differential calorimetry pattern for crystalline monohydrate Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. The DSC curve of the monohydrate exhibits an endotherm at approximately 154° C. which is likely due to dehydration followed by an endotherm at approximately 231° C. which is likely due to melting. -
FIG. 5 shows an exemplary dynamic water vapor sorption pattern for crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. The DVS curve of the monohydrate indicates the monohydrate is not hygroscopic. After the experiment the samples were analyzed by XRPD. The monohydrate remained unchanged. -
FIGS. 6 and 7 provide the X-ray powder diffraction pattern for crystalline anhydrous Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. Table 3 provides a listing of the reflections. -
TABLE 3 Pos. [°2Th.] d-spacing [Å] Height [cts] FWHM [°2Th.] 7.8499 11.25339 895.67 0.1707 9.5009 9.30126 2320.94 0.1654 10.2259 8.64344 4750.18 0.2032 10.9698 8.05886 18992.07 0.164 11.2525 7.85708 10175.98 0.1595 11.7171 7.54655 3014.31 0.1668 12.1661 7.26901 1145.84 0.2273 12.9299 6.84128 6553.68 0.1857 13.5713 6.51937 14717.58 0.1828 14.1376 6.25944 13082.42 0.2387 15.78 5.61146 13659.23 0.236 16.6445 5.3219 10574.32 0.39 16.8657 5.25261 9058.46 0.3716 17.4485 5.07847 51335.75 0.2087 17.814 4.97508 86267.17 0.1798 18.0524 4.90991 19854.59 0.2729 18.9679 4.67494 123782.4 0.199 19.1913 4.62102 31339.04 0.4525 19.9466 4.44771 3909.81 0.1923 20.5575 4.3169 10356.35 0.2796 21.2948 4.16907 3968.5 0.4668 22.0804 4.02248 4071.42 0.1664 22.7882 3.89912 32060.48 0.3358 23.7401 3.74489 21269.23 0.2247 24.8296 3.58298 11374.86 0.3818 25.2491 3.5244 9642.6 0.2188 25.471 3.49419 12822.77 0.2109 25.9789 3.42702 898.11 0.3533 26.5278 3.35734 1135.46 0.3302 26.9336 3.30767 8691.48 0.176 27.3191 3.26186 4697.95 0.304 27.5324 3.23707 7412.05 0.279 28.3515 3.14539 5097.68 0.1787 29.1345 3.06262 4974.1 0.254 29.6226 3.01325 685.05 0.0679 30.06 2.97039 3581.07 0.1928 30.6913 2.91071 1865.07 0.223 31.7871 2.81283 8828.05 0.5478 32.9385 2.71709 884.34 0.3145 33.3656 2.68328 1576.57 0.2445 34.2199 2.61822 1660.9 0.3393 34.9489 2.56526 699.93 0.2234 36.0738 2.4878 1800.14 0.2491 36.7177 2.44564 2321.23 0.3452 37.1849 2.41597 800.76 0.3354 38.4831 2.33741 2823.91 0.3912 38.7512 2.32185 925.86 0.3342 39.0789 2.30313 877.67 0.3596 39.8123 2.26238 765.08 0.5313 -
FIG. 2 shows an exemplary scanning differential calorimetry pattern for crystalline anhydrous Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. The DSC curve of the anhydrate exhibits an endotherm at approximately 230° C. which is likely due to melting. -
FIG. 8 shows an exemplary dynamic water vapor sorption pattern for crystalline anhydrous Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide. The DVS curve of the anhydrate is very hygroscopic and showed a weight gain of approximately 15.8% up to 95% RH. After the experiment the samples were analyzed by XRPD. The anhydrate converted to the monohydrate. - A composition comprising crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.
- The composition of paragraph [00133], wherein the crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide has an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . - The composition of paragraph [00133] or [00134], wherein the crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 9.5±0.2, 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 24.9±0.2, 25.6±0.2, 26.0±0.2, and 26.9±0.2.
- The composition of any one of paragraphs [00133]-[00135], wherein the crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide is characterized by an X-ray diffraction pattern reflection at 2θ=24.9±0.2.
- The composition of paragraph [00136], wherein the crystalline Form I is further characterized by X-ray diffraction pattern reflections at 2θ value of 9.5±0.2 and 26.0±0.2.
- The composition of paragraph [00136] or [00137], wherein the crystalline Form I is further characterized by X-ray diffraction pattern reflections at a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2.
- The composition of paragraph [00136] or [00137], wherein the crystalline Form I is further characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2.
- The composition of paragraph [00136] or [00137], wherein the crystalline Form I is further characterized by at least two X-ray diffraction pattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2.
- The composition of paragraph [00136] or [00137], wherein the crystalline Form I is further characterized by at least three X-ray diffraction pattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2.
- The composition of paragraph [00136] or [00137], wherein the crystalline Form I is further characterized by at least four X-ray diffraction pattern reflections selected from a 2θ value of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2.
- A composition comprising crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, wherein the crystalline Form I is characterized by a scanning differential calorimetry pattern substantially as shown in
FIG. 2 . - The composition of paragraph [00143], wherein the composition is the composition of any one of paragraphs [00133]-[00142].
- A composition comprising crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, wherein the crystalline Form I is characterized by a Raman spectroscopy pattern substantially as shown in
FIG. 3 . - The composition of paragraph [00145], wherein the composition is the composition of any one of paragraphs [00133]-[00144].
- A composition comprising crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, wherein the crystalline Form I is characterized by a dynamic water vapor sorption pattern substantially as shown in
FIG. 5 . - The composition of paragraph [00147], wherein the composition is the composition of any one of paragraphs [00133]-[00146].
- A composition comprising crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, wherein the crystalline Form I is characterized by an infrared spectroscopy pattern substantially as shown in
FIG. 4 . - The composition of paragraph [00149], wherein the composition is the composition of any one of paragraphs [00133]-[00148].
- The composition of any one of paragraphs [00133]-[00150], wherein the presence of Form III is characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 17.8±0.2, 19.0±0.2, or 22.8±0.2.
- The composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 20% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- The composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 15% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- The composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 10% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- The composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 8% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- The composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 6% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- The composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 4% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- The composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 3% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- The composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 2% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- The composition of any one of paragraphs [00133]-[00151], wherein substantially free of Form II and Form III means less than about 1% (w/w) combined total weight for Form II and Form III compared to the combined total weight of Form I, Form II and Form III.
- A composition comprising crystalline Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide and crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.
- A composition comprising crystalline Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.
- A composition comprising crystalline Form II 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide and crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.
- The composition of any one of paragraphs [00161]-[00163], wherein the crystalline Form II is characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 9.7±0.3, 12.8±0.3, 17.9±0.3, 19.7±0.3, and 21.8±0.3.
- The composition of any one of paragraphs [00161]-[00164], wherein the crystalline Form II has an X-ray powder diffraction pattern substantially as shown in
FIG. 9 for Form II. - A composition comprising crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide and crystalline Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.
- A composition comprising crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide.
- The composition of any one of paragraphs [00163]-[00167], wherein the crystalline Form III is characterized by at least one X-ray diffraction pattern reflection selected from a 2θ value of 17.8±0.2, 19.0±0.2, or 22.8±0.2.
- The composition of any one of paragraphs [00163]-[00167], wherein the crystalline Form III has an X-ray powder diffraction pattern substantially as shown in
FIG. 9 for Form III. - The composition of any one of paragraphs [00163]-[00167], wherein the crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide has an X-ray powder diffraction pattern substantially as shown in
FIG. 7 . - The composition of any one of paragraphs [00163]-[00170], wherein the crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide characterized by a dynamic water vapor sorption pattern substantially as shown in
FIG. 8 . - The composition of any one of paragraphs [00163]-[00171], wherein the crystalline Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide characterized by a scanning differential calorimetry pattern substantially as shown in
FIG. 2 . - A method of making crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, comprising dissolving a composition comprising Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide or Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, or a mixture thereof, in a solvent having a water:organic solvent ratio of about 10:1 to about 400:1 (v/v), and crystallizing the crystalline Form I.
- The method of paragraph [00173], wherein the water:organic solvent ratio is about 10:1 (v/v), about 50:1 (v/v), about 100:1 (v/v), about 200:1 (v/v), about 300:1 (v/v), or about 400:1 (v/v).
- The method of paragraph [00173], wherein the organic solvent is a polar solvent, a polar protic solvent, a polar aprotic solvent, an ether-containing solvent, or any combination thereof.
- The method of paragraph [00173], wherein the organic solvent is 2-propanol, acetone, methyl ethyl ketone, acetonitrile, acetic acid, formic acid, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof.
- The method of paragraph [00173], wherein the organic solvent is acetone, methyl ethyl ketone, acetonitrile, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof.
- The method of paragraph [00173], wherein the organic solvent is 2-propanol, acetic acid, formic acid, or any combination thereof.
- The method of paragraph [00173], wherein the organic solvent and water is heated prior to crystallization.
- A composition comprising crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide as described in any one of paragraphs 1-[00160], prepared by dissolving a composition comprising Form II of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide or Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, or a mixture thereof, in a solvent having a water:organic solvent ratio of about 10:1 to about 400:1 (v/v), and crystallizing the crystalline Form I.
- The composition of paragraph [00180], wherein the water:organic solvent ratio is about 10:1 (v/v), about 50:1 (v/v), about 100:1 (v/v), about 200:1 (v/v), about 300:1 (v/v), or about 400:1 (v/v).
- The composition of paragraph [00180], wherein the organic solvent is a polar solvent, a polar protic solvent, a polar aprotic solvent, an ether-containing solvent, or any combination thereof.
- The composition of paragraph [00180], wherein the organic solvent is 2-propanol, acetone, methyl ethyl ketone, acetonitrile, acetic acid, formic acid, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof.
- The composition of paragraph [00180], wherein the organic solvent is acetone, methyl ethyl ketone, acetonitrile, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof.
- The composition of paragraph [00180], wherein the organic solvent is 2-propanol, acetic acid, formic acid, or any combination thereof.
- The composition of paragraph [00180], wherein the organic solvent and water is heated prior to crystallization.
- The composition of any one of paragraphs [00133]-[00172] and [00180]-[00186], wherein the composition is a pharmaceutical composition.
- A pharmaceutical composition comprising crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form II and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, and at least one pharmaceutically acceptable excipient.
- The pharmaceutical composition of any one of paragraphs [00133]-[00188], wherein the composition is in an oral dosage form.
- The pharmaceutical composition of paragraph [00189], wherein the oral dosage form is a tablet or capsule.
- An article of manufacture comprising multiple unit doses of the pharmaceutical composition of any of paragraphs [00187]-[00190] in a sealed container with written instructions for use.
- The article of manufacture of paragraph [00191], further comprising an induction seal, desiccant, or any combination thereof.
- The pharmaceutical composition of paragraph [00187] or [00188] wherein the composition is in unit dose form.
Claims (30)
1. A composition consisting of crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate substantially free of Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate,
wherein
the crystalline Form I is characterized by an X-ray powder diffraction (XRPD) comprising diffraction angles at 2θ values of 9.5±0.2, 24.9±0.2, and 26.0±0.2 degrees, and is further characterized by at least two diffraction angles selected from a group consisting of 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2 degrees,
wherein substantially free of Form III means the composition consists of less than about 6% (w/w) total weight for Form III compared to the combined total weight of Form I and Form III; and
Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate is characterized by an X-ray powder diffraction (XRPD) comprising diffraction angles at 2θ values of 17.8±0.2, 19.0±0.2, and 22.8±0.2 degrees.
2. The composition of claim 1 , wherein the crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
3.-5. (canceled)
6. The composition of claim 1 , wherein the crystalline Form I is characterized by an X-ray powder diffraction (XRPD) comprising diffraction angles at 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2 degrees.
7.-8. (canceled)
9. The composition of claim 1 , wherein the crystalline Form I is characterized by an X-ray powder diffraction (XRPD) comprising at least three diffraction angles selected from a group consisting of 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2 degrees.
10. The composition of claim 1 , wherein the crystalline Form I is characterized by an X-ray powder diffraction (XRPD) comprising at least four X-ray diffraction angles selected from a group consisting of 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2 degrees.
11. The composition of claim 1 , A wherein the crystalline Form I is characterized by a scanning differential calorimetry pattern substantially as shown in FIG. 2 .
12. (canceled)
13. The composition of claim 1 , wherein the crystalline Form I is characterized by a Raman spectroscopy pattern substantially as shown in FIG. 3 .
14. (canceled)
15. The composition of claim 1 , wherein the crystalline Form I is characterized by a dynamic water vapor sorption pattern substantially as shown in FIG. 5 .
16. (canceled)
17. The composition of claim 1 , wherein the crystalline Form I is characterized by an infrared spectroscopy pattern substantially as shown in FIG. 4 .
18.-40. (canceled)
41. A method of making crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide substantially free of Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate, comprising dissolving a composition comprising Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate, or a mixture thereof, in a solvent having a water:organic solvent ratio of about 10:1 to about 400:1 (v/v), and crystallizing the crystalline Form I
wherein
crystalline Form I of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate is characterized by an X-ray powder diffraction (XRPD) comprising diffraction angles at 2θ values of 9.5±0.2, 24.9±0.2, and 26.0±0.2 degrees, and is further characterized by at least two diffraction angles selected from a group consisting of 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2, and 26.9±0.2 degrees; and
Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate is characterized by an X-ray powder diffraction (XRPD) comprising diffraction angles at 2θ values of 17.8±0.2, 19.0±0.2, and 22.8±0.2 degrees.
42.-47. (canceled)
48. The composition of claim 1 , prepared by dissolving a composition comprising Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate, or a mixture thereof, in a solvent having a water:organic solvent ratio of about 10:1 to about 400:1 (v/v), and crystallizing the crystalline Form I.
49. The composition of claim 48 , wherein the water:organic solvent ratio is about 10:1 (v/v), about 50:1 (v/v), about 100:1 (v/v), about 200:1 (v/v), about 300:1 (v/v), or about 400:1 (v/v).
50.-51. (canceled)
52. The composition of claim 48 , wherein the organic solvent is acetone, methyl ethyl ketone, acetonitrile, methyl tert-butyl ether, dioxane, dimethyl sulfoxide, or any combination thereof.
53. The composition of claim 48 , wherein the organic solvent is 2-propanol, acetic acid, formic acid, or any combination thereof.
54. (canceled)
55. The composition of claim 1 , wherein the composition is a pharmaceutical composition.
56. A pharmaceutical composition comprising the composition of claim 1 , and at least one pharmaceutically acceptable excipient.
57. The pharmaceutical composition of claim 56 , wherein the composition is in an oral dosage form.
58. The pharmaceutical composition of claim 57 , wherein the oral dosage form is a tablet or capsule.
59. An article of manufacture comprising multiple unit doses of the pharmaceutical composition of claim 58 in a sealed container with written instructions for use.
60. The article of manufacture of claim 59 , further comprising an induction seal, desiccant, or any combination thereof.
61. The pharmaceutical composition of claim 56 wherein the composition is in unit dose form.
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Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2020512350A (en) | 2017-03-27 | 2020-04-23 | テサロ, インコーポレイテッド | Nilaparib composition |
CA3060715A1 (en) | 2017-04-24 | 2018-11-01 | Tesaro, Inc. | Methods of manufacturing of niraparib |
CA3063715A1 (en) | 2017-05-18 | 2018-11-22 | Tesaro, Inc. | Combination therapies for treating cancer |
BR112020006039A2 (en) | 2017-09-26 | 2020-10-06 | Tesaro, Inc. | niraparib formulations |
KR20200086664A (en) | 2017-09-30 | 2020-07-17 | 테사로, 인코포레이티드 | Combination therapy to treat cancer |
WO2019071123A1 (en) | 2017-10-06 | 2019-04-11 | Tesaro, Inc. | Combination therapies and uses thereof |
KR20200118117A (en) | 2018-02-05 | 2020-10-14 | 테사로, 인코포레이티드 | Niraparip preparations for children and treatment methods for children |
WO2020072860A1 (en) | 2018-10-05 | 2020-04-09 | Johnson Matthey Public Limited Company | Niraparib solid state form |
CA3087392A1 (en) | 2019-07-16 | 2021-01-16 | Apotex Inc. | Crystalline forms of niraparib tosylate |
JP2023524808A (en) | 2020-05-08 | 2023-06-13 | ヤンセン ファーマシューティカ エヌ.ベー. | Treatment of prostate cancer with a combination of abiraterone acetate and niraparib |
KR20240037954A (en) | 2021-07-19 | 2024-03-22 | 얀센 파마슈티카 엔브이 | Treatment of metastatic castration-resistant prostate cancer with niraparib. |
WO2023159066A1 (en) | 2022-02-15 | 2023-08-24 | Tesaro, Inc. | Use of niraparib for the treatment of brain cancer |
WO2023201338A1 (en) | 2022-04-15 | 2023-10-19 | Ideaya Biosciences, Inc. | Combination therapy comprising a mat2a inhibitor and a parp inhibitor |
WO2023233295A1 (en) | 2022-06-01 | 2023-12-07 | Ideaya Biosciences, Inc. | Thiadiazolyl derivatives as dna polymerase theta inhibitors and uses thereof |
Family Cites Families (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0606663D0 (en) | 2006-04-03 | 2006-05-10 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
CA2647545C (en) | 2006-04-03 | 2016-02-23 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Amide substituted indazole and benzotriazole derivatives as poly(adp-ribose)polymerase (parp) inhibitors |
WO2008043024A2 (en) | 2006-10-04 | 2008-04-10 | Kalypsys, Inc. | Oral pharmaceutical formulation comprising a sulfonyl bicyclic modulator of ppar for the treatment of disease |
GEP20115337B (en) * | 2007-01-10 | 2011-11-25 | St Di Ricerche Di Biologia Molecolare P Angeletti Spa | Amide substituted indazoles as poly(adp-ribose)polymerase (parp) inhibitors |
US8183369B2 (en) * | 2007-10-17 | 2012-05-22 | Kudos Pharmaceuticals Limited | 4- [3- (4-cyclopropanecarbonyl-piperazine-I-carbonyl) -4 -fluoro-benzyl] -2H-phthalaz in-1-one |
CN101932572A (en) | 2008-01-08 | 2010-12-29 | 默沙东有限公司 | 2-{4-[(3S)-and piperidines-3-yl] phenyl }-pharmacologically acceptable salts of 2H-indazole-7-carboxylic acid amides |
US20100278921A1 (en) | 2009-04-30 | 2010-11-04 | Fischer Cristina M | Solid oral formulation of abt-263 |
EP2470540B1 (en) * | 2009-08-26 | 2016-04-20 | Cephalon, Inc. | Novel forms of a multicyclic compound |
CA2779052A1 (en) | 2012-05-31 | 2013-11-30 | Pharmascience Inc. | Pharmaceutical composition of entecavir and process of manufacturing |
US9580407B2 (en) | 2012-12-07 | 2017-02-28 | Merck Sharp & Dohme Corp. | Regioselective N-2 arylation of indazoles |
ES2672328T3 (en) | 2012-12-07 | 2018-06-13 | Merck Sharp & Dohme Corp. | Biocatalytic Transamination Process |
KR20160061911A (en) | 2013-04-08 | 2016-06-01 | 데니스 엠. 브라운 | Therapeutic benefit of suboptimally administered chemical compounds |
US9191894B2 (en) * | 2013-07-23 | 2015-11-17 | Disney Enterprises, Inc. | Power saving for multi-hop communications |
EP3089965B1 (en) | 2014-01-05 | 2018-08-29 | Washington University | Radiolabeled tracers for poly (adp-ribose) polymerase-1 (parp-1), methods and uses therefor |
EP3134088B1 (en) | 2014-04-22 | 2019-04-10 | Calitor Sciences, LLC | Bicylcic pyrazolone compounds and methods of use |
EP3148336B1 (en) | 2014-05-28 | 2019-10-02 | Eisai R&D Management Co., Ltd. | Eribulin and poly (adp ribose) polymerase (parp) inhibitors as combination therapy for the treatment of cancer |
CN106794185A (en) | 2014-08-22 | 2017-05-31 | 克洛维斯肿瘤有限公司 | The high dose strength tablet of Rucaparib |
WO2016094391A1 (en) | 2014-12-08 | 2016-06-16 | Myriad Genetics, Inc. | Methods and materials for predicting response to niraparib |
DK3317281T3 (en) | 2015-07-02 | 2020-06-15 | Acerta Pharma Bv | SOLID FORMS AND FORMULATIONS OF (S) -4- (8-AMINO-3- (1- (BUT-2-YNOYL) PYRROLIDIN-2-YL) IMIDAZO [1,5-A] PYRAZIN-1-YL) -N - (pyridin-2-yl) benzamide |
NZ749413A (en) * | 2016-06-29 | 2023-05-26 | Tesaro Inc | Methods of treating ovarian cancer |
CN106496187A (en) * | 2016-09-14 | 2017-03-15 | 陕西科技大学 | A kind of synthetic method for preparing PARP inhibitor Niraparib |
CN106831708A (en) | 2016-11-22 | 2017-06-13 | 西安泰科迈医药科技股份有限公司 | A kind of synthetic method of new oral cancer therapy drug Nirapairb |
CN108201537A (en) | 2016-12-16 | 2018-06-26 | 苏州苏融生物医药有限公司 | A kind of Ni Lapani sustained and controlled release medicaments composition and application thereof |
CN106854176A (en) | 2016-12-21 | 2017-06-16 | 南京艾德凯腾生物医药有限责任公司 | A kind of method for preparing Ni Lapani tosilate monohydrates |
WO2018122168A1 (en) | 2016-12-29 | 2018-07-05 | Bayer Pharma Aktiengesellschaft | Combinations of bub1 kinase and parp inhibitors |
JP2020512350A (en) | 2017-03-27 | 2020-04-23 | テサロ, インコーポレイテッド | Nilaparib composition |
WO2018183349A1 (en) | 2017-03-27 | 2018-10-04 | Tesaro, Inc. | Niraparib formulations |
CA3060715A1 (en) | 2017-04-24 | 2018-11-01 | Tesaro, Inc. | Methods of manufacturing of niraparib |
US20200289493A1 (en) | 2017-05-09 | 2020-09-17 | Tesaro, Inc. | Combination therapies for treating cancer |
CA3063715A1 (en) | 2017-05-18 | 2018-11-22 | Tesaro, Inc. | Combination therapies for treating cancer |
CN108530425A (en) | 2017-05-27 | 2018-09-14 | 广州科锐特生物科技有限公司 | A kind of Ni Lapani tosilate hydrate crystal forms and preparation method thereof |
BR112020006039A2 (en) | 2017-09-26 | 2020-10-06 | Tesaro, Inc. | niraparib formulations |
KR20200086664A (en) | 2017-09-30 | 2020-07-17 | 테사로, 인코포레이티드 | Combination therapy to treat cancer |
WO2019071123A1 (en) | 2017-10-06 | 2019-04-11 | Tesaro, Inc. | Combination therapies and uses thereof |
KR20200105862A (en) | 2017-12-27 | 2020-09-09 | 테사로, 인코포레이티드 | How to treat cancer |
KR20200118117A (en) | 2018-02-05 | 2020-10-14 | 테사로, 인코포레이티드 | Niraparip preparations for children and treatment methods for children |
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2023
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CA3058375A1 (en) | 2018-10-04 |
IL269630A (en) | 2019-11-28 |
BR112019020211A2 (en) | 2020-04-22 |
US11673877B2 (en) | 2023-06-13 |
AU2018246214A1 (en) | 2019-11-07 |
CN110944638A (en) | 2020-03-31 |
EP3600314A1 (en) | 2020-02-05 |
MX2019011496A (en) | 2020-01-23 |
WO2018183354A1 (en) | 2018-10-04 |
TW201840315A (en) | 2018-11-16 |
JP2020512350A (en) | 2020-04-23 |
EA201992177A1 (en) | 2020-02-25 |
KR20200014736A (en) | 2020-02-11 |
US11091459B2 (en) | 2021-08-17 |
AU2018246214B2 (en) | 2021-07-08 |
SG11201909011PA (en) | 2019-10-30 |
US20200017462A1 (en) | 2020-01-16 |
AU2021245223A1 (en) | 2021-11-04 |
US20210403448A1 (en) | 2021-12-30 |
TWI761476B (en) | 2022-04-21 |
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